Механистические и переводческие данные о натуральных продуктах растительного происхождения в предклинических исследованиях по миеломе: текущие данные.

Introduction

Multiple myeloma (MM) is a malignant disease characterized by the abnormal proliferation of clonal plasma cells, representing the second most common hematologic malignancy in many countries [ 1 ]. The clinical manifestations of MM are driven by monoclonal proteins, malignant cells, or cytokines secreted by malignant cells, and include signs of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and/or bone disease with lytic lesions (i.e., lesions caused by the disease process) or pathological fractures. These symptoms significantly impair patients' quality of life and survival rates [ 2 ]. Despite significant therapeutic advances in recent years, including the emergence of novel treatments such as proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs), and chimeric antigen receptor T-cell (CAR-T) therapy, the persistent challenges of drug resistance and high relapse rates remain [ 3 ]. While existing treatment strategies, such as conventional chemotherapy, radiotherapy, or autologous stem cell transplantation (ASCT), have extended patient survival to some extent, their limitations and side effects cannot be overlooked. Therefore, exploring novel therapeutic approaches and agents represents an urgent research priority.

Plant-derived natural products have garnered increasing interest due to their structurally diverse chemical constituents and multi-target synergistic mechanisms. These compounds have demonstrated unique potential in inducing MM cell apoptosis, reversing drug resistance, and modulating the immune microenvironment. Preclinical studies indicate that their anti-myeloma activity is mediated through key signaling pathways, including NF-κB, PI3K/AKT, and JAK/STAT, and some agents exhibit synergistic effects when combined with standard-of-care therapies, suggesting their promise as adjunct or combination treatments. However, substantial barriers continue to impede their clinical translation, including poor bioavailability, unclear pharmacokinetic profiles, a lack of standardization of botanical extracts, and potential toxicity associated with certain compounds. Moreover, most current evidence remains limited to in vitro or animal models, with insufficient validation across molecular subtypes and a lack of systematic safety evaluation, resulting in a persistent gap between laboratory findings and clinical application.

To address these challenges, this study adopts a structured narrative review approach to comprehensively synthesize preclinical progress on fourteen plant-derived natural products with reported anti-MM activity, including plant-derived monomeric compounds (baicalein, artemisinin, curcumin, celastrol, gambogic acid, resveratrol, ginsenosides, icariin, oridonin, plumbagin, formononetin) and standardized plant extracts ( Strychnos nux-vomica root extract, dandelion flavonoids, Hedyotis diffusa polysaccharides). Selection criteria were based on documented in vitro and/or in vivo anti-MM efficacy, mechanistic clarity, and potential advantages in overcoming drug resistance or modulating the immune microenvironment. This review aims to provide a critical synthesis of their molecular mechanisms, pharmacological activities, pharmacokinetic characteristics, and translational barriers, thereby offering scientific insights and future directions for developing natural product–based integrative therapeutic strategies for MM.

In summary, the objective of this review is not only to consolidate current mechanistic evidence but also to elucidate common preclinical bottlenecks, translational potential, and optimization pathways of plant-derived natural products, ultimately contributing to the development of clinically applicable multi-target phytotherapeutics.

Baicalein

Baicalein ( Fig. 1 A), a major bioactive flavonoid isolated from the root of Scutellaria baicalensis , possesses broad-spectrum pharmacological properties, including antioxidant, anti-inflammatory, and antitumor activities [ 4 ]. Its multi-target regulatory capacity enables intervention in key oncogenic pathways of MM, demonstrating significant potential as an adjunct chemotherapeutic agent. Fig. 1 Chemical structures of plant-derived bioactive compounds used in the treatment of MM. Fig. 1

Studies have shown that baicalein blocks the nuclear factor kappa B (NF-κB) pathway by inhibiting the phosphorylation of inhibitor of κB-alpha (IκB-α), thereby reducing the expression of interleukin-6 (IL-6) and X-linked inhibitor of apoptosis protein (XIAP) [ 5 ]. It specifically induces apoptosis in MPC-1⁻ immature myeloma cells (IC₅₀ = 16.8 μM) by activating the mitochondrial-mediated caspase-9/caspase-3 apoptotic pathway, while exhibiting minimal toxicity toward mature subtypes and normal cells. This effect has been validated in MM cell lines (e.g., U266, ILKM2) and patient-derived primary cells, supporting its potential as a novel therapeutic strategy targeting immature myeloma cells [ 5 ]. IL-6 is a critical factor for MM cell survival and growth. Baicalein (10–50 μM) significantly inhibits IL-6-induced phosphorylation of Janus kinase 1/tyrosine kinase 2 (Jak1/Tyk2), signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase 1/2 (Erk1/2), and protein kinase B (Akt), while downregulating the expression of the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-xL), thereby inducing apoptosis in U266, NOP2, AMO1, and ILKM2 cells. Furthermore, its combination with dexamethasone enhances the inhibition of proliferation in both dexamethasone-resistant U266 cells and sensitive ILKM2 cells. Baicalein is effective against both IL-6-dependent and IL-6-independent cells and does not interfere with the insulin-like growth factor 1 (IGF-1)/Akt pathway, indicating a specific mechanism of action [ 6 ].

Side Population (SP) cells, characterized by high expression of the ATP-binding cassette subfamily G member 2 (ABCG2) transporter, are associated with tumor chemoresistance [ 7 ]. Scutellaria baicalensis extracts and their main flavonoid components target SP cells by modulating ABCG2 protein expression, providing a new strategy for targeting MM cancer stem cells [ 8 ]. Further research revealed that baicalein significantly reduces the proportion of SP cells in the MM RPMI 8226 cell line (IC₅₀ = 168.5 μM) and enhances their sensitivity to chemotherapeutic drugs by downregulating ABCG2 protein expression. In vitro experiments demonstrated that baicalein dose-dependently inhibits SP cell activity within the concentration range of 10–50 μM. Molecular docking studies indicated that baicalein shares a similar binding site (e.g., the TM5–TM6 region and the key residue Arg482) with the classical ABCG2 inhibitor fumitremorgin C (FTC), suggesting it functions through competitive inhibition of ABCG2 [ 9 ]. Additionally, baicalein suppresses the proliferation of U266 cells and promotes early apoptosis in a dose- (40–80 μM) and time-dependent (24–30 hours treatment) manner. This is achieved by upregulating cereblon (CRBN) mRNA expression and post-transcriptionally downregulating the protein levels of key transcription factors Ikaros family zinc finger protein 1 (IKZF1) and Ikaros family zinc finger protein 3 (IKZF3) via the proteasomal degradation pathway [ 10 ]. In vitro , baicalein (5.2×10 2 μM) combined with bortezomib significantly inhibited the viability and induced apoptosis in MM.1R and IM-9 cells. In vivo , intravenous administration of baicalein (120 mg/kg) combined with bortezomib significantly reduced tumor volume in nude mice bearing MM xenografts without significantly affecting body weight [ 11 ]. A schematic illustration of the major signaling pathways modulated by baicalein in MM cells is provided in Fig. 2 . Fig. 2 Mechanistic actions of baicalein in multiple myeloma. Fig. 2

Although baicalein has demonstrated antitumor potential in vitro and in animal models through the modulation of NF-κB, STAT3, and Akt-related signaling pathways, its clinical translation remains significantly limited by pharmacokinetic constraints. Pharmacokinetic studies indicate that baicalein exhibits extremely low oral exposure due to poor solubility, rapid glucuronidation, and extensive first-pass metabolism, resulting in plasma concentrations that are often far below the effective in vitro range [ 12 ]. Although baicalein is generally considered to have a favorable safety profile, dose-dependent hepatotoxicity has been reported, and variations in purity caused by different botanical sources or preparation methods pose additional challenges for quality control and clinical consistency [ 13 ]. To date, no clinical trials targeting multiple myeloma have been conducted, and clinical evidence remains extremely limited. Future research should prioritize strategies to enhance its bioavailability—such as phospholipid complexes, nanocarriers, or structurally modified derivatives—and further evaluate its anti-myeloma efficacy in models that more closely recapitulate the bone marrow microenvironment [ 14 ].

Artemisinin

Artemisinin ( Fig. 1 B), a natural sesquiterpene lactone compound isolated from Artemisia annua [ 15 ], was first isolated and characterized through breakthrough research by Chinese scientist Tu Youyou's team. Artemisinin-based Combination Therapies (ACTs) are now the WHO-recommended first-line treatment for malaria. In recent years, artemisinin and its derivatives have demonstrated significant potential in anti-tumor applications through various mechanisms [ 16 ], with dihydroartemisinin (DHA) and artesunate (ART) receiving particular attention for MM treatment.

Studies show that ART (1.04×10 3 μM) inhibits proliferation and induces apoptosis in the mouse MM cell line SP2/0 in a dose- and time-dependent manner [ 17 ]. This mechanism may involve downregulating nuclear NF-κB p65 protein levels while upregulating cytoplasmic IκBα expression, thereby suppressing NF-κB signaling activity [ 17 ]. ART (0.3–16.6 µM) significantly inhibits MM cell proliferation and induces apoptosis by downregulating MYC and anti-apoptotic Bcl-2 family proteins (e.g., Bcl-xL, Mcl-1), concurrently activating caspase-3 cleavage. Furthermore, in co-culture systems with patient-derived bone marrow stromal cells, ART effectively induced apoptosis in primary MM cells, with IC₅₀ values approximately 10 µM for some clones, suggesting clinical feasibility [ 18 ]. Notably, ART primarily relies on non-caspase-mediated pathways to induce MM cell apoptosis. This process involves mitochondrial outer membrane permeabilization (MOMP), nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G (EndoG), and is accompanied by increased reactive oxygen species (ROS) and mitochondrial superoxide levels. These changes precede apoptosis and correlate with intracellular ferrous iron (Fe²⁺) levels [ 19 ]. DHA (1–100 µmol/L) significantly induces apoptosis in U266 cells by activating the c-Jun N-terminal kinase (JNK) signaling pathway and upregulating caspase-3 expression [ 20 ]. Through in vitro (U266, CAG, JJN3, etc.) and in vivo (xenograft mouse model) experiments, DHA was confirmed to induce MM cell death via complex regulation of autophagy and apoptosis. Importantly, autophagy—a highly conserved cellular self-degradation process—typically maintains intracellular homeostasis and stress responses. In the MM context of this study, DHA-induced autophagy exhibited pro-death functions. Specifically, DHA critically regulates the interplay between autophagy and apoptosis by activating P38 mitogen-activated protein kinase (MAPK) and inhibiting Wnt/β-catenin signaling, collectively promoting MM cell death [ 21 ]. This dual mechanism reveals DHA's core pathway for inducing MM cell death and highlights its potential for synergistic anti-tumor effects across multiple signaling pathways. Additionally, both DHA and ART target the tumor microenvironment: Using RPMI8226 cells and the chicken chorioallantoic membrane (CAM) angiogenesis model, DHA (3–12 mmol/L) inhibited MM-mediated angiogenesis under hypoxia by downregulating vascular endothelial growth factor (VEGF) expression and suppressing phosphorylation of ERK1/2 [ 22 ]. Similarly, ART (3–12 μmol/L) inhibited neovascularization by suppressing VEGF and angiopoietin-1 (Ang-1) secretion via ERK1/2 pathway inhibition [ 23 ].

