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Marizomib in the therapy of brain tumors-how far did we go and where do we stand?

Out of several types of tumors of the central nervous system (CNS), glioblastoma (GBM) represents one of the most frequent and malignant forms of brain neoplasms. To date, GBM holds very limited therapeutic options leaving patients with poor prognosis of survival. As such, novel treatment approaches are constantly quested. One of these strategies is based on the utilization of proteasome inhibitors (PIs). However, although several PIs have been approved as therapy for patients with hematological malignancies, these treatment benefits cannot not be easily extrapolated to brain tumors. This is m

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… Structure-wise, they can be divided into boronic acid derivatives, epoxyketones, and beta-lactones, whereas in terms of their mode of action, PIs can be separated into reversible/irreversible inhibitors of various subunits (C-L, T-L or CT-L) of proteasome [ 19 ]. … Finally, a separate group of PIs of β-lactone origin is represented by marizomib (MZB; salinosporamide A) [ 50 ]. MZB is an irreversible, II class PI active after both intravenous and oral administration. …

Homoharringtonine: updated insights into its efficacy in hematological malignancies, diverse cancers and other biomedical applications.

HHT has emerged as a notable compound in the realm of cancer treatment, particularly for hematological malignancies. Its multifaceted pharmacological properties extend beyond traditional applications, warranting an extensive review of its mechanisms and efficacy. This review aims to synthesize comprehensive insights into the efficacy of HHT in treating hematological malignancies, diverse cancers, and other biomedical applications. It focuses on elucidating the molecular mechanisms, therapeutic potential, and broader applications of HHT. A comprehensive search for peer-reviewed papers was condu

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… Recently, Dang et al. [ 47 ] reacted an oxo-containing α-tetrasubstituted lactone with Cephalotaxine and synthesized HHT, with a high yield. … Synthesis of the ester side chains of homoharringtonine and harringtonine using lactones as building blocks. Synth Commun. 2021;51(2):317–323. doi: 10.1080/00397911.2020.1829643. 48. Hiranuma S, Hudlicky T. …

The Most Competent Plant-Derived Natural Products for Targeting Apoptosis in Cancer Therapy.

Cancer is a challenging problem for the global health community, and its increasing burden necessitates seeking novel and alternative therapies. Most cancers share six basic characteristics known as "cancer hallmarks", including uncontrolled proliferation, refractoriness to proliferation blockers, escaping apoptosis, unlimited proliferation, enhanced angiogenesis, and metastatic spread. Apoptosis, as one of the best-known programmed cell death processes, is generally promoted through two signaling pathways, including the intrinsic and extrinsic cascades. These pathways comprise several compone

Activation of the steroid and xenobiotic receptor (human pregnane X receptor) by nontaxane microtubule-stabilizing agents.

PURPOSE: Because induction of drug efflux transporters is one of the major underlying mechanisms of drug resistance in cancer chemotherapy, and human pregnane X receptor (hPXR) is one of the principal "xenobiotic" receptors whose activation induces transporter and drug-metabolizing enzyme gene transcription, it would be ideal to develop chemotherapy drugs that do not activate hPXR. This report describes studies undertaken to explore the characteristics of hPXR stimulation and mechanisms of drug-receptor interactions in vitro with new anti-tubulin drugs. EXPERIMENTAL DESIGN: In vitro transient

Proteasome inhibition and its therapeutic potential in multiple myeloma.

Due to an unmet clinical need for treatment, the first in class proteasome inhibitor, bortezomib, moved from drug discovery to FDA approval in multiple myeloma in an unprecedented eight years. In the wake of this rapid approval arose a large number of questions about its mechanism of action and toxicity as well as its ultimate role in the treatment of this disease. In this article, we briefly review the preclinical and clinical development of the drug as the underpinning for a systematic review of the large number of clinical trials that are beginning to shed some light on the full therapeutic

Biosynthesis of anticancer phytochemical compounds and their chemistry.

Cancer is a severe health issue, and cancer cases are rising yearly. New anticancer drugs have been developed as our understanding of the molecular mechanisms behind diverse solid tumors, and metastatic malignancies have increased. Plant-derived phytochemical compounds target different oncogenes, tumor suppressor genes, protein channels, immune cells, protein channels, and pumps, which have attracted much attention for treating cancer in preclinical studies. Despite the anticancer capabilities of these phytochemical compounds, systemic toxicity, medication resistance, and limited absorption re

Advancements in Biomarkers and Molecular Targets in Hematological Neoplasias.

Hematological neoplasias are among the most common cancers worldwide, and the number of new cases has been on the rise since 1990, reaching 1 [...].

Bortezomib inhibits chikungunya virus replication by interfering with viral protein synthesis.

