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Therapeutic Potential of Thymoquinone in Triple-Negative Breast Cancer Prevention and Progression through the Modulation of the Tumor Microenvironment.
Adinew, GM, Taka, E, Mochona, B, Badisa, RB, Mazzio, EA, Elhag, R, Soliman, KFA
Nutrients. 2021;(1)
Abstract
To date, the tumor microenvironment (TME) has gained considerable attention in various areas of cancer research due to its role in driving a loss of immune surveillance and enabling rapid advanced tumor development and progression. The TME plays an integral role in driving advanced aggressive breast cancers, including triple-negative breast cancer (TNBC), a pivotal mediator for tumor cells to communicate with the surrounding cells via lymphatic and circulatory systems. Furthermore, the TME plays a significant role in all steps and stages of carcinogenesis by promoting and stimulating uncontrolled cell proliferation and protecting tumor cells from the immune system. Various cellular components of the TME work together to drive cancer processes, some of which include tumor-associated adipocytes, fibroblasts, macrophages, and neutrophils which sustain perpetual amplification and release of pro-inflammatory molecules such as cytokines. Thymoquinone (TQ), a natural chemical component from black cumin seed, is widely used traditionally and now in clinical trials for the treatment/prevention of multiple types of cancer, showing a potential to mitigate components of TME at various stages by various pathways. In this review, we focus on the role of TME in TNBC cancer progression and the effect of TQ on the TME, emphasizing their anticipated role in the prevention and treatment of TNBC. It was concluded from this review that the multiple components of the TME serve as a critical part of TNBC tumor promotion and stimulation of uncontrolled cell proliferation. Meanwhile, TQ could be a crucial compound in the prevention and progression of TNBC therapy through the modulation of the TME.
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Clarifying the molecular mechanism of tomentosin‑induced antiproliferative and proapoptotic effects in human multiple myeloma via gene expression profile and genetic interaction network analysis.
Virdis, P, Migheli, R, Bordoni, V, Fiorentino, FP, Sanna, L, Marchesi, I, Pintore, G, Galleri, G, Muroni, MR, Bagella, L, et al
International journal of molecular medicine. 2021;(6)
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Abstract
Multiple myeloma (MM) is an aggressive B cell malignancy. Substantial progress has been made in the therapeutic context for patients with MM, however it still represents an incurable disease due to drug resistance and recurrence. Development of more effective or synergistic therapeutic approaches undoubtedly represents an unmet clinical need. Tomentosin is a bioactive natural sesquiterpene lactone extracted by various plants with therapeutic properties, including anti‑neoplastic effects. In the present study, the potential antitumor activity of tomentosin was evaluated on the human RPMI‑8226 cell line, treated with increasing tomentosin concentration for cytotoxicity screening. The data suggested that both cell cycle arrest and cell apoptosis could explain the antiproliferative effects of tomentosin and may result in the inhibition of RPMI‑8226 cell viability. To assess differentially expressed genes contributing to tomentosin activity and identify its mechanism of action, a microarray gene expression profile was performed, identifying 126 genes deregulated by tomentosin. To address the systems biology and identify how tomentosin deregulates gene expression in MM from a systems perspective, all deregulated genes were submitted to enrichment and molecular network analysis. The Protein‑Protein Interaction (PPI) network analysis showed that tomentosin in human MM induced the downregulation of genes involved in several pathways known to lead immune‑system processes, such as cytokine‑cytokine receptor interaction, chemokine or NF‑κB signaling pathway, as well as genes involved in pathways playing a central role in cellular neoplastic processes, such as growth, proliferation, migration, invasion and apoptosis. Tomentosin also induced endoplasmic reticulum stress via upregulation of cyclic AMP‑dependent transcription factor ATF‑4 and DNA damage‑inducible transcript 3 protein genes, suggesting that in the presence of tomentosin the protective unfolded protein response signaling may induce cell apoptosis. The functional connections analysis executed using the Connectivity Map tool, suggested that the effects of tomentosin on RPMI‑8226 cells might be similar to those exerted by heat shock proteins inhibitors. Taken together, these data suggested that tomentosin may be a potential drug candidate for the treatment of MM.