Research utilizing in vitro MM cell lines (ARP1, H929, and resistant model MM.1R), primary CD138⁺ MM cells, and NOD-SCID mouse xenografts confirmed that DHA overcomes dexamethasone resistance in MM cells through Fe²⁺-dependent ROS generation. This activates the mitochondrial apoptotic pathway and reverses dexamethasone-induced Bcl-2 overexpression. DHA combined with dexamethasone significantly enhanced anti-tumor efficacy [ 24 ]. ART induces ferroptosis in MM cells by inhibiting nuclear localization of sterol regulatory element-binding protein 2 (SREBP2), downregulating isopentenyl pyrophosphate (IPP) and glutathione peroxidase 4 (GPX4) expression. Treatment with 40 μM ART (below IC₅₀) significantly increased ROS, Fe²⁺, and lipid peroxidation markers (e.g., malondialdehyde [MDA], Liperfluo fluorescence) in MM cells—effects reversible by ferroptosis inhibitors ferrostatin-1 (Fer-1) and deferoxamine mesylate (DFO) [ 25 ]. This ART-induced ferroptosis via the SREBP2-IPP-GPX4 axis provides a novel strategy for resistant MM. Artemisinin derivatives exhibit synergistic effects with frontline drugs like bortezomib and are effective against both primary and resistant MM cells [ 18 , 19 ]. The principal oxidative stress–related and mitochondrial pathways affected by artemisinin derivatives are summarized in Fig. 3 . Fig. 3 Mechanistic actions of DHA/ART in multiple myeloma. Fig. 3

Artemisinin and its derivatives have shown antitumor potential in preclinical studies of hematological malignancies, including multiple myeloma, primarily through the induction of iron-dependent ROS production, mitochondrial damage, apoptosis, autophagy, or ferroptosis, as well as through the inhibition of key signaling pathways such as NF-κB and MYC. However, artemisinin-type compounds are characterized by rapid metabolism and short elimination half-lives, posing significant challenges in achieving and maintaining therapeutically effective plasma concentrations following oral administration [ 26 ]. Although these agents are generally well tolerated in antimalarial use, their long-term safety profile in oncologic settings has not yet been systematically evaluated [ 27 ]. At present, there is no validated clinical evidence supporting their efficacy in multiple myeloma. Future research should therefore focus on strategies to prolong systemic exposure and enhance bioavailability, as well as on evaluating their feasibility and mechanistic rationale in combination with standard-of-care therapies using models that better recapitulate the bone marrow microenvironment [ 28 ].

Curcumin

Curcumin ( Fig. 1 C), the core polyphenolic active constituent extracted from the rhizomes of Curcuma longa , possesses diverse pharmacological properties including anti-inflammatory, antioxidant, and anti-tumor effects [ 29 ]. It plays a crucial role in multi-target regulation of the MM pathological process and reversal of drug resistance.

Studies demonstrate that curcumin (50 μM treatment for 4–8 hours) effectively inhibits constitutively activated NF-κB signaling in multiple MM cell lines (e.g., U266, RPMI 8226, MM.1, and MM.1R). Its mechanism involves inhibiting IκB kinase (IKK) activity, reducing IκBα phosphorylation and its degradation, thereby preventing NF-κB nuclear translocation. This downregulates the expression of NF-κB-regulated anti-apoptotic proteins (e.g., Bcl-2, Bcl-xL) and pro-proliferative factors (e.g., cyclin D1, IL-6), ultimately inducing G1/S phase cell cycle arrest and activating caspase-dependent apoptotic pathways in MM cells [ 30 ]. Curcumin is also a potent inhibitor of STAT3 phosphorylation. By inhibiting IL-6-induced STAT3 phosphorylation and its nuclear translocation, it suppresses MM cell survival and proliferation, an effect more rapid and significant than that of the Janus Kinase 2 (JAK2) inhibitor AG490 [ 31 ]. Furthermore, curcumin (25–50 μM) inhibits IL-6/sIL-6R-mediated phosphorylation of STAT3 and Extracellular Regulated Protein Kinases (Erk), and reduces the secretion of pro-inflammatory factors like VEGF by interfering with the interaction between bone marrow stromal cells (BMSCs) and MM cells. This effect was significant in U266 cells and three separate BMSC samples [ 32 ]. Notably, the cytotoxic effect of curcumin in vitro exhibits molecular subtype heterogeneity: among 29 human myeloma cell lines (HMCLs) covering major molecular subtypes, cell lines harboring the t(11;14) translocation showed lower sensitivity to curcumin (median LD50 32.9 μM), while non-t(11;14) cell lines, including high-risk subtypes t(4;14) and t(14;16), were more susceptible to killing (median LD50 17.9 μM, p=0.023). This difference was independent of TP53 gene status but closely associated with downregulation of myeloid cell leukemia 1 (Mcl-1) in primary MM cells [ 33 ]. Curcumin also induces apoptosis in a dose- (5–15 μmol/L) and time-dependent (24–72 h) manner by upregulating p53 and the pro-apoptotic gene Bax, while inhibiting the MDM2 gene [ 34 ]. Further research revealed that curcumin not only downregulates Enhancer of Zeste Homolog 2 (EZH2) expression and reduces the modification level of its catalytic product histone H3 lysine 27 trimethylation (H3K27me3) by regulating the miR-101–EZH2 negative feedback loop, but also induces DNA hypermethylation in the promoter region of mTOR gene, thereby suppressing its expression [ 35 , 36 ]. These mechanisms collectively contribute to curcumin's anti-tumor effects, providing a theoretical basis for developing novel MM therapeutic strategies based on natural compounds.

In drug resistance modulation, curcumin significantly reverses resistance to the chemotherapeutic agent melphalan in the MOLP-2/R cell line by blocking the Fanconi Anemia/Breast Cancer Susceptibility Gene (FA/BRCA) pathway. Specifically, treatment with 10 μM curcumin combined with melphalan reduced the IC₅₀ of MOLP-2/R cells from 45.5 μM to 19 μM. Curcumin dose-dependently inhibited FANCD2 monoubiquitination expression, thereby reducing DNA damage repair and promoting G2/M phase arrest and apoptosis [ 37 ]. Preclinical studies indicate that curcumin enhances the efficacy of proteasome inhibitors (e.g., bortezomib, carfilzomib): its combination with bortezomib synergistically inhibits STAT3/Erk phosphorylation and enhances cytotoxicity against H929 cells by activating the JNK pathway [ 38 , 32 ]; combination with carfilzomib potentiates G0/G1 phase arrest and apoptosis by synergistically activating the p53/p21 axis [ 39 ]. Clinical trials show that curcumin improves free light chain levels (rFLC, dFLC, iFLC) in patients with Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM), and reduces levels of the bone resorption marker urinary deoxypyridinoline (uDPYD) and serum creatinine, suggesting its potential to delay disease progression (Trial Registration: ACTRN12610000962033) [ 40 ]. However, due to the small sample size and limited follow-up, its long-term efficacy and safety require further validation. To improve efficacy, researchers have developed curcumin derivatives (e.g., GO-Y030, GO-Y078) and hybrid compounds (e.g., thalidomide-curcumin hybrids 5 and 7), which exhibit significantly enhanced inhibitory capacity against pathways like NF-κB, PI3K/AKT, and JAK/STAT3 [ 41 , 42 ]. Additionally, a synthetic compound containing isovanillin, harmine, and curcumin, GZ17-6.02, can induce autophagic death by regulating the ATM/AMPK/mTORC1/NF-κB signaling network and shows strong synergy with bortezomib [ 43 ]. Although the challenge of curcumin's low bioavailability remain [ 44 ], its antioxidant/anti-inflammatory effects mediated through the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) pathway provide a novel strategy for MM treatment [ 45 ]. The major signaling cascades targeted by curcumin in MM are depicted in Fig. 4 . Fig. 4 Mechanistic actions of curcumin in multiple myeloma. Fig. 4

Unlike many other natural products, curcumin exhibits a distinctly multi-pathway and systemic regulatory profile in multiple myeloma. It suppresses key signaling axes such as NF-κB and STAT3 and downregulates their downstream target genes, thereby exerting effects on both tumor cells and the bone marrow microenvironment. Multiple in vitro studies have indicated synergistic interactions with bortezomib, lenalidomide, and dexamethasone, suggesting enhanced proteasome inhibition or mitigation of inflammation-driven drug resistance. However, its clinical translation is markedly limited by extremely low oral bioavailability and restricted systemic exposure, which makes it difficult to achieve in vivo concentrations comparable to those effective in vitro [ 46 ]. Although early studies have reported a generally favorable safety profile, clinical evidence supporting its therapeutic efficacy in multiple myeloma remains insufficient. Future investigations should clarify its biological activity at clinically achievable concentrations and further define its potential value in combination with standard therapies [ 47 ].

Celastrol

Celastrol ( Fig. 1 D), a pentacyclic triterpenoid compound extracted from the medicinal plant Tripterygium wilfordii , exhibits broad-spectrum anticancer activity [ 48 ]. It inhibits cancer cell proliferation and induces apoptosis through multiple mechanisms, positioning it as a focal point in MM research.

