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Mouse Models of Tumor Bone Metastasis and Invasion for Studying CCN Proteins.

Bone metastasis and bone destruction are common occurrences in human malignancies, including breast, prostate, and lung cancer, and are associated with a high morbidity rate because of intractable bone pain, pathological fractures, hypercalcemia, and nerve compression. Animal models of bone metastasis and bone destruction are important tools to investigate the pathogenesis and develop treatment strategies. However, there are few models of spontaneous bone metastasis despite the fact that animals often spontaneously develop cancer. Here, we describe methods for developing a mouse model of breas

Discovery of a Novel G-Quadruplex and Histone Deacetylase (HDAC) Dual-Targeting Agent for the Treatment of Triple-Negative Breast Cancer.

The development of triple-negative breast cancer (TNBC) is highly associated with G-quadruplex (G4); thus, targeting G4 is a potential strategy for TNBC therapy. Because concomitant histone deacetylases (HDAC) inhibition could amplify the impact of G4-targeting compounds, we designed and synthesized two novel series of G4/HDAC dual-targeting compounds by connecting the zinc-binding pharmacophore of HDAC inhibitors to the G4-targeting isaindigotone scaffold (1). Among the new compounds, a6 with the potent HDAC inhibitory and G4 stabilizing activity could induce more DNA G4 formation than SAHA a

Ambrisentan, an endothelin receptor type A-selective antagonist, inhibits cancer cell migration, invasion, and metastasis.

Several studies reported a central role of the endothelin type A receptor (ETAR) in tumor progression leading to the formation of metastasis. Here, we investigated the in vitro and in vivo anti-tumor effects of the FDA-approved ETAR antagonist, Ambrisentan, which is currently used to treat patients with pulmonary arterial hypertension. In vitro, Ambrisentan inhibited both spontaneous and induced migration/invasion capacity of different tumor cells (COLO-357 metastatic pancreatic adenocarcinoma, OvCar3 ovarian carcinoma, MDA-MB-231 breast adenocarcinoma, and HL-60 promyelocytic leukemia). Whole

Thymus‑expressed chemokine secreted by breast cancer cells promotes metastasis and inhibits apoptosis.

The aim of the present study was to investigate the underlying mechanisms of thymus‑expressed chemokine (TECK) autocrine signaling, and its effect on carcinogenesis and the development of breast cancer. The present study also assessed epithelial‑mensenchymal transition (EMT) and cell migration, invasion, proliferation and apoptosis. Breast cancer cell lines MCF‑7 and MDA‑MB‑231 were used in the present study, and TECK basic expression in cancer cells was investigated using western blotting (WB). EMT markers, Akt pathway molecules and apoptosis indicators were detected by reverse transcription‑

Lysine-embedded cellulose-based nanosystem for efficient dual-delivery of chemotherapeutics in combination cancer therapy.

Combination therapy by two or multiple drugs with different mechanisms of action is a promising strategy in cancer treatment. In this regard, a wide range of chemotherapeutics has used simultaneously to achieve the synergistic effect and overcome the adverse side effects of single-drug therapy. Herein, we developed a biocompatible nanoparticle-based system composed of nanocrystalline cellulose (NCC) and amino acid l-lysine for efficient co-delivery of model chemotherapeutic methotrexate (MTX) and polyphenol compound curcumin (CUR) to the MCF-7 and MDA-MB-231 cells. The drugs could release in a…

De Novo Design of Cu(II) Complex Containing CNC-Pincer-Vitamin B3 and B7 Conjugates for Breast Cancer Application.

A Cu(II) complex, that is, [Cu(CNC-B3)(IM-B7)](PF6)2, 1, containing CNC-B3 (L2) = CNC-pincer-vitamin B3 and IM-B7 (L3) = 1H-imidazole-1-methanamine-vitamin B7 conjugates, was developed as a potential chemotherapeutic agent for breast cancer cell lines. The Cu(II) complex brings about a remarkable in vitro cytotoxicity in comparison with cisplatin and tamoxifen against MDA-MB-231 and MCF-7 cancer cell lines. Interestingly, the Cu(II) complex was considerably less toxic to MRC-5 normal cells. The DNA/human serum albumin-binding capacity of the Cu(II) complex was confirmed by spectrometric method

Intersectin adaptor proteins are associated with actin-regulating protein WIP in invadopodia.

Invasive cancer cells form actin-rich membrane protrusions called invadopodia that degrade extracellular matrix and facilitate cell invasion and metastasis. WIP (WASP-interacting protein) together with N-WASP (neural Wiskott-Aldrich syndrome protein) are localized in invadopodia and play a crucial role in their formation. Here we show that WIP interacts with endocytic adaptor proteins of the intersectin (ITSN) family, ITSN1 and ITSN2. The interaction is mediated by the SH3 domains of ITSNs and the middle part of the WIP proline-rich motifs. We have also demonstrated that ITSN1, WIP and N-WASP

Matrix metalloproteinase-1 promotes breast cancer angiogenesis and osteolysis in a novel in vivo model.