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In silico identification of natural products from Traditional Chinese Medicine for cancer immunotherapy.
Cai, C, Wu, Q, Hong, H, He, L, Liu, Z, Gu, Y, Zhang, S, Wang, Q, Fan, X, Fang, J
Scientific reports. 2021;(1):3332
Abstract
Advances in immunotherapy have revolutionized treatments in many types of cancer. Traditional Chinese Medicine (TCM), which has a long history of clinical adjuvant application against cancer, is emerging as an important medical resource for developing innovative cancer treatments, including immunotherapy. In this study, we developed a quantitative and systems pharmacology-based framework to identify TCM-derived natural products for cancer immunotherapy. Specifically, we integrated 381 cancer immune response-related genes and a compound-target interaction network connecting 3273 proteins and 766 natural products from 66 cancer-related herbs based on literature-mining. Via systems pharmacology-based prediction, we uncovered 182 TCM-derived natural products having potential anti-tumor immune responses effect. Importantly, 32 of the 49 most promising natural products (success rate = 65.31%) are validated by multiple evidence, including published experimental data from clinical studies, in vitro and in vivo assays. We further identified the mechanism-of-action of TCM in cancer immunotherapy using network-based functional enrichment analysis. We showcased that three typical natural products (baicalin, wogonin, and oroxylin A) in Huangqin (Scutellaria baicalensis Georgi) potentially overcome resistance of known oncology agents by regulating tumor immunosuppressive microenvironments. In summary, this study offers a novel and effective systems pharmacology infrastructure for potential cancer immunotherapeutic development by exploiting the medical wealth of natural products in TCM.
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Curcumin and Photobiomodulation in Chronic Viral Hepatitis and Hepatocellular Carcinoma.
Ailioaie, LM, Litscher, G
International journal of molecular sciences. 2020;(19)
Abstract
Immune modulation is a very modern medical field for targeting viral infections. In the race to develop the best immune modulator against viruses, curcumin, as a natural product, is inexpensive, without side effects, and can stimulate very well certain areas of the human immune system. As a bright yellow component of turmeric spice, curcumin has been the subject of thousands of scientific and clinical studies in recent decades to prove its powerful antioxidant properties and anticancer effects. Curcumin has been shown to influence inter- and intracellular signaling pathways, with direct effects on gene expression of the antioxidant proteins and those that regulate the immunity. Experimental studies have shown that curcumin modulates several enzyme systems, reduces nitrosative stress, increases the antioxidant capacity, and decreases the lipid peroxidation, protecting against fatty liver pathogenesis and fibrotic changes. Hepatitis B virus (HBV) affects millions of people worldwide, having sometimes a dramatic evolution to chronic aggressive infection, cirrhosis, and hepatocellular carcinoma. All up-to-date treatments are limited, there is still a gap in the scientific knowledge, and a sterilization cure may not yet be possible with the removal of both covalently closed circular DNA (cccDNA) and the embedded HBV DNA. With a maximum light absorption at 420 nm, the cytotoxicity of curcumin as photosensitizer could be expanded by the intravenous blue laser blood irradiation (IVBLBI) or photobiomodulation in patients with chronic hepatitis B infection, Hepatitis B e-antigen (HBeAg)-positive, noncirrhotic, but nonresponsive to classical therapy. Photobiomodulation increases DNA repair by the biosynthesis of complex molecules with antioxidant properties, the outset of repairing enzyme systems and new phospholipids for regenerating the cell membranes. UltraBioavailable Curcumin and blue laser photobiomodulation could suppress the virus and control better the disease by reducing inflammation/fibrosis and stopping the progression of chronic hepatitis, reversing fibrosis, and diminishing the progression of cirrhosis, and decreasing the incidence of hepatocellular carcinoma. Photodynamic therapy with blue light and curcumin opens new avenues for the effective prevention and cure of chronic liver infections and hepatocellular carcinoma. Blue laser light and UltraBioavailable Curcumin could be a new valuable alternative for medical applications in chronic B viral hepatitis and hepatocarcinoma, saving millions of lives.
