Paris saponin VII inhibits triple-negative breast cancer by targeting the MEK/ERK/STMN1 signaling axis.

BACKGROUND: Triple-negative breast cancer (TNBC) is a category of breast cancer characterized with high molecular heterogeneity. Owing to the lack of effective therapeutic strategies, patients with TNBC have a poor prognosis. Paris saponin VII (PSⅦ), a steroidal saponin extracted from the rhizome of Trichillium tschonoskii Maxim, exhibits excellent anti-cancer activity in a variety of solid tumors. However, the role and potential mechanism of PSⅦ against TNBC remain unexplored. PURPOSE: This study aimed to elucidate the therapeutic effects of PSⅦ against TNBC and explore the potential mechanism of action. METHODS: We combined the analysis of public single-cell sequencing data with weighted gene co-expression network analysis (WGCNA) to identity differentially expressed genes (DEGs) that distinguished malignant and normal epithelial cells in TNBC. Subsequently, the biological features of DEGs in TNBC were evaluated. Gene set enrichment analysis (GSEA) was used to define potential pathways associated with the DEGs. The pharmacological activity of PSⅦ for TNBC was evidenced via in vitro and in vivo experiments, and molecular docking, molecular dynamics (MD), surface plasmon resonance (SPR) assay and western blotting were employed to confirm the relative mechanisms. RESULTS: Single-cell sequencing and WGCNA revealed STMN1 as a pivotal biomarker of TNBC. STMN1 overexpression in TNBC was associated with poor patient prognosis. GSEA revealed a significant accumulation of STMN1 within the MAPK signaling pathway. Furthermore, In vitro experiments showed that PSⅦ showed significantly suppressive actions on the proliferation, migration and invasion abilities for TNBC cells, while inducing apoptosis. Molecular docking, MD analysis and SPR assay indicated a robust interaction between PSⅦ and the MEK protein. Western blotting revealed that PSⅦ may inhibit tumor progression by suppressing the phosphorylation of MEK1/2 and the downstream phosphorylation of ERK1/2 and STMN1. Intraperitoneal injection of PSⅦ (10 mg/kg) notably reduced tumor growth by 71.26 % in a 4T1 xenograft model. CONCLUSION: In our study, the systems biology method was used to identify potential therapeutic targets for TNBC. In vitro and in vivo experiments demonstrated PSⅦ suppresses cancer progression by targeting the MEK/ERK/STMN1 signaling axis. For the first time, the inhibition of STMN1 phosphorylation has been indicated as a possible mechanism for the anticancer effects of PSⅦ. These results emphasize the potential value of PSⅦ as a promising anti-cancer drug candidate for further development in the field of TNBC therapeutics.

Natural Flavonoid Apigenin, an Effective Agent Against Nervous System Cancers.

Cancer is a serious public health concern worldwide, and nervous system (NS) cancers are among the most life-threatening malignancies. Efforts have been devoted to introduce natural anticancer agents with minimal side effects. Apigenin is an edible flavonoid that is abundantly found in many vegetables and fruits. Various pharmaceutical activities, including anti-inflammatory, antioxidative, antimicrobial, and anticancer effects have been reported for apigenin. This review provides insights into the therapeutic effects of apigenin and flavonoids with similar structure on glioblastoma and neuroblastoma. Current evidence indicates that apigenin has the unique ability to cross the blood-brain barrier, and its antioxidative, anti-inflammatory, neurogenic, and neuroprotective effects have made this flavonoid a great option for the treatment of neurodegenerative disorders. Meanwhile, apigenin has low toxicity on normal neuronal cells, while induces cytotoxicity on NS cancer cells via triggering several signal pathways and molecular targets. Anticancer effects of apigenin have been contributed to various mechanisms such as induction of cell cycle arrest and apoptosis, and inhibition of migration, invasion, and angiogenesis. Although apigenin is a promising pharmaceutical agent, its low bioavailability is an important issue that must be solved before introducing to clinic. Recently, nano-delivery of apigenin by liposomes and poly lactic-co-glycolide nanoparticles has greatly improved functionality of this agent. Hence, investigating pharmaceutical effects of apigenin-loaded nanocarriers on NS cancer cell lines and animal models is recommended for future studies.