Matrix metalloproteinase-1 (MMP-1) is critical for mediating breast cancer metastasis to bone. We investigated the role of MMP-1 in breast cancer invasion of soft tissues and bone using human MDA MB-231 breast cancer cells stably transfected with shRNAs against MMP-1 and a novel murine model of bone invasion. MMP-1 produced by breast cancer cells with control shRNA facilitated invasion of tumors into soft tissue in vivo, which correlated with enhanced blood vessel formation at the invasive edge, compared to tumors with silenced MMP-1 expression. Tumors expressing MMP-1 were also associated wit

Inhibitory effects of naringenin on tumor growth in human cancer cell lines and sarcoma S-180-implanted mice.

We have investigated the effect of naringenin (NGEN) on tumor growth in various human cancer cell lines and sarcoma S-180-implanted mice. NGEN showed cytotoxicity in cell lines derived from cancer of the breast (MCF-7, MDA-MB-231), stomach (KATOIII, MKN-7), liver (HepG2, Hep3B, Huh7), cervix (Hela, Hela-TG), pancreas (PK-1), and colon (Caco-2) as well as leukemia (HL-60, NALM-6, Jurkat, U937). NGEN-induced cytotoxicity was low in Caco-2 and high in leukemia cells compared to other cell lines. NGEN dose-dependently induced apoptosis, with hypodiploid cells detected in both Caco-2 and HL-60 by f

ΔA146Ply exerts anti-triple-negative breast cancer effects by inducing ferroptosis via regulation of the CYP24A1-mediated calcitriol-vitamin D receptor pathway.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, typically associated with poor clinical outcomes. Recently, ferroptosis has emerged as a promising therapeutic target for TNBC. ΔA146Ply, a novel pneumolysin variant, has demonstrated potential as an anti-tumor agent; however, its role in regulating ferroptosis remains unclear. This study investigates whether ΔA146Ply exerts anti-TNBC effects by promoting ferroptosis via the CYP24A1-mediated Calcitriol/vitamin D receptor (VDR) pathway. Our in vitro results reveal that ΔA146Ply inhibits MDA-MB-231 cells by induci…

Quinoline/Pyrido-Pyrimidine Derivatives as Tubulin Polymerization Inhibitors: Design, Synthesis, Computational, and Anticancer Evaluation.

Cancer prevails a substantial health threat, with breast and colon cancers being the second and third most recurrent worldwide. In recent decades, quinoline/pyrido[2,3-d]pyrimidin-4(3H)-one derivatives have procured attention as propitious anticancer agents. This study acquaint a series of such compounds synthesized and characterized using spectroscopic (1H NMR, 13C NMR, IR, MS) and computational (DFT) methods. Their tubulin polymerization inhibitory and antiproliferative activities were assessed against cancer cell lines MCF-7, MDA-MB-231, and HCT-116, accompanying cytotoxicity screening agai

Sclerostin induced tumor growth, bone metastasis and osteolysis in breast cancer.

Breast cancer is the second leading cause of cancer-related deaths among women worldwide. Many patients suffer from bone metastasis. Sclerostin, a key regulator of normal bone remodeling, is critically involved in osteolytic bone diseases. However, its role in breast cancer bone metastasis remains unknown. Here, we found that sclerostin was overexpressed in breast cancer tumor tissues and cell lines. Inhibition of sclerostin by antibody (Scl-Ab) significantly reduced migration and invasion of MDA-MB-231 and MCF-7 cells in a time- and dose-dependent manner. In xenograft model, sclerostin inhibi

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… MTT assays were performed at 1d, 2d, and 3d after treatment with sclerostin antibody (at 0, 1 and 4 µg/ml, respectively) in ( A ) MCF-7 and ( B ) MDA-MB-231 cells. ( C ) Cell migration assays were performed using Transwell system. … A surgical scalpel was used to drill a tiny hole on the cortex and MDA-MB-231 cells (5 × 10 6 cells in 30 μl PBS) were injected into the bone marrow space through the hole with a 100-μl Hamilton microsyringe (Shanghai Linbo Scientific Instruments, Shanghai, China). …

Decellularized Extracellular Matrix-Based Tunable 3D Hydrogel: An Alternative Methodology for the Development of a Doxorubicin-Independent 3D Breast Cancer Microphysiological Chemoresistance Model.