Celastrol demonstrates significant antitumor activity in various MM cell lines (e.g., LP-1, RPMI 8226, U266). Mechanisms include inhibition of NF-κB and STAT3 signaling pathways, downregulation of pro-proliferative proteins (e.g., cyclin D1) and anti-apoptotic proteins (e.g., Bcl-2, Mcl-1, survivin), activation of JNK, and suppression of Akt phosphorylation, thereby inducing cell cycle arrest (G0/G1 phase) and caspase-dependent apoptosis [ [49] , [50] , [51] , [52] ]. These findings provide a robust experimental basis for celastrol as a potential therapeutic agent. Additionally, celastrol inhibits Toll-like receptor 4 (TLR4)-mediated NF-κB signaling, significantly reducing lipopolysaccharide (LPS)-induced VEGF secretion, thereby suppressing migration and invasion of human umbilical vein endothelial cells (HUVECs) induced by LP-1 cells. At concentrations of 0.025–0.1 μM, celastrol dose-dependently decreased VEGF levels by 64.8%–92.9% and blocked nuclear translocation of the NF-κB p65 subunit [ 53 ]. Celastrol inhibits the activity of purified human 20S proteasomal β1, β2, and β5 subunits (IC₅₀ = 7.1, 6.3, and 9.3 μmol/L, respectively) and proteasomal activity in MM.1S cells (IC₅₀ = 2.3, 2.1, and 0.9 μmol/L), inducing G0/G1 arrest and caspase-dependent apoptosis. This leads to aberrant protein aggregation and disruption of proteostasis [ 54 ]. Notably, its promiscuous modification of multiple proteins (e.g., PRDX1, PRDX2) may cause off-target effects, limiting clinical translation [ 55 ].

Celastrol exhibits potential in overcoming chemoresistance. Its derivative, dihydrocelastrol (DHCE), suppresses JAK2/STAT3 and PI3K/Akt signaling pathways, downregulating the expression of the resistance-associated proteasomal subunit PSMB5, thereby overcoming bortezomib resistance [ 56 ]. DHCE also downregulates cyclin D1 and CDK4/6 expression by inhibiting IL-6/STAT3 and ERK1/2 pathways, inducing G0/G1 arrest and caspase-dependent apoptosis in MM cells. Furthermore, its combination with the histone deacetylase inhibitor panobinostat (LBH589) enhances antitumor effects, suggesting synergistic therapeutic value [ 57 ]. In a xenograft mouse model (established using patient-derived CD138⁺ MM cells), celastrol combined with bortezomib synergistically inhibited tumor growth and reduced levels of inflammatory cytokines (e.g., IL-6, TNF-α) [ 58 ]. The multifaceted inhibitory effects of celastrol on oncogenic signaling pathways are illustrated in Fig. 5 . Fig. 5 Mechanistic actions of celastrol in multiple myeloma. Fig. 5

Celastrol exhibits multi-target inhibitory effects in multiple myeloma, blocking key signaling axes such as NF-κB and STAT3 and inducing ROS generation, apoptosis, and autophagy, thereby suppressing cell survival and, in certain models, reversing drug resistance. However, its clinical translation is hindered by a narrow therapeutic window and pronounced dose-dependent toxicity, including hepatic, renal, and systemic toxic reactions observed in multiple animal studies [ 59 ]. In addition, the poor aqueous solubility, low oral bioavailability, and rapid systemic clearance of celastrol make it difficult to maintain therapeutically effective exposure levels without increasing toxicity risks [ 60 ]. Future studies should focus on defining tolerable dosing ranges and developing strategies to reduce systemic toxicity in order to more accurately assess its true therapeutic potential in malignant diseases.

Gambogic acid

Gambogic Acid (GA, Fig. 1 E), a caged xanthone dimer isolated from the resin of Garcinia hanburyi , exhibits diverse pharmacological effects including anticancer, antiviral, anti-inflammatory, and anti-infective activities [ 61 ]. It demonstrates potent anticancer activity in certain solid tumors and hematological malignancies.

GA exerts significant antitumor effects in RPMI-8226 cells by inducing the accumulation of ROS. Experimental results demonstrated that treatment with 1.5–2.0 µM GA dose-dependently inhibited cell proliferation and induced apoptosis, manifested by caspase-3 activation and PARP cleavage. Furthermore, GA treatment led to downregulation of silent information regulator 1 (SIRT1) expression, and SIRT1 inhibition contributes to overcoming resistance to chemotherapeutic agents [ 62 , 63 ]. In tumor microenvironment regulation, stromal cell-derived factor-1α (SDF-1α) and its receptor CXC chemokine receptor 4 (CXCR4) are recognized as modulators of bone resorption. GA not only reduced CXCR4 expression in U266 and NCI H929 MM cells by inhibiting NF-κB binding to DNA but also, at concentrations as low as 5 nmol/L, inhibited RANKL-induced differentiation of RAW264.7 macrophages into osteoclasts. Additionally, it prevented myeloma cell self-induced osteoclastogenesis by suppressing IL-6 expression [ 64 ]. Under hypoxic conditions, GA inhibited PI3K/Akt/mTOR pathway, reducing the generation of hypoxia-inducible factor-1α (HIF-1α) and its downstream effector VEGF, thereby suppressing tumor angiogenesis in U266 cells. In a U266 xenograft mouse model, intravenous administration of GA at 2 or 4 mg/kg every two days significantly inhibited tumor growth and the expression of CD31, VEGF, and HIF-1α [ 65 ]. The pro-apoptotic and stress-associated pathways activated by gambogic acid are shown in Fig. 6 . Fig. 6 Mechanistic actions of GaVmbogic acid in multiple myeloma. Fig. 6

Gambogic acid has demonstrated preclinical potential in multiple myeloma by suppressing tumor growth and inhibiting signaling pathways associated with bone destruction. It modulates NF-κB, STAT3, and the CXCR4/SDF-1 axis, and induces apoptosis, with some models showing synergistic trends when combined with standard therapies. However, its poor aqueous solubility, low oral bioavailability, limited plasma and in vivo stability, and dose-dependent toxicity constitute major barriers to clinical translation. Consistent with these findings, recent reviews have identified pharmacokinetic and safety limitations as central bottlenecks, underscoring the need for formulation optimization or structural modification to broaden the therapeutic window [ 66 ]. Systematic clinical evidence in the context of multiple myeloma is currently lacking. Future studies should define tolerable dosing ranges and characterize exposure–response relationships, while mechanistically evaluating the feasibility of combining gambogic acid with existing therapeutic regimens [ 67 ]. To mitigate systemic toxicity and enhance exposure and stability, pharmaceutical strategies such as nano-delivery systems and carrier-based formulations have been extensively reviewed and are considered promising approaches to improve bioavailability and safety. These strategies warrant further validation in models that more closely recapitulate the bone marrow microenvironment to determine their true translational benefit [ 68 ].

Resveratrol

Resveratrol ( Fig. 1 F), a natural polyphenol compound widely present in plants such as grapes, peanuts, and berries [ 69 ], exerts anti-MM effects through multimodal mechanisms including activation of the mitochondrial apoptotic pathway, inhibition of signaling pathways, and modulation of epigenetic modifications, effectively reversing drug resistance.

In drug-resistant non-Hodgkin lymphoma (NHL) and MM cell lines, the combination of resveratrol (10 μM) with paclitaxel (10 nM) selectively downregulated anti-apoptotic proteins Bcl-xL and Mcl-1 while upregulating pro-apoptotic proteins Bax and Apaf-1. This induced mitochondrial membrane potential loss, cytochrome c/Smac/DIABLO release, and activation of the caspase cascade, achieving synergistic apoptotic effects [ 70 ]. Resveratrol inhibits the NF-κB and STAT3 signaling pathways, downregulating the expression of multiple gene products associated with cell survival and proliferation, including cyclin D1, cIAP-2, XIAP, survivin, Bcl-2, Bcl-xL, Bfl-1/A1, TRAF2, VEGF, and MMP-2/9. It also enhances the apoptosis-inducing effects of bortezomib and thalidomide on MM cells. Mechanisms involve blocking IKK-mediated IκBα/p65 phosphorylation, inhibiting IL-6-induced STAT3 activation, and attenuating sustained AKT signaling [ [71] , [72] , [73] ]. These effects collectively lead to cell cycle arrest, reduced invasion, and increased apoptosis, highlighting its potential as an adjunctive therapeutic agent for MM. Resveratrol also targets the unfolded protein response (UPR), activating inositol-requiring enzyme 1α (IRE1α) to induce X-box binding protein 1 (XBP1) mRNA splicing in ANBL-6, OPM2, and MM.1S cell lines. Concurrently, it represses the transcriptional activity of XBP1s through Sirtuin 1 (SIRT1)-mediated epigenetic regulation, promoting pro-apoptotic endoplasmic reticulum stress [ 74 ].

Resveratrol exhibits significant synergistic effects when combined with conventional and novel anti-MM agents. The combination of resveratrol (50 µM) and the proteasome inhibitor carfilzomib (40 nM) showed marked synergistic pro-apoptotic effects in MM cell lines (e.g., LP-1, MM.1S). Mechanisms include induction of mitochondrial dysfunction, promotion of Smac release, significant increase in ROS generation, and downregulation of SIRT1 and its downstream target survivin, thereby enhancing oxidative stress. Furthermore, the combination induced protective autophagy, and co-treatment with the autophagy inhibitor 3-MA amplified ROS accumulation and apoptosis, suggesting that simultaneously targeting oxidative stress and autophagy pathways represents a promising combinatorial strategy [ 75 ]. Resveratrol (60 µM) combined with rapamycin (20 nM) synergistically induced apoptosis in MM1.S cells by inhibiting mammalian target of rapamycin complexes 1/2 (mTORC1/mTORC2), reducing cyclin D1 levels, and activating caspase-3/PARP cleavage [ 76 ]. Resveratrol effectively inhibited proliferation, migration, and invasion of MM cells by downregulating long non-coding RNA nuclear-enriched abundant transcript 1 (lncRNA NEAT1) expression, thereby suppressing the Wnt/β-catenin signaling pathway and UPR. These effects were validated in U266 and LP1 MM cell lines, with resveratrol concentrations of 15-50 µM and IC50 values for proliferation inhibition of 33.74 µM (U266) and 40.72 µM (LP1), respectively [ 77 ]. In clinical research, resveratrol combined with trace copper (doses: 5.6 mg twice daily and 560 ng twice daily, respectively) significantly reduced transplantation-related toxicity in MM patients receiving high-dose melphalan. This combination therapy decreased the incidence of grade 3/4 oral mucositis from 100% in the control group to 40% (p=0.039) and significantly reduced exposure to the pro-inflammatory cytokines TNF- α(p=0.012) and IL-1β (p=0.009) in saliva (Trial Registration: CTRI/2018/02/011905) [ 78 ]. Despite promising results, limitations include small sample size, high risk of control group bias, unclear mechanisms for changes in some serum inflammatory markers, and low bioavailability of resveratrol. Thus, larger randomized controlled trials are needed to validate its clinical value. Screening of resveratrol derivatives pinostilbene (PIN) and piceatannol (PIC) in combination with bortezomib revealed that 5 µM PIN combined with 5 nM BTZ produced significant synergistic antitumor effects in RPMI 8226, U266, and NCI-H929 cells, characterized by induced apoptosis, upregulated cleaved caspase-3 and cleaved PARP1 expression, and enhanced oxidative stress (OS). This combination effectively induced apoptosis even in a Transwell co-culture model mimicking the bone marrow microenvironment, suggesting its ability to overcome stroma-mediated resistance [ 79 ]. Additionally, resveratrol significantly upregulated the expression of the tumor-suppressive lncRNA TERRA at six chromosomal regions (2q, 7p, 10q, 15q, XpYp, XqYq) by stabilizing its G-quadruplex structure in AMO-1 and NCI-H929 cells, with increases up to 17-fold. Concurrently, resveratrol induced the deposition of telomeric heterochromatin marks H3K27Me3 and H4K20Me3 and upregulated the pro-apoptotic marker cleaved-PARP-1, contributing to its antitumor effects [ 80 ]. The key regulatory pathways modulated by resveratrol in MM cells are summarized in Fig. 7 . Fig. 7 Mechanistic actions of resveratrol in multiple myeloma. Fig. 7