Enterolactone and trabectedin suppress epithelial ovarian cancer synergistically via upregulating THBS1.

Epithelial ovarian cancer (EOC) is the most common and fatal subtype of ovarian malignancies, with no effective therapeutics available. Our previous studies have demonstrated extraordinary suppressive efficacy of enterolactone (ENL) on EOC. A chemotherapeutic agent, trabectedin (Trabe), is shown to be effective on ovarian cancer, especially when combined with other therapeutics, such as pegylated liposomal doxorubicin or oxaliplatin. Thrombospondin 1 (THBS1), a kind of matrix glycoprotein, plays important roles against cancer development through inhibiting angiogenesis but whether it is involved in the suppression of EOC by ENL or Trabe remains unknown. To test combined suppressive effects of ENL and Trabe on EOC and possible involvement of THBS1 in the anticancer activities of ENL and Trabe. The EOC cell line ES-2 was transfected with overexpressed THBS1 by lentivirus vector. We employed tube formation assay to evaluate the anti-angiogenesis activity of ENL and of its combined use with Trabe after THBS1 overexpression and established drug intervention and xenograft nude mouse cancer models to assess the in vivo effects of the hypothesized synergistic suppression between the agents and the involvement of THBS1. Mouse fecal samples were collected for 16S rDNA sequencing and microbiota analysis. We detected strong inhibitory activities of ENL and Trabe against the proliferation and migration of cancer cells and observed synergistic effects between ENL and Trabe in suppressing EOC. ENL and Trabe, given either separately or in combination, could suppress the tube formation capability of human microvascular endothelial cells, and this inhibitory effect became even stronger with THBS1 overexpression. In the ENL plus Trabe combination group, the expression of tissue inhibitor of metalloproteinases 3 and cluster of differentiation 36 was both upregulated, whereas matrix metalloproteinase 9, vascular endothelial growth factor, and cluster of differentiation 47 were all decreased. With the overexpression of THBS1, the results became even more pronounced. In animal experiments, combined use of ENL and Trabe showed superior inhibitory effects to either single agent and significantly suppressed tumor growth, and the overexpression of THBS1 further enhanced the anti-cancer activities of the drug combination group. ENL and Trabe synergistically suppress EOC and THBS1 could remarkably facilitate the synergistic anticancer effects of ENL and Trabe.

Natural products modulate cell apoptosis: a promising way for treating endometrial cancer.

Endometrial cancer (EC) is a prevalent epithelial malignancy in the uterine corpus's endometrium and myometrium. Regulating apoptosis of endometrial cancer cells has been a promising approach for treating EC. Recent in-vitro and in-vivo studies show that numerous extracts and monomers from natural products have pro-apoptotic properties in EC. Therefore, we have reviewed the current studies regarding natural products in modulating the apoptosis of EC cells and summarized their potential mechanisms. The potential signaling pathways include the mitochondria-dependent apoptotic pathway, endoplasmic reticulum stress (ERS) mediated apoptotic pathway, the mitogen-activated protein kinase (MAPK) mediated apoptotic pathway, NF-κB-mediated apoptotic pathway, PI3K/AKT/mTOR mediated apoptotic pathway, the p21-mediated apoptotic pathway, and other reported pathways. This review focuses on the importance of natural products in treating EC and provides a foundation for developing natural products-based anti-EC agents.