Chikungunya virus (CHIKV) is an alphavirus that causes a febrile illness accompanied by myalgia and arthralgia. Despite having re-emerged as a significant public health threat, there are no approved therapeutics or prophylactics for CHIKV infection. In this study, we explored the anti-CHIKV effects of proteasome inhibitors and their potential mechanism of antiviral action. A panel of proteasome inhibitors with different functional groups reduced CHIKV infectious titers in a dose-dependent manner. Bortezomib, which has been FDA-approved for multiple myeloma and mantle cell lymphoma, was further

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… Proteasome inhibitors tested belong to different compound classes, namely peptide aldehydes: MG132; peptide boronates: MLN-9708, MLN-2238 and delanzomib; peptide epoxyketones: carfilzomib, ONX-0914, epoxomicin and oprozomib; β-lactones: lactacystin; anthracycline derivatives: aclacinomycin A. *** P ≤ … Separation of cathepsin A-like enzyme and the proteasome: evidence that lactacystin/beta-lactone is not a specific inhibitor of the proteasome. Int J Biochem Cell Biol. 2000;32(7):747–57. 10.1016/s1357-2725(00)00021-2 61. Kupperman E, Lee EC, Cao Y, Bannerman B, Fitzgerald M, Berger A, et al. …

Assessment of the availability of repurposed orphan drugs in India.

India has a massive burden of rare diseases (RDs), with an estimated 96 million people living with RDs but limited options for treatment. Repurposing drugs used for other common conditions are essential alternative for RDs due to their cost-effectiveness and reduced timeline. India's patent regime prevents the evergreening of drugs, and a large generic manufacturing industry provides ample opportunity to explore the potential of repurposed drugs for treating RDs, known as repurposed orphan drugs (ROD). However, there is no portal or other source for information on orphan drugs in India. This s

Anti-Cancer Natural Products and Their Bioactive Compounds Inducing ER Stress-Mediated Apoptosis: A Review.

Cancer is the second biggest cause of death worldwide. Despite a number of studies being conducted, the effective mechanism for treating cancer has not yet been fully understood. The tumor-microenvironment such as hypoxia, low nutrients could disturb function of endoplasmic reticulum (ER) to maintain cellular homeostasis, ultimately leading to the accumulation of unfolded proteins in ER, so-called ER stress. The ER stress has a close relation with cancer. ER stress initiates unfolded protein response (UPR) to re-establish ER homeostasis as an adaptive pathway in cancer. However, persistent ER

Looking for the Holy Grail-Drug Candidates for Glioblastoma Multiforme Chemotherapy.

Glioblastoma multiforme (GBM) is the deadliest and the most heterogeneous brain cancer. The median survival time of GBM patients is approximately 8 to 15 months after initial diagnosis. GBM development is determined by numerous signaling pathways and is considered one of the most challenging and complicated-to-treat cancer types. Standard GBM therapy consist of surgery followed by radiotherapy or chemotherapy, and combined treatment. Current standard of care (SOC) does not offer a significant chance for GBM patients to combat cancer, and the selection of available drugs is limited. For almost

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… What made sesquiterpene lactones reach cancer clinical trials Drug Discov. Today 2010 15 668 678 10.1016/j.drudis.2010.06.002 20541036 63. Lickliter J.D. Jennens R. Lemech C.R. Su S.Y.C. Chen Y. … Population pharmacokinetic analysis of AR-67, a lactone stable camptothecin analogue in cancer patients with solid tumors Investig. New Drugs 2019 37 1218 1230 10.1007/s10637-019-00744-0 30820810 PMC6713628 85. Kumthekar P. Raizer J. Cavaliere R. Devoe C. Jensen R. Stieber V. Runk T. Grewal J. …

Nucleo-cytoplasmic transport as a therapeutic target of cancer.

Shuttling of specific proteins out of the nucleus is essential for the regulation of the cell cycle and proliferation of both normal and malignant tissues. Dysregulation of this fundamental process may affect many other important cellular processes such as tumor growth, inflammatory response, cell cycle, and apoptosis. It is known that XPO1 (Exportin-1/Chromosome Region Maintenance 1/CRM1) is the main mediator of nuclear export in many cell types. Nuclear proteins exported to the cytoplasm by XPO1 include the drug targets topoisomerase IIα (topo IIα) and BCR-ABL and tumor suppressor proteins s

Plant-Derived Natural Products in Cancer Research: Extraction, Mechanism of Action, and Drug Formulation.

Cancer is one of the main causes of death globally and considered as a major challenge for the public health system. The high toxicity and the lack of selectivity of conventional anticancer therapies make the search for alternative treatments a priority. In this review, we describe the main plant-derived natural products used as anticancer agents. Natural sources, extraction methods, anticancer mechanisms, clinical studies, and pharmaceutical formulation are discussed in this review. Studies covered by this review should provide a solid foundation for researchers and physicians to enhance basi

Development and application of decatungstate catalyzed C-H 18F- and 19F-fluorination, fluoroalkylation and beyond.

Over the past few decades, photocatalytic C-H functionalization reactions have received increasing attention due to the often mild reaction conditions and complementary selectivities to conventional functionalization processes. Now, photocatalytic C-H functionalization is a widely employed tool, supporting activities ranging from complex molecule synthesis to late-stage structure-activity relationship studies. In this perspective, we will discuss our efforts in developing a photocatalytic decatungstate catalyzed C-H fluorination reaction as well as its practical application realized through co

Emerging role of carfilzomib in treatment of relapsed and refractory lymphoid neoplasms and multiple myeloma.