Resveratrol inhibits proliferation and induces apoptosis in multiple myeloma by modulating key signaling pathways such as NF-κB, JAK/STAT3, and SIRT1/p53. Its anti-inflammatory and antioxidant properties may attenuate the protective effects of the bone marrow microenvironment on tumor cells and enhance the sensitivity of myeloma cells to proteasome inhibitors and immunomodulatory drugs. Despite its multi-target therapeutic potential, the clinical application of resveratrol is limited by its low bioavailability and rapid metabolism [ 81 ]. Current studies are predominantly cell-based, with limited in vivo validation and a lack of large-scale clinical evidence, making it difficult to establish standardized therapeutic recommendations. Therefore, future research should focus on developing novel drug delivery systems and molecular modification strategies to improve the bioavailability and stability of resveratrol. High-quality animal studies and clinical trials are also needed to support its transition from a nutraceutical to a clinically applicable therapeutic agent.

Mechanisms of anti-MM activity of other plant-derived natural products

Beyond the major categories discussed, numerous botanical constituents exhibit significant antitumor activity by targeting key signaling pathways and cell death mechanisms in MM cells.

Regarding the induction of apoptosis and regulation of the cell cycle, ginsenosides, the primary active constituents of Panax ginseng , exert anti-MM effects through various subtypes by modulating apoptosis-related pathways. Ginsenoside Rg3 ( Fig. 1 G) inhibits proliferation of U266 and RPMI8226 cells in a dose-dependent manner (0–80 µM). In U266 cells, it induces apoptosis by upregulating Bax mRNA expression and activating caspase-3-dependent pathways [ 82 , 83 ]. Ginsenoside Rg1 ( Fig. 1 I) reverses bortezomib resistance in RPMI8226R-resistant cells by inducing autophagy via the AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) pathway. In vitro, Rg1 (10 μM, 24 h) significantly promotes apoptosis, inhibits proliferation, upregulates autophagy-related proteins LC3B-II/LC3B-I and Beclin1, and reduces p62 levels. In vivo, Rg1 (50 mg/kg) combined with bortezomib (2.06 μM) suppresses tumor growth and enhances apoptosis more effectively than monotherapy [ 84 ]. The ultra-low molecular weight ginsenoside compound K (KBB-N1) selectively activates p53 phosphorylation and upregulates apoptosis-related proteins (e.g., Bcl-2, HIF-1α, HO-1, p27/Kip1), inducing cell cycle arrest and apoptosis. It demonstrates significant antitumor activity in ARH77, U266, and RPMI8226 cell lines and murine MM models [ 85 ]. Despite its safety profile and selective action against MM cells—potentially beneficial for elderly patients—its poor aqueous solubility and low oral bioavailability (approximately 24%) limit clinical translation, necessitating further formulation optimization. Oridonin ( Fig. 1 K), a natural diterpenoid isolated from Rabdosia rubescens , exhibits potent antitumor activity in RPMI8226, U266, Jurkat, and MT-1 cell models. Studies show oridonin (1–64 µmol/L) concentration-dependently inhibits RPMI8266 cell proliferation (IC₅₀ = 6.74 µmol/L). Mechanisms include: suppression of NF-κB, modulation of Bcl-2/Bax balance, activation of caspase-3/PARP1 pathways, downregulation of Survivin, and induction of protective autophagy via the ROS/SIRT1 axis [ [86] , [87] , [88] ]. Proteomic analysis further identifies differentially expressed proteins (e.g., stathmin, dihydrofolate reductase [DHFR], pyruvate dehydrogenase E1 [PDHE1]) significantly downregulated during oridonin-induced apoptosis, suggesting their roles as potential therapeutic targets [ 89 ]. Strychnos nux-vomica (SN) root extract, rich in alkaloids (e.g., brucine and strychnine), exhibits potent anti-proliferative effects on RPMI 8226 and U266B1 cell lines in vitro, inducing apoptosis and cell cycle arrest in dose- and time-dependent manners. Mechanisms involve mitochondrial membrane potential disruption, cytochrome c release, and modulation of signaling molecules (e.g., IL-6, CD138) [ [90] , [91] , [92] ]. Brucine ( Fig. 1 N) downregulates receptor activator of nuclear factor kappa-B ligand (RANKL) while upregulaing alkaline phosphatase (ALP), osteocalcin (OC), and osteoprotegerin (OPG), thereby inhibiting osteoclast differentiation and promoting osteogenesis to ameliorate MM-related bone disease [ 93 ]. Plumbagin (5–50 µM) inhibits OPM1 cell proliferation and induces dose-dependent apoptosis by activating caspase-3, increasing lactate dehydrogenase release, and downregulating PI3K, p-Akt, and p-mTOR proteins [ 94 ]. Hedyotis diffusa polysaccharides (PEHD, 1–4 mg/ml) suppress RPMI 8226 cell proliferation and induce apoptosis by downregulating p-Akt and NF-κB expression while activating apoptosis-related proteins (caspase-3, -8, -9, PARP) [ 95 ].

Concerning the inhibition of pro-survival pathways, icaritin, the main active component of Epimedium species, induces cell cycle arrest and apoptosis in RPMI8226 and U266 cells by inhibiting the IL-6/JAK2/STAT3 pathway [ 96 ]. It also upregulates circular RNA circ_0000190, which sequesters microRNA-301a (miR-301a) to relieve its suppression of the tumor suppressor PTEN. This mechanism shows significant tumor suppression in in vivo xenograft models [ 97 ]. Its derivative C3, a novel DEP domain-containing mTOR-interacting protein (DEPTOR) inhibitor, enhances mTORC1/C2 activity to induce aberrant downstream signaling and cell death, demonstrating antitumor effects in animal models [ 98 , 99 ]. Although C3 shows specificity for DEPTOR, potential off-target effects on other DEP domain-associated proteins require further investigation. Formononetin ( Fig. 1 O) induces apoptosis and suppresses proliferation in MM cells by inhibiting STAT3/STAT5 phosphorylation and downstream signaling via ROS accumulation. In nude mouse xenograft models, it significantly inhibits tumor growth without apparent toxicity, indicating robust in vivo anti-MM activity [ 100 ]. It also downregulates oncoproteins linked to MM cell survival and progression by suppressing NF-κB, PI3K/AKT, and activator protein-1 (AP-1) pathways, while enhancing bortezomib-induced apoptosis [ 101 ]. Dandelion flavone ( Fig. 1 L) significantly reduces MM cell migration and invasion by inhibiting the PI3K/AKT pathway [ 102 ].

Regarding other unique mechanisms, ginsenoside Rh4 induces ferroptosis by modulating sirtuin 2 (SIRT2), inhibiting MM proliferation and promoting apoptosis in NCI-H929 cells [ 103 ]. This provides a novel direction for ferroptosis-targeted MM therapy, though the lack of in vivo validation and pharmacokinetic data limits clinical translation. The regulation of circRNA/miRNA pathways by icaritin also represents an epigenetic mechanism of action [ 97 ].