Essential oil of lemon myrtle (Backhousia citriodora) induces S-phase cell cycle arrest and apoptosis in HepG2 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Lemon myrtle (Backhousia citriodora F.Muell.) leaves, whether fresh or dried, are used traditionally in folk medicine to treat wounds, cancers, skin infections, and other infectious conditions. However, the targets and mechanisms related to anti-cancer effect of lemon myrtle are unavailable. In our study, we found that the essential oil of lemon myrtle (LMEO) showed anti-cancer activity in vitro, and we initially explored its mechanism of action. MATERIALS AND METHODS: We analyzed the chemical compositions of LMEO by GC-MS. We tested the cytotoxicity of LMEO on various cancer cell lines using the MTT assay. Network pharmacology was used also to analyze the targets of LMEO. Moreover, the mechanisms of LMEO were investigated through scratch assay, flow cytometry analysis, and western blot in the HepG2 liver cancer cell line. RESULTS: LMEO showed cytotoxicity on various cancer cell lines with values of IC50 40.90 ± 2.23 (liver cancer HepG2 cell line), 58.60 ± 6.76 (human neuroblastoma SH-SY5Y cell line), 68.91 ± 4.62 (human colon cancer HT-29 cell line) and 57.57 ± 7.61 µg/mL (human non-small cell lung cancer A549 cell line), respectively. The major cytotoxic chemical constituent in LMEO was identified as citrals, which accounted for 74.9% of the content. Network pharmacological analysis suggested that apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1), androgen receptor (AR), cyclin-dependent kinases 1 (CDK1), nuclear factor erythroid 2-related factor 2 (Nrf-2), fatty acid synthase (FASN), epithelial growth factor receptor (EGFR), estrogen receptor 1 (ERα) and cyclin-dependent kinases 4 (CDK4) are potential cytotoxic targets of LMEO. These targets are closely related to cell migration, cycle and apoptosis. Notley, the p53 protein had the highest confidence to co-associate with the eight common targets, which was further confirmed by scratch assay, flow cytometry analysis, and western blot in the HepG2 liver cancer cell line. LMEO significantly inhibited the migration of HepG2 cells in time-dependent and dose-dependent manner. Moreover, LMEO caused a S-phase blocking on HepG2 cells and promoted apoptosis in the meanwhile. Western blot results indicated that p53 protein, Cyclin A2 and Bax proteins were up-regulated, while Cyclin E1 and Bcl-2 proteins were down-regulated. CONCLUSION: LMEO showed cytotoxicity in various cancer cell lines in vitro. Pharmacological networks showed LMEO to have multi-component and multi-targeting effects that are related to inhibit migration of HepG2 cells, and affect cell cycle S-phase arrest and apoptosis through modulation of p53 protein.

7,8-Dihydroxyflavone induces mitochondrial apoptosis and down-regulates the expression of ganglioside GD3 in malignant melanoma cells.

Malignant melanoma is a skin cancer with poor prognosis and high resistance to conventional treatment. 7,8-dihydroxyflavone (7,8-DHF) has shown anti-carcinogenic, anti-inflammatory, anti-oxidant, and pharmacological effects in several types of cancer. However, the relationship between ganglioside expression and the anti-cancer effects of 7,8-DHF in melanoma is not fully understood. In the present study, 7,8-DHF exhibits specific anti-proliferation, anti-migration, and G2/M phase cell-cycle arrest effects on both melanoma cancer cell lines, and induces mitochondrial dysfunction and apoptosis, making it a potent candidate for anti-melanoma treatment. Furthermore, we confirmed that 7,8-DHF significantly reduces the expression levels of ganglioside GD3 and its synthase, which are known to be closely involved in carcinogenesis. Taken together, our findings suggest that 7,8-DHF may be a potent anti-cancer drug candidate for the treatment of malignant melanoma.

Lithium: A Promising Anticancer Agent.

Lithium is a therapeutic cation used to treat bipolar disorders but also has some important features as an anti-cancer agent. In this review, we provide a general overview of lithium, from its transport into cells, to its innovative administration forms, and based on genomic, transcriptomic, and proteomic data. Lithium formulations such as lithium acetoacetate (LiAcAc), lithium chloride (LiCl), lithium citrate (Li3C6H5O7), and lithium carbonate (Li2CO3) induce apoptosis, autophagy, and inhibition of tumor growth and also participate in the regulation of tumor proliferation, tumor invasion, and metastasis and cell cycle arrest. Moreover, lithium is synergistic with standard cancer therapies, enhancing their anti-tumor effects. In addition, lithium has a neuroprotective role in cancer patients, by improving their quality of life. Interestingly, nano-sized lithium enhances its anti-tumor activities and protects vital organs from the damage caused by lipid peroxidation during tumor development. However, these potential therapeutic activities of lithium depend on various factors, such as the nature and aggressiveness of the tumor, the type of lithium salt, and its form of administration and dosage. Since lithium has been used to treat bipolar disorder, the current study provides an overview of its role in medicine and how this has changed. This review also highlights the importance of this repurposed drug, which appears to have therapeutic cancer potential, and underlines its molecular mechanisms.