Breast cancer is the most prevalent malignancy among women and the second leading cause of cancer-related mortality worldwide, with 2.26 mil … hydrogel with tunable matrix crosslinking and rheology. Drug resistance was evaluated by culturing MDA-MB-231 cells encapsulated in 3D hydrogels with variable matrix crosslinking and rheology, and assessing the CD44+/CD24- cancer stem cell-associated phenotype linked to aggressiveness and therapy resistance.

Antioxidant Activity and Dose-Dependent Toxicity of a Traditionally Consumed Ipomoea pes-caprae Infusion Evaluated in a Triple-Negative Breast Cancer Xenograft Model.

Background/Objectives: Triple-negative breast cancer (TNBC) is one of the most aggressive breast cancer subtypes and remains associated with limited therapeutic options and high systemic toxicity from conventional chemotherapy. Ipomoea pes-caprae is a coastal medicinal plant traditionally consumed in Mexico for inflammatory and renal disorders and contains bioactive metabolites with reported antioxidant and pharmacological properties. However, its antitumoral activity and systemic safety profile remain poorly understood. This study aimed to characterize the phytochemical composition, antioxida

CliCAR: A non-genetic CAR engineering strategy to empower NK cells for targeted cancer immunotherapy.

Conventional CAR-based immunotherapy has demonstrated promising efficacy in hematological malignancies. However, the inherently low transduction efficiency of viral vectors in innate immune cells, particularly natural killer (NK) cells, represents a significant barrier to the broader application of CAR-based immunotherapies. To overcome these limitations, in this study, we developed a nonviral platform, recombinant chimeric antigen receptor fusion protein (CliCAR), that rapidly converts immune cells into CAR-expressing cells without gene editing. CliCAR protein was rapidly internalized and loc

Strategic Development of Activatable Turn-On Fluorogenic Prodrugs of Celecoxib with Selective Anticancer Activity and Attenuated Cardiotoxicity.

Herein, we report the first examples of ROS-responsive fluorogenic prodrugs that enable sustained intracellular delivery of celecoxib with a fluorescence turn-on readout and exhibit selective anticancer activity with reduced cardiotoxicity. Spectroscopic and HPLC analysis confirmed efficient ROS-mediated activation and time-dependent release of both celecoxib and the fluorophore, providing mechanistic insights into the stimuli-triggered prodrug activation and the self-immolative drug release profile under physiological conditions. The lead prodrug Cou-Coxib exhibited selective anticancer activ

Viscosity-responsive AIEgen with mitochondrial/endoplasmic reticulum dual targeting for fatty liver fluorescence imaging and tumor photodynamic therapy.

Combining quantum chemical calculations with molecular dynamics simulations, we rationally designed a near-infrared (NIR) viscosity-responsi … ty responsiveness. Colocalization experiments confirmed TTPL3's precise dual organelle targeting in MDA-MB-231 cells, with Pearson's correlation coefficients of 0.94 and 0.96. TTPL3 was applicable for fatty liver fluorescence imaging and induced tumor cell apoptosis via the mitochondrial apoptotic pathway. In vivo studies showed TTPL3 achieved efficient tumor phot …

Evaluating the Anticancer and Anti-Angiogenic Efficacy of Bergaptol in 2D and 3D Tumor Microtissue Models.

Furanocoumarins are plant-derived compounds with diverse biological activities and emerging therapeutic potential. This study evaluated the anticancer and anti-angiogenic properties of bergaptol by using MDA-MB-231, HepG2, and HeLa cancer cell lines, as well as HUVEC endothelial cells, with HDFs serving as the healthy control group. Cell viability, apoptosis, cell-cycle progression, and angiogenesis were evaluated using complementary two-dimensional (2D) and three-dimensional (3D) experimental models. Bergaptol exhibited selective cytotoxicity toward cancer and endothelial cells, with no appar

Targeting VEGFR-2 with piperazine bridged indolin-2-one derivatives.

As a key mediator of tumor angiogenesis, VEGFR-2 has emerged as a promising therapeutic target for combating cancer. In the present study, a series of 6-substituted-3-(4-(4-(substitutedphenyl/benzyl)piperazin-1-yl)benzylidene) indolin-2-one derivatives (2-24) were synthesized in good yields and structurally confirmed by IR, NMR, and HRMS analyses. Several compounds exhibited strong VEGFR-2 inhibition, with activities comparable to or exceeding that of sorafenib, but lower than sunitinib. Cytotoxicity assays against MCF-7 breast cancer cells revealed five derivatives (4, 7, 9, 10, and 12) more

High-Throughput Screening of Photo-Cross-Linking Peptide Libraries for Site-Specific Conjugation of IgG.

An affinity-guided photo-cross-linking reaction based on Fc-binding peptide harboring p-benzoyl-l-phenylalanine (PEptide-DIrected Photo-cros … selectivity and exhibited potent cytotoxicity in HER2+ HCC1954 cells with minimal activity in HER2- MDA-MB-231 cells.