Summary and future perspectives

This review systematically integrates the preclinical evidence surrounding fourteen plant-derived natural products investigated for the treatment of multiple myeloma (MM) ( Table 1 ). The representative plant-derived monomeric compounds discussed include baicalein, artemisinin, curcumin, celastrol, gambogic acid, resveratrol, ginsenosides, icaritin, oridonin, plumbagin, and formononetin; well-characterized standardized plant extracts include Strychnos nux-vomica root extract (featuring a characteristic alkaloid profile), flavonoid-enriched dandelion flavone, and Hedyotis diffusa polysaccharides. A substantial body of preclinical research indicates that these plant-derived agents modulate MM biology through multiple layers of activity, including broad inhibition of key oncogenic signaling pathways (e.g., NF-κB, STAT3, PI3K/Akt), induction of apoptosis, ferroptosis, and autophagy, and regulation of the immunosuppressive bone marrow microenvironment. Table 1 Summary of mechanisms of plant-derived natural products in the treatment of MM. Table 1 Herbal medicine names Primary active constituents Experimental model Main mechanism of action Key targets/signaling pathways Summary of efficacy References Scutellaria baicalensis Baicalein In vitro (U266, NOP2, etc. MM cell lines) + in vivo (mouse model) Targeting multiple key pathways including apoptosis, autophagy, angiogenesis, and ferroptosis. NF-κB,STAT3,Bcl-2,CRBN,IL-6/JAK/STAT3 Inhibiting proliferation, enhancing chemosensitivity, and reversing IMiD resistance [ 6 , 5 , 7 ]; Liu 108 et al. 2018 Artemisia annua Dihydroartemisinin;Artesunate In vitro (SP2/0, U266 etc. MM cell lines) + in vivo (mouse model) Intervening in key pathways such as IL-6, NF-κB, Akt, the Bcl-2 family, and ABCG2. IL-6,NF-κB,Akt,Bcl-2,ABCG2,SP,CRBN Overcoming drug resistance, inhibiting angiogenesis [ 17 , 25 , 19 , 20 , 22 , 21 ] Curcuma longa Curcumin In vitro (U266, H929 etc. MM cell lines) + in vivo (mouse model) Intervening in multiple pathways including NF-κB, STAT3, epigenetic modifications, and cell cycle regulation. NF-κB,STAT3,IL-6,p53,FA/BRCA Targeting high-risk subtypes; enhancing proteasome inhibitor efficacy Bharti et al. 2003; Bharti, Donato and Aggarwal 2003; [ 38 , 35 , 32 , 58 , 36 , 37 ] Tripterygium wilfordii Celastrol In vitro (U266, MM.1S etc. MM cell lines) + in vivo (mouse model) Intervening in NF-κB, STAT3, JNK/Akt, and proteasome activity. NF-κB,STAT3,JNK,TLR4,VEGF Reversing drug resistance, inhibiting angiogenesis, and producing synergistic effects [ 56 , 53 , 58 , 52 , 55 , 54 ] Garcinia gummi-gutta Gambogic Acid In vitro (RPMI 8226, U266 etc. MM cell lines) Intervening in multiple pro-survival pathways such as STAT3, PI3K/Akt/mTOR, and CXCR4 STAT3,SIRT1,CXCR4,PI3K/Akt/mTOR Inhibiting bone resorption and overcoming bortezomib resistance [ 62 , 64 , 65 , 63 ] Vitis vinifera Resveratrol In vitro (RPMI 8226, KM3 etc. MM cell lines) Intervening in NF-κB, STAT3, Wnt/β-catenin, and epigenetic pathways. NF-κB,STAT3,Wnt/β-catenin Synergizing with carfilzomib, reducing transplant toxicity [ 71 , 70 ]; SUN, Hu, Guo, et al. 2006; Sun, Hu, Liu, et al. 2006; [ 77 , 76 , 74 ] Panax ginseng Ginsenosides In vitro (RPMI 8226, U266 etc. MM cell lines) + in vivo (mouse model) Modulating SIRT2 to induce ferroptosis; inhibiting the AMPK-mTOR pathway; activating p53 phosphorylation SIRT2,AMPK/mTOR,p53 Selective cytotoxicity, reducing hematopoietic toxicity [ 85 , 82 , 84 , 83 , 103 ] Epimedium Lcaritin In vitro (RPMI 8226, U266 etc. MM cell lines) + in vivo (mouse model) Inhibiting the IL-6/JAK2/STAT3 pathway; upregulating circ_ 0000190 to regulate miR30la; targeting DEPTOR protein. JAK2/STAT3,circ_0000190/miR-301a,DEPTOR Inhibiting the cell cycle, inducing apoptosis [ 98 , 99 , 97 ] Rabdosia rubescens Oridonin In vitro (RPMI 8226, U266 etc. MM cell lines) Inhibiting the NF-kB pathway; modulating the ROS/SIRT1 balance; downregulating Survivin. NF-κB,ROS/SIRT1,Survivin Dual regulation of cell death pathways [ [86] , [87] , [88] , [89] ] Strychnos nux-vomica Brucine In vitro (RPMI 8226, U266 etc. MM cell lines) Downregulating RANKL expression, upregulating ALP/OC/OPG; inhibiting osteoclast differentiation. RANKL,ALP,OC,OPG Improving MM bone disease. promoting bone formation [ 90 , 93 ]

From a comparative perspective, these fourteen natural products exhibit both mechanistic convergence and marked heterogeneity. Curcumin, celastrol, and oridonin exert broad inhibitory activity across NF-κB, PI3K/AKT, and JAK/STAT signaling pathways. In contrast, baicalein, resveratrol, and ginsenosides demonstrate more selective pathway modulation with moderate potency, while additionally displaying immunomodulatory or anti-inflammatory effects that may indirectly influence the myeloma microenvironment. Importantly, not all agents rely on NF-κB–centered mechanisms: artemisinin, icariin, and Hedyotis diffusa polysaccharides primarily function through oxidative stress, immune regulation, or differentiation-related mechanisms. Moreover, research on molecular subtype-specific responses in MM (e.g., t(4;14), del17p) remains extremely limited. Aside from reports of subtype-selective activity for curcumin, most compounds have not been evaluated within clearly defined genomic backgrounds, representing a key knowledge gap that may limit the clinical relevance of existing preclinical findings.

Integrating mechanistic profiles, the breadth of preclinical evidence, pharmacokinetic and safety characteristics, and the potential for synergy with standard-of-care agents, the plant-derived compounds reviewed here display a stratified pattern of translational feasibility. Overall, curcumin, resveratrol, and certain ginsenosides show relatively higher translational potential, supported by more comprehensive mechanistic studies, manageable safety profiles, and preliminary evidence of treatment-sensitizing effects. Oridonin, icariin, and dandelion flavonoids demonstrate promising anti-myeloma activity in vitro and in vivo, but their translational potential remains moderate due to limited pharmacokinetic data or incomplete mechanistic coverage. In contrast, celastrol, gambogic acid, and Strychnos nux-vomica root extract exhibit pronounced toxicity or compositional complexity, posing greater challenges for clinical advancement. It should be emphasized that this stratification is not intended as a strict ranking, but rather as a translational framework to guide future research priorities.

From a translational standpoint, significant differences exist in pharmacokinetics, bioavailability, and safety among these compounds. Despite strong in vitro activity, agents such as curcumin and celastrol are limited by poor bioavailability and potential toxicity, whereas resveratrol, ginsenosides, and icariin exhibit comparatively more favorable pharmacokinetic features. Extract-based agents, including Strychnos nux-vomica root extract and Hedyotis diffusa polysaccharides, possess immunomodulatory potential but require rigorous safety assessment and compositional standardization to avoid risks associated with alkaloid toxicity or batch variability. Collectively, these findings underscore that high in vitro potency alone does not predict clinical translational success; greater emphasis should be placed on optimizing pharmacokinetics, improving delivery strategies, and ensuring toxicity controllability.

Notably, many plant-derived compounds demonstrate synergistic effects with existing standard MM therapies—including bortezomib, carfilzomib, lenalidomide, and dexamethasone—and some enhance drug sensitivity or reverse resistance phenotypes. In the context of rapidly evolving therapeutic landscapes, including anti-CD38 antibodies, CELMoDs, and bispecific antibodies, plant-derived natural products may serve as “adjunct sensitizers” or “resistance modulators” offering new avenues to improve therapeutic response and delay relapse.

Although many of the molecular targets modulated by these compounds are not MM-specific, they represent core drivers of MM pathophysiology, particularly within the bone marrow microenvironment where they regulate cell survival, proliferation, immune evasion, and bone destruction. Studies of baicalein, curcumin, gambogic acid, and brucine/strychnine-containing extracts have validated their ability to modulate these critical pathogenic pathways in MM models, supporting their disease relevance.

However, it must be emphasized that these conclusions are predominantly supported by preclinical data, and no plant-derived natural product has yet demonstrated confirmed efficacy in phase II/III clinical trials for MM. Most studies rely on supraphysiological doses or non-physiological administration routes, and results from animal models do not readily translate to humans. More comprehensive pharmacokinetic, toxicological, and formulation studies are required to assess translational feasibility. In particular, although Strychnos nux-vomica root extract exhibits in vitro anti-myeloma activity, its narrow therapeutic window and risk of neurotoxicity necessitate stringent safety evaluation and rigorous standardization.

Multiple limitations persist in the current evidence base. Many studies focus primarily on phenotypic observations with limited deep mechanistic interrogation of bone marrow microenvironment dynamics, long-term toxicity, or subtype-specific or clone-specific responses. Single-compound studies cannot fully represent the multi-component synergy characteristic of botanical medicines, and current model systems (e.g., cell lines and subcutaneous xenografts) inadequately recapitulate tumor heterogeneity and the pathological microenvironment. Additionally, the literature is biased toward positive findings, with few reports of negative or null results, increasing uncertainty in preclinical evidence.

Thus, clinical development of plant-derived natural products for MM remains at an early stage, constrained primarily by low bioavailability, insufficient pharmacokinetic data, and the lack of systematic clinical validation. Future research should focus on developing innovative drug delivery systems to improve solubility, stability, bioavailability, and bone marrow targeting. Complementarily, systems pharmacology and multi-omics approaches should be employed to elucidate multi-target networks and synergistic mechanisms. Integrating molecular subtyping and resistance profiling may help identify compounds or combinations most suitable for specific MM subgroups. Strengthening research on immunomodulation and non-apoptotic cell death pathways (e.g., ferroptosis, pyroptosis) and establishing models that better reflect clinical pathology will further enhance predictive value and translational efficiency.

In summary, plant-derived natural products offer multi-target, multi-level therapeutic strategies and constitute an important source of novel agents for MM, particularly in overcoming drug resistance and remodeling the tumor microenvironment. Realizing their clinical potential will require bridging the gap from “test tubes and mice” to “patients and clinics”. Through multidisciplinary collaboration, systematic optimization of drug-like properties and safety, deeper mechanistic investigation, and well-designed clinical trials, this ancient reservoir of natural compounds may ultimately be transformed into tangible therapeutic benefit for patients with MM.

CRediT authorship contribution statement

Lulu Li: Writing – review & editing, Writing – original draft. Jie Xu: Conceptualization. Liming Yu: Formal analysis. Jingbo Shi: Visualization. Changnian Li: Resources. Jiabao Gu: Investigation. Yaru Wang: Methodology. Siyuan Cui: Validation, Supervision, Funding acquisition.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

1 Dimopoulos M.A. Moreau P. Terpos E. Mateos M.a.-V. Zweegman S. Cook G. Delforge M. Hcjek R. Schjesvold F. Cavo M. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Hemasphere 5 2021 e528 33554050 10.1097/HS9.0000000000000528 PMC7861652

2 Vrtis M.C. Multiple myeloma Home Healthc. Now 42 2024 140 149 38709580 10.1097/NHH.0000000000001249

3 Nishida H. Rapid progress in immunotherapies for multiple myeloma: an updated comprehensive review Cancers 13 2021 2712 34072645 10.3390/cancers13112712 PMC8198014

4 Gupta S. Buttar H.S. Kaur G. Tuli H.S. Baicalein: promising therapeutic applications with special reference to published patents Pharm. Pat. Anal. 11 2022 23 32 35345898 10.4155/ppa-2021-0027

5 Ma Z. Otsuyama K.-i. Liu S. Abroun S. Ishikawa H. Tsuyama N. Obata M. Li F.-J. Zheng X. Maki Y. Baicalein, a component of Scutellaria radix from Huang-Lian-Jie-Du-Tang (HLJDT), leads to suppression of proliferation and induction of apoptosis in human myeloma cells Blood 105 2005 3312 3318 15626742 10.1182/blood-2004-10-3915