Therapeutic Use of Bee Venom and Potential Applications in Veterinary Medicine.

Apitherapy is a branch of alternative medicine that consists of the treatment of diseases through products collected, processed, and secreted by bees, specifically pollen, propolis, honey, royal jelly, and bee venom. In traditional medicine, the virtues of honey and propolis have been well-known for centuries. The same, however, cannot be said for venom. The use of bee venom is particularly relevant for many therapeutic aspects. In recent decades, scientific studies have confirmed and enabled us to understand its properties. Bee venom has anti-inflammatory, antioxidant, central nervous system inhibiting, radioprotective, antibacterial, antiviral, and antifungal properties, among others. Numerous studies have often been summarised in reviews of the scientific literature that have focused on the results obtained with mouse models and their subsequent transposition to the human patient. In contrast, few reviews of scientific work on the use of bee venom in veterinary medicine exist. This review aims to take stock of the research achievements in this particular discipline, with a view to a recapitulation and stabilisation in the different research fields.

The Impact of Ellagitannins and Their Metabolites through Gut Microbiome on the Gut Health and Brain Wellness within the Gut-Brain Axis.

Ellagitannins (ETs) are a large group of bioactive compounds found in plant-source foods, such as pomegranates, berries, and nuts. The consumption of ETs has often been associated with positive effects on many pathologies, including cardiovascular diseases, neurodegenerative syndromes, and cancer. Although multiple biological activities (antioxidant, anti-inflammatory, chemopreventive) have been discussed for ETs, their limited bioavailability prevents reaching significant concentrations in systemic circulation. Instead, urolithins, ET gut microbiota-derived metabolites, are better absorbed and could be the bioactive molecules responsible for the antioxidant and anti-inflammatory activities or anti-tumor cell progression. In this review, we examined the dietary sources, metabolism, and bioavailability of ETs, and analyzed the last recent findings on ETs, ellagic acid, and urolithins, their intestinal and brain activities, the potential mechanisms of action, and the connection between the ET microbiota metabolism and the consequences detected on the gut-brain axis. The current in vitro, in vivo, and clinical studies indicate that ET-rich foods, individual gut microbiomes, or urolithin types could modulate signaling pathways and promote beneficial health effects. A better understanding of the role of these metabolites in disease pathogenesis may assist in the prevention or treatment of pathologies targeting the gut-brain axis.

Effects of Cheonggukjang (Fermented Soybean) on the Development of Colitis-Associated Colorectal Cancer in Mice.

Colorectal cancer (CRC) is the third most common type of cancer and is caused by multiple factors. Chronic inflammation, known to cause inflammatory bowel disease (IBD), is closely associated with CRC. Cheonggukjang (CJ), a traditional Korean fermented soybean, is a functional food with anti-inflammatory effects in the intestines, but its anti-cancer effects have not yet been explored. In this study, we investigated the cancer-protective effects of cheonggukjang in an azoxymethane/DSS (AOM/DSS)-induced colitis-associated colorectal cancer (CAC) mouse model. The CJ alleviated AOM/DSS-induced pathological symptoms such as colonic shortening, increased spleen weight, tumor formation, and histological changes. It also modulated pro-inflammatory and anti-inflammatory cytokine levels via the suppression of NF-κB and inflammatory mediator signaling pathways. Furthermore, the CJ improved intestinal integrity by regulating mucin-associated and tight junction proteins. In addition, it suppressed tumor growth by regulating apoptosis and proliferation. These results highlight the anti-tumor effects of CJ in an AOM/DSS-induced CAC mouse model.

Therapeutic Properties of Flavonoids in Treatment of Cancer through Autophagic Modulation: A Systematic Review.