Proteasome inhibition forms the cornerstone of antimyeloma therapy. The first-in-class proteasome inhibitor, bortezomib, either alone or in combination with other chemotherapeutic agents, induces high overall response rates and response qualities in patients with clinically and molecularly defined high-risk disease. However, resistance to bortezomib and neurotoxicity associated with the treatment remain challenging issues. Carfilzomib is a novel, well tolerated, irreversible proteasome inhibitor with minimal neurotoxicity. Carfilzomib demonstrates promising activity in myeloma patients who are

Interplay of non-coding RNAs and approved antimetabolites such as gemcitabine and pemetrexed in mesothelioma.

Gemcitabine and pemetrexed are clinically approved antimetabolites for the therapy of mesothelioma diseases. These drugs are often applied in combination with platinum complexes and other drugs. The activity of antimetabolites depended on the expression levels of certain non-coding RNAs, in particular, of small microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). The development of tumor resistance towards antimetabolites was regulated by non-coding RNAs. An overview of the interplay between gemcitabine/pemetrexed antimetabolites and non-coding RNAs in mesothelioma is provided. Further to th

Indian Ayurvedic medicine: Overview and application to brain cancer.

Ayurveda is the traditional medicine system of India, and has been in practice for millennia. It is a traditional approach that uses 1000's of different plant preparations in various combinations for treatment of human ailments, including cancer. Ethnopharmacological and phytochemical analyses are now elucidating the bioactive constituents of the different plant species and herbal formulations, including ashwagandha, curcumin, guduchi, triphala, and others. To provide an overview of: 1) the ethnopharmacology of Ayurveda and several of its most important plant species and formulations, includin

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… Several different classes of bioactive phytochemicals have been isolated from ashwagandha, including steroidal lactones (e.g., withanolides, withaferin A), alkaloids (e.g., withanine), flavonoids (e.g., quercetin), steroids, salts, and nitrogen-containing compounds (e.g., withanol) [ [10] , [11] , [12 … MAPK/ERK, PI3K/Akt/mTOR, & NF-κB/p53 pathways, suppress VEGF/VEGFR2 | reduce proliferation enhance apoptosis increase ROS inhibit cell cycle reduce angiogenesis The ethnopharmacological and phytochemical analyses of aswhagandha have suggested that the most bioactive constituents are the steroidal lactones …

Vitamin C Transporters and Their Implications in Carcinogenesis.

Vitamin C is implicated in various bodily functions due to its unique properties in redox homeostasis. Moreover, vitamin C also plays a great role in restoring the activity of 2-oxoglutarate and Fe2+ dependent dioxygenases (2-OGDD), which are involved in active DNA demethylation (TET proteins), the demethylation of histones, and hypoxia processes. Therefore, vitamin C may be engaged in the regulation of gene expression or in a hypoxic state. Hence, vitamin C has acquired great interest for its plausible effects on cancer treatment. Since its conceptualization, the role of vitamin C in cancer t

Synergistic induction of apoptosis in human leukemia cells (U937) exposed to bryostatin 1 and the proteasome inhibitor lactacystin involves dysregulation of the PKC/MAPK cascade.

Cotreatment with a minimally toxic concentration of the protein kinase C (PKC) activator (and down-regulator) bryostatin 1 (BRY) induced a marked increase in mitochondrial dysfunction and apoptosis in U937 monocytic leukemia cells exposed to the proteasome inhibitor lactacystin (LC). This effect was blocked by cycloheximide, but not by alpha-amanitin or actinomycin D. Qualitatively similar interactions were observed with other PKC activators (eg, phorbol 12-myristate 13-acetate and mezerein), but not phospholipase C, which does not down-regulate the enzyme. These events were examined in relati

Habb-e-Asgandh Suppresses Cell Proliferation and Induces Apoptosis through Mitochondria Dysfunction in Multiple Myeloma Cells (RPMI8226).

ObjectiveThis study was conducted to assess the anti-neoplastic properties of Habb-e-Asgandh in multiple myeloma cells (RPMI8226).MethodsMultiple myeloma cells (RPMI8226) were cultured according to the ATCC's instruction. The anti-proliferative effect of HeA was assessed by MTT assay and proliferating cellnuclear antigen (PCNA) activity. Cell cycle analysis, cellular apoptosis, and mitochondria membrane potential analysis was done by flow cytometry. Total antioxidants, migratory potential, angiogenesis and inflammatory biomarkers were also estimated after treatment of RPMI8226 with HeA.Results

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… Steroidal lactones from Withania somnifera, an ancient plant for novel medicine. Molecules. 2009;14:2373–93. doi: 10.3390/molecules14072373. Nishida H, Yamada T. Monoclonal antibody therapies in multiple myeloma: A Challenge to Develop Novel Targets. …