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As-Needed Vs Immediate Etoposide Chemotherapy in Combination With Antiretroviral Therapy for Mild-to-Moderate AIDS-Associated Kaposi Sarcoma in Resource-Limited Settings: A5264/AMC-067 Randomized Clinical Trial.
Hosseinipour, MC, Kang, M, Krown, SE, Bukuru, A, Umbleja, T, Martin, JN, Orem, J, Godfrey, C, Hoagland, B, Mwelase, N, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2018;(2):251-260
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Abstract
BACKGROUND Mild-to-moderate AIDS-associated Kaposi sarcoma (KS) often responds to antiretroviral therapy (ART) alone; the role of chemotherapy is unclear. We assessed the impact of immediate vs as-needed oral etoposide (ET) among human immunodeficiency virus (HIV)-infected individuals with mild-to-moderate KS initiating ART. METHODS Chemotherapy-naive, HIV type 1-infected adults with mild-to-moderate KS initiating ART in Africa and South America were randomized to ART (tenofovir/emtricitabine/efavirenz) alone (chemotherapy "as-needed" arm) vs ART plus up to 8 cycles of oral ET (immediate arm). Participants with KS progression on ART alone received ET as part of the as-needed strategy. Primary outcome was ordinal as follows: failure, stable, and response at 48 weeks. Secondary outcomes included time to initial KS progression, KS-associated immune reconstitution inflammatory syndrome (KS-IRIS), and KS response. RESULTS Of 190 randomized participants (as-needed = 94, immediate = 96), the majority were men (71%) and African (93%). Failure (53.8% vs 56.6%), stable (16.3% vs 10.8%), and response (30% vs 32.5%) did not differ between arms (as-needed vs immediate) among those with week 48 data potential (N = 163, P = .91). Time to KS progression (P = .021), KS-IRIS (P = .003), and KS response (P = .003) favored the immediate arm. Twenty-five participants died (13%). Mortality, adverse events, CD4+ T-cell changes, and HIV RNA suppression were similar at 48 weeks. CONCLUSIONS Among HIV-infected adults with mild-to-moderate KS, immediate ET provided early, nondurable clinical benefits. By 48 weeks, no clinical benefit was observed compared to use of ET as needed. Mortality was high and tumor response was low. CLINICAL TRIALS REGISTRATION NCT01352117.
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[Immunostimulatory properties of mistletoe extracts and their application in oncology].
Wrotek, S, Skawiński, R, Kozak, W
Postepy higieny i medycyny doswiadczalnej (Online). 2014;:1216-24
Abstract
For a long time cancer immunotherapy was overshadowed by chemotherapy and radiotherapy. Recently, "Science", one of the world's top scientific journals, named the stimulation of the body's own immune system to fight cancer cells as the "breakthrough of the year". In Germany, Switzerland and Austria, extracts derived from mistletoe (Viscum album L.) such as Iscador, Abnobaviscum, Helixor, Iscar, Iscucin and Isorel have been used in oncology for many years. These extracts have immunomodulating and immunostimulating properties, as demonstrated by experimental studies as well as in clinical trials. The aim of our paper is to present immunological disorders associated with cancer, which can be counteracted by treatment with extracts derived from mistletoe. Although these drugs cannot replace conventional cancer treatment, they may improve the patient's quality and length of life.
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Inhibition of the ubiquitin-proteasome system by natural products for cancer therapy.