6 Liu S. Ma Z. Cai H. Li Q. Rong W. Kawano M. Inhibitory effect of baicalein on IL-6-mediated signaling cascades in human myeloma cells Eur. J. Haematol. 84 2010 137 144 19878271 10.1111/j.1600-0609.2009.01365.x

7 Stacy A.E. Jansson P.J. Richardson D.R. Molecular pharmacology of ABCG2 and its role in chemoresistance Mol. Pharmacol. 84 2013 655 669 24021215 10.1124/mol.113.088609

8 Lin M.-G. Liu L.-P. Li C.-Y. Zhang M. Chen Y. Qin J. Gu Y.-Y. Li Z. Wu X.-L. Mo S.-L. Scutellaria extract decreases the proportion of side population cells in a myeloma cell line by down-regulating the expression of ABCG2 protein Asian Pac. J. Cancer Prev. 14 2013 7179 7186 24460272 10.7314/apjcp.2013.14.12.7179

9 Gu Y.-Y. Liu L.-P. Qin J. Zhang M. Chen Y. Wang D. Li Z. Tang J.-Z. Mo S.-L. Baicalein decreases side population proportion via inhibition of ABCG2 in multiple myeloma cell line RPMI 8226 in vitro Fitoterapia 94 2014 21 28 24468191 10.1016/j.fitote.2014.01.019

10 Liu X.-P. He L. Zhang Q.-P. Zeng X.-T. Liu S.-Q. Baicalein inhibits proliferation of myeloma U266 cells by downregulating IKZF1 and IKZF3 Med. Sci. Monit.: Int. Med. J. Exp. Clin. Res. 24 2018 2809 10.12659/MSM.907058 PMC5958785 29729093

11 Shi L. Wu Y. Feng L. Scutellarein selectively targets multiple myeloma cells by increasing mitochondrial superoxide production and activating intrinsic apoptosis pathway Biomed. Pharmacother. 109 2019 2109 2118 30551468 10.1016/j.biopha.2018.09.024

12 Gu, Y., Zheng, Q., Fan, G., Liu, R., 2022. Advances in anti-cancer activities of flavonoids in scutellariae radix: perspectives on mechanism. 23, 11042. 10.3390/ijms231911042 PMC9570317 36232344

13 Lei C. Yu Y. Zhu Y. Li Y. Ma C. Ding L. Han L. Zhang H.J.B. The most recent progress of baicalein in its anti-neoplastic effects and mechanisms Pharmacotherapy 176 2024 116862 10.1016/j.biopha.2024.116862 38850656

14 Wang, R., Wang, C., Lu, L., Yuan, F., He, F.J.P.R., 2024. Baicalin and baicalein in modulating tumor microenvironment for cancer treatment: a comprehensive review with future perspectives. 199, 107032. 10.1016/j.phrs.2023.107032 38061594

15 Wen L. Chan B.C.-L. Qiu M.-H. Leung P.-C. Wong C.-K. Artemisinin and its derivatives as potential anticancer agents Molecules 29 2024 3886 39202965 10.3390/molecules29163886 PMC11356986

16 Zeng Z.-w. Chen D. Chen L. He B. Li Y. A comprehensive overview of Artemisinin and its derivatives as anticancer agents Eur. J. Med. Chem. 247 2023 115000 10.1016/j.ejmech.2022.115000 36538859

17 Li S. Xue F. Cheng Z. Yang X. Wang S. Geng F. Pan L. Effect of artesunate on inhibiting proliferation and inducing apoptosis of SP2/0 myeloma cells through affecting NF¦ÊB p65 Int. J. Hematol. 90 2009 513 521 19728025 10.1007/s12185-009-0409-z

18 Holien T. Olsen O.E. Misund K. Hella H. Waage A. R T.B. Sundan A. Lymphoma and myeloma cells are highly sensitive to growth arrest and apoptosis induced by artesunate Eur. J. Haematol. 91 2013 339 346 23869695 10.1111/ejh.12176

19 Papanikolaou X. Johnson S. Garg T. Tian E. Tytarenko R. Zhang Q. Stein C. Barlogie B. Epstein J. Heuck C. Artesunate overcomes drug resistance in multiple myeloma by inducing mitochondrial stress and non-caspase apoptosis Oncotarget 5 2014 4118 24948357 10.18632/oncotarget.1847 PMC4147310

20 Wang Y. Xu X. Wu X. Chen W. Huang F. Gui X. Dihydroartemisinin treatment of multiple myeloma cells causes activation of c-Jun leading to cell apoptosis Oncol. Lett. 15 2018 2562 2566 29434974 10.3892/ol.2017.7582 PMC5777289

21 Wu X. Liu Y. Zhang E. Chen J. Huang X. Yan H. Cao W. Qu J. Gu H. Xu R. Dihydroartemisinin modulates apoptosis and autophagy in multiple myeloma through the P38/MAPK and wnt/¦Â©\Catenin Signaling pathways Oxidative Med. Cell. Longev. 2020 2020 6096391 10.1155/2020/6096391 PMC7448255 32879652

22 Wu X.-H. Zhou H.-J. Lee J. Dihydroartemisinin inhibits angiogenesis induced by multiple myeloma RPMI8226 cells under hypoxic conditions via downregulation of vascular endothelial growth factor expression and suppression of vascular endothelial growth factor secretion Anti-Cancer Drugs 17 2006 839 848 16926633 10.1097/01.cad.0000224443.85834.32

23 Chen H. Shi L. Yang X. Li S. Guo X. Pan L. Artesunate inhibiting angiogenesis induced by human myeloma RPMI8226 cells Int. J. Hematol. 92 2010 587 597 20945119 10.1007/s12185-010-0697-3

24 Chen Y. Li R. Zhu Y. Zhong S. Qian J. Yang D. Jurczyszyn A. Beksac M. Gu C. Yang Y. Dihydroartemisinin induces growth arrest and overcomes dexamethasone resistance in multiple myeloma Front. Oncol. 10 2020 767 32500030 10.3389/fonc.2020.00767 PMC7242728

25 Liang L. Liu Y. Wu X. Chen Y. Artesunate induces ferroptosis by inhibiting the nuclear localization of SREBP2 in myeloma cells Int. J. Med. Sci. 20 2023 1535 37859702 10.7150/ijms.86409 PMC10583180

26 Nagelschmitz J. Voith B. Wensing G. Roemer A. Fugmann B. Haynes R.K. Kotecka B.M. Rieckmann K.H. Edstein M.D.J.A.A. First assessment in humans of the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of the new artemisinin derivative artemisone Chemotherapy 52 2008 3085 3091 10.1128/AAC.01585-07 PMC2533467 18559649

27 Gautam, A., Ahmed, T., Batra, V., Paliwal, J.J.C.d.m., 2009. Pharmacokinetics and pharmacodynamics of endoperoxide antimalarials. 10, 289-306. 10.2174/138920009787846323 19442090

28 Mancuso R.I. Foglio M.A. Olalla Saad S.J.C.C. Artemisinin-type drugs for the treatment of hematological malignancies Pharmacology 87 2021 1 22 10.1007/s00280-020-04170-5 33141328

29 Giordano A. Tommonaro G. Curcumin and cancer Nutrients 11 2019 2376 31590362 10.3390/nu11102376 PMC6835707

30 Bharti A.C. Donato N. Singh S. Aggarwal B.B. Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor¨C¦ÊB and I¦ÊB¦Á kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood J. Am. Soc. Hematol. 101 2003 1053 1062 10.1182/blood-2002-05-1320 12393461

31 Bharti A.C. Donato N. Aggarwal B.B. Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells J. Immunol. 171 2003 3863 3871 14500688 10.4049/jimmunol.171.7.3863

32 Park J. Ayyappan V. Bae E.-K. Lee C. Kim B.-S. Kim B.K. Lee Y.-Y. Ahn K.-S. Yoon S.-S. Curcumin in combination with bortezomib synergistically induced apoptosis in human multiple myeloma U266 cells Mol. Oncol. 2 2008 317 326 19383353 10.1016/j.molonc.2008.09.006 PMC5527772

33 Gomez-Bougie P. Halliez M. Maïga S. Godon C. Kervoëlen C. Pellat-Deceunynck C. Moreau P. Amiot M. Curcumin induces cell death of the main molecular myeloma subtypes, particularly the poor prognosis subgroups Cancer Biol. Ther. 16 2015 60 65 25517601 10.4161/15384047.2014.986997 PMC4622499

34 Li W. Wang Y. Song Y. Xu L. Zhao J. Fang B. A preliminary study of the effect of curcumin on the expression of p53 protein in a human multiple myeloma cell line Oncol. Lett. 9 2015 1719 1724 25789029 10.3892/ol.2015.2946 PMC4356419

35 Chen J. Ying Y. Zhu H. Zhu T. Qu C. Jiang J. Fang B. Curcumin-induced promoter hypermethylation of the mammalian target of rapamycin gene in multiple myeloma cells Oncol. Lett. 17 2019 1108 1114 30655872 10.3892/ol.2018.9662 PMC6312997

36 Wu C. Ruan T. Liu W. Zhu X. Pan J. Lu W. Yan C. Tao K. Zhang W. Zhang C. Effect and mechanism of curcumin on EZH2-miR-101 regulatory feedback loop in multiple myeloma Curr. Pharm. Des. 24 2018 564 575 28322158 10.2174/1381612823666170317164639

37 Xiao H. Xiao Q. Zhang K. Zuo X. Shrestha U.K. Reversal of multidrug resistance by curcumin through FA/BRCA pathway in multiple myeloma cell line MOLP-2/R Ann. Hematol. 89 2010 399 404 19756599 10.1007/s00277-009-0831-6

38 Bai Q.-X. Zhang X.-Y. Curcumin enhances cytotoxic effects of bortezomib in human multiple myeloma H929 cells: potential roles of NF-¦ÊB/JNK Int. J. Mol. Sci. 13 2012 4831 4838 22606012 10.3390/ijms13044831 PMC3344248

39 Allegra A. Speciale A. Molonia M.S. Guglielmo L. Musolino C. Ferlazzo G. Costa G. Saija A. Cimino F. Curcumin ameliorates the in vitro efficacy of carfilzomib in human multiple myeloma U266 cells targeting p53 and NF-¦ÊB pathways Toxicol. Vitro 47 2018 186 194 10.1016/j.tiv.2017.12.001 29223572

40 Golombick, T., Diamond, T.H., Manoharan, A., Ramakrishna, R., 2012. Monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and curcumin: a randomized, double-blind placebo-controlled cross-over 4g study and an open-label 8g extension study. 87, 455-460. 10.1002/ajh.23159 22473809