Tsukamoto, S, Yokosawa, H
Planta medica. 2010;(11):1064-74
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Abstract
The ubiquitin-proteasome system plays a critical role in selective protein degradation and regulates almost all cellular events such as cell cycle progression, signal transduction, cell death, immune responses, metabolism, protein quality control, development, and neuronal function. The recent approval of bortezomib, a synthetic proteasome inhibitor, for the treatment of relapsed multiple myeloma has opened the way to the discovery of drugs targeting the proteasome and ubiquitinating and deubiquitinating enzymes as well as the delivery system. To date, various synthetic and natural products have been reported to inhibit the components of the ubiquitin-proteasome system. Here, we review natural products targeting the ubiquitin-proteasome system as well as synthetic compounds with potent inhibitory effects.
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Combined treatment with denbinobin and Fas ligand has a synergistic cytotoxic effect in human pancreatic adenocarcinoma BxPC-3 cells.
Yang, CR, Guh, JH, Teng, CM, Chen, CC, Chen, PH
British journal of pharmacology. 2009;(7):1175-85
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Abstract
BACKGROUND AND PURPOSE Human pancreatic carcinoma is a highly malignant cancer. Previous studies have shown that the decoy receptor 3 (DcR3) for Fas ligand (FasL) plays significant roles in tumour progression and immune suppression. In the present study, we evaluated the anti-cancer activity of a natural compound, denbinobin (5-hydroxy-3,7-dimethoxy-1,4-phenanthraquinone), through decreasing DcR3 levels in human pancreatic adenocarcinoma cell lines. EXPERIMENTAL APPROACH We used immunoprecipitation and ELISA assays to examine DcR3 levels, and used FACS to determine the percentage of cells with a sub-G1 DNA content. KEY RESULTS AsPC-1 and BxPC-3 human pancreatic cancer cells express high levels of DcR3. Denbinobin concentration-dependently decreased DcR3 levels in BxPC-3 cells. MTT and flow cytometry assays indicated that BxPC-3 was FasL-resistant because high concentrations (100 ng.mL(-1)) of soluble FasL did not inhibit cell growth. However, combinations of denbinobin (3 micromol.L(-1)) with lower concentrations of soluble FasL (10, 30 and 50 ng.mL(-1)) or membrane-bound FasL, were synergistic on cell growth inhibition and apoptosis. Exogenous excess DcR3 reversed this synergistic effect. We observed no significant increase in the levels of surface Fas, cleaved forms of caspase-8, -3, -9, Bax, Bid, Bcl-xL, cytochrome c or mitochondrial membrane potentials following denbinobin treatment. However, denbinobin treatment increased the levels of apoptosis-inducing factor. CONCLUSIONS AND IMPLICATIONS Denbinobin and FasL trigger a synergistic cytotoxic effect in human pancreatic adenocarcinoma cells. Denbinobin mediated a decrease in levels of DcR3, which played a major role in this synergistic effect, and also increased caspase-independent apoptosis, via apoptosis-inducing factor.
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How to design a phase I trial of an anticancer botanical.
Vickers, AJ
Journal of the Society for Integrative Oncology. 2006;(1):46-51
Abstract
Phase I trials are an important part of traditional drug development in oncology. Such trials address two key issues: safety and dose. Currently, there is a dearth of phase I trials of anticancer botanicals. This may result from the apparently widespread view that a history of human use precludes the need for early-phase study. However, the safe use of a botanical by the population at large does not guarantee safety when the botanical is used in combination with other agents in the complex medical setting of oncology. Several cases of unpredictable adverse events have been recorded following the use of botanicals by cancer patients. We propose a simple, robust design for phase I trials of anticancer botanicals. This design incorporates important characteristics of botanical medicines including low toxicity, prior data on a likely safe dose, a limit on the highest dose it is feasible to administer, and the unknown relationship between dose-toxicity and dose-response curves. Two principal design features are the use of predetermined dose levels and the direct measurement of a response endpoint such as survival or immunity. This response end point can be used to determine the optimal dose if toxicity is acceptable at all dose levels. Increasing the use of phase I methodology would ensure a more systematic development of botanicals as anticancer agents. This would likely increase the chance that at least one such agent would be proven to extend lives.