41 Kudo C. Yamakoshi H. Sato A. Ohori H. Ishioka C. Iwabuchi Y. Shibata H. Novel curcumin analogs, GO-Y030 and GO-Y078, are multi-targeted agents with enhanced abilities for multiple myeloma Anticancer Res. 31 2011 3719 3726 22110192

42 Liu K. Zhang D. Chojnacki J. Du Y. Fu H. Grant S. Zhang S. Design and biological characterization of hybrid compounds of curcumin and thalidomide for multiple myeloma Org. Biomol. Chem. 11 2013 4757 4763 23784627 10.1039/c3ob40595h PMC6089070

43 Booth L. Roberts J.L. West C. Dent P. GZ17-6.02 interacts with proteasome inhibitors to kill multiple myeloma cells Oncotarget 15 2024 159 38441437 10.18632/oncotarget.28558 PMC10913917

44 Chelimela N. Alavala R.R. Satla S.R. Curcumin¨CBioavailability enhancement by prodrug approach and novel formulations Chem. Biodivers. 21 2024 e202302030 10.1002/cbdv.202302030 38401117

45 Shahcheraghi S.H. Salemi F. Peirovi N. Ayatollahi J. Alam W. Khan H. Saso L. Nrf2 regulation by curcumin: molecular aspects for therapeutic prospects Molecules 27 2021 10.3390/molecules27010167 PMC8746993 35011412

46 Entezari, M., Tayari, A., Paskeh, M.D.A., Kheirabad, S.K., Naeemi, S., Taheriazam, A., Dehghani, H., Salimimoghadam, S., Hashemi, M., Mirzaei, S.J.J.o.T., Medicine, C., 2024. Curcumin in treatment of hematological cancers: promises and challenges. 14, 121-134. 10.1016/j.jtcme.2023.10.004 PMC10927384 38481552

47 Mirzaei, H., Bagheri, H., Ghasemi, F., Khoi, J.M., Pourhanifeh, M.H., Heyden, Y.V., Mortezapour, E., Nikdasti, A., Jeandet, P., Khan, H.J.A.-C.A.i.M.C.-A.-C.A., 2021. Anti-cancer activity of curcumin on multiple myeloma. 21, 575-586. 10.2174/1871520620666200918113625 32951583

48 Wang C. Dai S. Zhao X. Zhang Y. Gong L. Fu K. Ma C. Peng C. Li Y. Celastrol as an emerging anticancer agent: current status, challenges and therapeutic strategies Biomed. Pharmacother. = Biomed. Pharmacother. 163 2023 114882 10.1016/j.biopha.2023.114882 37196541

49 Kannaiyan R. Hay H.S. Rajendran P. Li F. Shanmugam M.K. Vali S. Abbasi T. Kapoor S. Sharma A. Kumar A.P. Celastrol inhibits proliferation and induces chemosensitization through down©\regulation of NF©\¦ÊB and STAT3 regulated gene products in multiple myeloma cells Br. J. Pharmacol. 164 2011 1506 1521 21506956 10.1111/j.1476-5381.2011.01449.x PMC3221104

50 Kannaiyan R. Manu K.A. Chen L. Li F. Rajendran P. Subramaniam A. Lam P. Kumar A.P. Sethi G. Celastrol inhibits tumor cell proliferation and promotes apoptosis through the activation of c-Jun N-terminal kinase and suppression of PI3 K/Akt signaling pathways Apoptosis 16 2011 1028 1041 21786165 10.1007/s10495-011-0629-6

51 Ni H. Zhao W. Kong X. Li H. Ouyang J. NF-kappa B modulation is involved in celastrol induced human multiple myeloma cell apoptosis PLoS One 9 2014 e95846 10.1371/journal.pone.0095846 PMC3995890 24755677

52 Tozawa K. Sagawa M. Kizaki M. Quinone methide tripterine, celastrol, induces apoptosis in human myeloma cells via NF-κb pathway Int. J. Oncol. 39 2011 1117 1122 21850367 10.3892/ijo.2011.1161

53 Ni H. Zhao W. Kong X. Li H. Ouyang J. Celastrol inhibits lipopolysaccharide-induced angiogenesis by suppressing TLR4-triggered nuclear factor-kappa B activation Acta Haematol. 131 2014 102 111 24157922 10.1159/000354770

54 Zhong Y.-l. Xu G.-j. Huang S. Zhao L. Zeng Y. Xiao X.-f. An J.-l. Liu J. Yang T. Celastrol induce apoptosis of human multiple myeloma cells involving inhibition of proteasome activity Eur. J. Pharmacol. 853 2019 184 192 30928629 10.1016/j.ejphar.2019.03.036

55 Vilaboa N. Lopez J.A. de Mesa M. Escudero-Duch C. Winfield N. Bayford M. Voellmy R. Disruption of proteostasis by natural products and synthetic compounds that induce pervasive unfolding of proteins: therapeutic implications Pharmaceuticals 16 2023 10.3390/ph16040616 PMC10145903 37111374

56 Jin S. Li B. Zhang B. Gao X. Jia X. Xu L. Chang S. Hu K. Wang G. Xu Z. Dihydrocelastrol induces antitumor activity and enhances the sensitivity of bortezomib in resistant multiple myeloma by inhibiting STAT3-dependent PSMB5 regulation Acta Biochim. Biophys. Sin. 55 2023 1884 1891 38009004 10.3724/abbs.2023260 PMC11294055

57 Hu L. Wu H. Li B. Song D. Yang G. Chen G. Xie B. Xu Z. Zhang Y. Yu D. Dihydrocelastrol inhibits multiple myeloma cell proliferation and promotes apoptosis through ERK1/2 and IL-6/STAT3 pathways in vitro and in vivo Acta Biochim. Biophys. Sin. 49 2017 420 427 28338993 10.1093/abbs/gmx021

58 Shanmugam M.K. Ahn K.S. Lee J.H. Kannaiyan R. Mustafa N. Manu K.A. Siveen K.S. Sethi G. Chng W.J. Kumar A.P. Celastrol attenuates the invasion and migration and augments the anticancer effects of bortezomib in a xenograft mouse model of multiple myeloma Front. Pharmacol. 9 2018 365 29773987 10.3389/fphar.2018.00365 PMC5943600

59 Shi J. Li J. Xu Z. Chen L. Luo R. Zhang C. Gao F. Zhang J. Fu C. Celastrol: a review of useful strategies overcoming its limitation in anticancer application J. Front. Pharmacol. 11 2020 558741 10.3389/fphar.2020.558741 PMC7751759 33364939

60 Sun Y. Wang C. Li X. Lu J. Wang M. Recent advances in drug delivery of celastrol for enhancing efficiency and reducing the toxicity J. Front. Pharmacol. 15 2024 1137289 10.3389/fphar.2024.1137289 PMC10904542 38434700

61 Liu Y. Chen Y. Lin L. Li H. Gambogic acid as a candidate for cancer therapy: a review Int. J. Nanomed. 15 2020 10385 10399 10.2147/IJN.S277645 PMC7764553 33376327

62 Chauhan D. Bandi M. Singh A.V. Ray A. Raje N. Richardson P. Anderson K.C. Preclinical evaluation of a novel SIRT1 modulator SRT1720 in multiple myeloma cells Br. J. Haematol. 155 2011 588 598 21950728 10.1111/j.1365-2141.2011.08888.x PMC4391196

63 Yang L.-J. Chen Y. He J. Yi S. Wen L. Zhao S. Cui G.-H. Effects of gambogic acid on the activation of caspase-3 and downregulation of SIRT1 in RPMI-8226 multiple myeloma cells via the accumulation of ROS Oncol. Lett. 3 2012 1159 1165 22783411 10.3892/ol.2012.634 PMC3389632

64 Pandey M.K. Kale V.P. Song C. Sung S.-S. Sharma A.K. Talamo G. Dovat S. Amin S.G. Gambogic acid inhibits multiple myeloma mediated osteoclastogenesis through suppression of chemokine receptor CXCR4 signaling pathways Exp. Hematol. 42 2014 883 896 25034231 10.1016/j.exphem.2014.07.261

65 Wang F. Zhang W. Guo L. Bao W. Jin N. Liu R. Liu P. Wang Y. Guo Q. Chen B. Gambogic acid suppresses hypoxia-induced hypoxia-inducible factor-1α/vascular endothelial growth factor expression via inhibiting phosphatidylinositol 3-kinase/Akt/mammalian target protein of rapamycin pathway in multiple myeloma cells Cancer Sci. 105 2014 1063 1070 24890366 10.1111/cas.12458 PMC4317858

66 Li, M., Su, F., Zhu, M., Zhang, H., Wei, Y., Zhao, Y., Li, J., Lv, S.J.M., 2022. Research progress in the field of gambogic acid and its derivatives as antineoplastic drugs. 27, 2937. 10.3390/molecules27092937 PMC9102264 35566290

67 Liu, Y., Chen, Y., Lin, L., Li, H.J.I.J.o.N., 2020. Gambogic acid as a candidate for cancer therapy: a review. 10385-10399. 10.2147/IJN.S277645 PMC7764553 33376327

68 Fahmy, S.A., Elghanam, R., Rashid, G., Youness, R.A., Sedky, N.K.J.R.a., 2024. Emerging tendencies for the nano-delivery of gambogic acid: a promising approach in oncotherapy. 14, 4666-4691. 10.1039/d3ra08042k PMC10840092 38318629

69 Rauf A. Imran M. Butt M.S. Nadeem M. Peters D.G. Mubarak M.S. Resveratrol as an anti-cancer agent: a review Crit. Rev. Food Sci. Nutr. 58 2018 1428 1447 28001084 10.1080/10408398.2016.1263597

70 Jazirehi A.R. Bonavida B. Resveratrol modifies the expression of apoptotic regulatory proteins and sensitizes non-Hodgkin's lymphoma and multiple myeloma cell lines to paclitaxel-induced apoptosis Mol. Cancer Ther. 3 2004 71 84 14749477

71 Bhardwaj A. Sethi G. Vadhan-Raj S. Bueso-Ramos C. Takada Y. Gaur U. Nair A.S. Shishodia S. Aggarwal B.B. Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-¦ÊB¨cregulated antiapoptotic and cell survival gene products in human multiple myeloma cells Blood 109 2007 2293 2302 17164350 10.1182/blood-2006-02-003988

72 SUN C. Hu Y. Guo T. WANG H. ZHANG X. HE W. Tan H. Resveratrol as a novel agent for treatment of multiple myeloma with matrix metalloproteinase inhibitory activity Acta Pharmacol. Sin. 27 2006 1447 1452 17049120 10.1111/j.1745-7254.2006.00343.x

73 Sun C. Hu Y. Liu X. Wu T. Wang Y. He W. Wei W. Resveratrol downregulates the constitutional activation of nuclear factor-¦ÊB in multiple myeloma cells, leading to suppression of proliferation and invasion, arrest of cell cycle, and induction of apoptosis Cancer Genet. Cytogenet. 165 2006 9 19 16490592 10.1016/j.cancergencyto.2005.06.016

74 Wang F.-M. Galson D.L. Roodman G.D. Ouyang H. Resveratrol triggers the pro-apoptotic endoplasmic reticulum stress response and represses pro-survival XBP1 signaling in human multiple myeloma cells Exp. Hematol. 39 2011 999 1006 21723843 10.1016/j.exphem.2011.06.007 PMC3261654

75 Li Q. Yue Y. Chen L. Xu C. Wang Y. Du L. Xue X. Liu Q. Wang Y. Fan F. Resveratrol sensitizes carfilzomib-induced apoptosis via promoting oxidative stress in multiple myeloma cells Front. Pharmacol. 9 2018 334 29867453 10.3389/fphar.2018.00334 PMC5961230

76 Jin H.-G. Wu G.-Z. Wu G.-H. Bao Y.-G. Combining the mammalian target of rapamycin inhibitor, rapamycin, with resveratrol has a synergistic effect in multiple myeloma Oncol. Lett. 15 2018 6257 6264 29731844 10.3892/ol.2018.8178 PMC5920858

77 Geng W. Guo X. Zhang L. Ma Y. Wang L. Liu Z. Ji H. Xiong Y. Resveratrol inhibits proliferation, migration and invasion of multiple myeloma cells via NEAT1-mediated wnt/¦Â-catenin signaling pathway Biomed. Pharmacother. 107 2018 484 494 30107344 10.1016/j.biopha.2018.08.003

78 Agarwal A. Khandelwal A. Pal K. Khare N.K. Jadhav V. Gurjar M. Punatar S. Gokarn A. Bonda A. Nayak L. A novel pro-oxidant combination of resveratrol and copper reduces transplant related toxicities in patients receiving high dose melphalan for multiple myeloma (RESCU 001) PLoS One 17 2022 e0262212 10.1371/journal.pone.0262212 PMC8815866 35120140

79 Staskiewicz, A., Wong, E., Tucker, M., Farhin, R., Park, J., Saade, R., Alkhazali, T., Dang, T., Wang, X., 2023. Cytotoxic and apoptotic effects of pinostilbene and bortezomib combination treatment on Human Multiple myeloma cells. 24, 12590. 10.3390/ijms241612590 PMC10454535 37628771

80 Rocca R. Ascrizzi S. Citriniti E.L. Scionti F. Juli G. Di Martino M.T. Caracciolo D. Artese A. Tagliaferri P. Tassone P. TERRA G-quadruplex stabilization behind the anti-multiple myeloma activity: novel insights about resveratrol pleiotropic effects Arch. Pharm. 357 2024 e2400269 10.1002/ardp.202400269 39365272

81 Intagliata S. Modica M.N. Santagati L.M. Montenegro L. Strategies to improve resveratrol systemic and topical bioavailability: an update Antioxidants 8 2019 244 31349656 10.3390/antiox8080244 PMC6719186

82 Li Y. Yang T. Li J. Hao H.-L. Wang S.-Y. Yang J. Luo J.-M. Inhibition of multiple myeloma cell proliferation by ginsenoside Rg3 via reduction in the secretion of IGF-1 Mol. Med. Rep. 14 2016 2222 2230 27430248 10.3892/mmr.2016.5475

83 Luo Y. Zhang P. Zeng H.-Q. Lou S.-F. Wang D.-X. Ginsenoside Rg3 induces apoptosis in human multiple myeloma cells via the activation of Bcl-2-associated X protein Mol. Med. Rep. 12 2015 3557 3562 25998024 10.3892/mmr.2015.3802

84 Lin L. Chen D. Li S. Wang T. Ginsenoside Rg1 inhibits multiple myeloma and overcomes bortezomib resistance through AMPK-mTOR pathway Heliyon 10 2024 10.1016/j.heliyon.2024.e33935 PMC11283037 39071579

85 Lee Y.E. Kim J.Y. Kim H.R. Shin M.G. Therapeutic effect and molecular mechanism of the ultra-low molecule compound K on multiple myeloma Biomed. Pharmacother. = Biomed. Pharmacother. 180 2024 117440 10.1016/j.biopha.2024.117440 39303449

86 Ikezoe T. Yang Y. Bandobashi K. Saito T. Takemoto S. Machida H. Togitani K. Koeffler H.P. Taguchi H. Oridonin, a diterpenoid purified from Rabdosia rubescens, inhibits the proliferation of cells from lymphoid malignancies in association with blockade of the NF-¦ÊB signal pathways Mol. Cancer Ther. 4 2005 578 586 15827331 10.1158/1535-7163.MCT-04-0277

87 Yaning H. Fei Z. Yuanyuan L. Mei Z. Shasha L. Inhibitory effect of oridonin on proliferation of RPMI8226 cells and the possible underlying mechanism J. Tradit. Chin. Med. 36 2016 225 230 27400478 10.1016/s0254-6272(16)30031-0

88 Zeng R. Chen Y. Zhao S. Cui G.-h. Autophagy counteracts apoptosis in human multiple myeloma cells exposed to oridonin in vitro via regulating intracellular ROS and SIRT1 Acta Pharmacol. Sin. 33 2012 91 100 22158107 10.1038/aps.2011.143 PMC4010261

89 Zhao J. Zhang M. He P. Zhao J. Chen Y. Qi J. Wang Y. Proteomic analysis of oridonin-induced apoptosis in multiple myeloma cells Mol. Med. Rep. 15 2017 1807 1815 28259901 10.3892/mmr.2017.6213

90 Liu W. Tang X. Fan C. He G. Wang X. Liang X. Bao X. Chemical constituents, pharmacological action, antitumor application, and toxicity of strychnine semen from Strychnons pierriana AW Hill.: a review J. Ethnopharmacol. 317 2023 116748 10.1016/j.jep.2023.116748 37348797

91 Rao P.S. Prasad M.N.V. Strychnos nux-vomica root extract induces apoptosis in the human multiple myeloma cell line¡ªU266B1 Cell Biochem. Biophys. 66 2013 443 450 23250582 10.1007/s12013-012-9492-5

92 Rao P.S. Ramanadham M. Prasad M.N.V. Anti-proliferative and cytotoxic effects of Strychnos nux-vomica root extract on human multiple myeloma cell line¨CRPMI 8226 Food Chem. Toxicol. 47 2009 283 288 19027818 10.1016/j.fct.2008.10.027

93 Ma Y. Zhao J. Wang Y. Li Z. Feng J. Ren H. Effects of brucine on bone metabolism in multiple myeloma Mol. Med. Rep. 6 2012 367 370 22614932 10.3892/mmr.2012.920

94 Wu H. Dai X. Wang E. Plumbagin inhibits cell proliferation and promotes apoptosis in multiple myeloma cells through inhibition of the PI3K/Akt-mTOR pathway Oncol. lett. 12 2016 3614 3618 27900044 10.3892/ol.2016.5048 PMC5104058

95 Lin, S., Shen, C., Jiang, J., Wu, L., Dai, T., Qian, W., Meng, H., 2013. Apoptosis of multiple myeloid cells induced by polysaccharides extracts from Hedyotis diffusa and its mechanism. 34, 337-340. 10.3760/cma.j.issn.0253-2727.2013.04.019 23668208

96 Zhu S. Wang Z. Li Z. Peng H. Luo Y. Deng M. Li R. Dai C. Xu Y. Liu S. Icaritin suppresses multiple myeloma, by inhibiting IL-6/JAK2/STAT3 Oncotarget 6 2015 10460 10.18632/oncotarget.3399 PMC4496367 25865044

97 Zhu Y. Zhang X. Zhang Q. Chai J. Icaritin-elevated circ_0000190 suppresses the malignant progression of multiple myeloma by targeting miR-301a Kaohsiung J. Med. Sci. 38 2022 447 456 35174633 10.1002/kjm2.12504 PMC11896316

98 Hou Y. Kuang W. Min W. Liu Z. Zhang F. Yuan K. Wang X. Sun C. Cheng H. Wang L. Design, synthesis, and biological evaluation of icaritin derivatives as novel putative DEPTOR inhibitors for multiple myeloma treatment J. Med. Chem. 64 2021 14942 14954 34644502 10.1021/acs.jmedchem.1c00087

99 Peterson T.R. Laplante M. Thoreen C.C. Sancak Y. Kang S.A. Kuehl W.M. Gray N.S. Sabatini D.M. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival Cell 137 2009 873 886 19446321 10.1016/j.cell.2009.03.046 PMC2758791

100 Kim C. Lee S.-G. Yang W.M. Arfuso F. Um J.-Y. Kumar A.P. Bian J. Sethi G. Ahn K.S. Formononetin-induced oxidative stress abrogates the activation of STAT3/5 signaling axis and suppresses the tumor growth in multiple myeloma preclinical model Cancer Lett. 431 2018 123 141 29857127 10.1016/j.canlet.2018.05.038

101 Kim C. Lee J.H. Ko J.-H. Chinnathambi A. Alharbi S.A. Shair O.H. Sethi G. Ahn K.S. Formononetin regulates multiple oncogenic signaling cascades and enhances sensitivity to bortezomib in a multiple myeloma mouse model Biomolecules 9 2019 262 31284669 10.3390/biom9070262 PMC6681380

102 Gui H. Fan X. Anti-tumor effect of dandelion flavone on multiple myeloma cells and its mechanism Discov. Oncol. 15 2024 215 38850433 10.1007/s12672-024-01076-z PMC11162407

103 Ying Q. Lou J. Zheng D. Ginsenoside Rh4 inhibits the malignant progression of multiple myeloma and induces ferroptosis by regulating SIRT2 Clin. Exp. Pharmacol. Physiol. 50 2023 757 765 37452691 10.1111/1440-1681.13805

Acknowledgments

This study was funded by the 10.13039/501100001809 National Natural Science Foundation of China General Program ( 82574790 ), Development Project of Science and Technology of Medical and Health of Shandong Province(202303041540), Shandong Medical Association Scientific Research Project (YXH2025YS080).