Cancers have high morbidity and mortality rates worldwide. Current anticancer therapies have demonstrated specific signaling pathways as a target in the involvement of carcinogenesis. Autophagy is a quality control system for proteins and plays a fundamental role in cancer carcinogenesis, exerting an anticarcinogenic role in normal cells and can inhibit the transformation of malignant cells. Therefore, drugs aimed at autophagy can function as antitumor agents. Flavonoids are a class of polyphenolic secondary metabolites commonly found in plants and, consequently, consumed in diets. In this review, the systematic search strategy was used, which included the search for descriptors "flavonoids" AND "mTOR pathway" AND "cancer" AND "autophagy", in the electronic databases of PubMed, Cochrane Library, Web of Science and Scopus, from January 2011 to January 2021. The current literature demonstrates that flavonoids have anticarcinogenic properties, including inhibition of cell proliferation, induction of apoptosis, autophagy, necrosis, cell cycle arrest, senescence, impaired cell migration, invasion, tumor angiogenesis and reduced resistance to multiple drugs in tumor cells. We demonstrate the available evidence on the roles of flavonoids and autophagy in cancer progression and inhibition. (Registration No. CRD42021243071 at PROSPERO).

Therapeutic Properties of Flavonoids in Treatment of Cancer through Autophagic Modulation: A Systematic Review / 中国结合医学杂志

Cancers have high morbidity and mortality rates worldwide. Current anticancer therapies have demonstrated specific signaling pathways as a target in the involvement of carcinogenesis. Autophagy is a quality control system for proteins and plays a fundamental role in cancer carcinogenesis, exerting an anticarcinogenic role in normal cells and can inhibit the transformation of malignant cells. Therefore, drugs aimed at autophagy can function as antitumor agents. Flavonoids are a class of polyphenolic secondary metabolites commonly found in plants and, consequently, consumed in diets. In this review, the systematic search strategy was used, which included the search for descriptors "flavonoids" AND "mTOR pathway" AND "cancer" AND "autophagy", in the electronic databases of PubMed, Cochrane Library, Web of Science and Scopus, from January 2011 to January 2021. The current literature demonstrates that flavonoids have anticarcinogenic properties, including inhibition of cell proliferation, induction of apoptosis, autophagy, necrosis, cell cycle arrest, senescence, impaired cell migration, invasion, tumor angiogenesis and reduced resistance to multiple drugs in tumor cells. We demonstrate the available evidence on the roles of flavonoids and autophagy in cancer progression and inhibition. (Registration No. CRD42021243071 at PROSPERO).

Natural Products from Actinobacteria as a Potential Source of New Therapies Against Colorectal Cancer: A Review.

Colorectal cancer (CRC) is a common, and deadly disease. Despite the improved knowledge on CRC heterogeneity and advances in the medical sciences, there is still an urgent need to cope with the challenges and side effects of common treatments for the disease. Natural products (NPs) have always been of interest for the development of new medicines. Actinobacteria are known to be prolific producers of a wide range of bioactive NPs, and scientific evidence highlights their important protective role against CRC. This review is a holistic picture on actinobacter-derived cytotoxic compounds against CRC that provides a good perspective for drug development and design in near future. This review also describes the chemical structure of 232 NPs presenting anti-CRC activity with the being majority of quinones, lactones, alkaloids, peptides, and glycosides. The study reveals that most of these NPs are derived from marine actinobacteria followed by terrestrial and endophytic actinobacteria, respectively. They are predominantly produced by Streptomyces, Micromonospors, Saliniospors and Actinomadura, respectively, in which Streptomyces, as the predominant contributor generating over 76% of compounds exclusively. Besides it provides a valuable snapshot of the chemical structure-activity relationship of compounds, highlighting the presence or absence of some specific atoms and chemical units in the structure of compounds can greatly influence their biological activities. To the best of our knowledge, this is the first comprehensive review on natural actinobacterial compounds affecting different types of CRC. Our study reveals that the high diversity of actinobacterial strains and their NPs derivatives, described here provides a new perspective and direction for the production of new anti-CRC drugs and paves the way to innovation for drugs discovery in the future. The knowledge obtain from this review can help us to understand the pivotal application of actinobacteria in future drugs development.

GB7 acetate, a galbulimima alkaloid from Galbulimima belgraveana, possesses anticancer effects in colorectal cancer cells.

GB7 acetate is a galbulimima alkaloid obtained from Galbulimima belgraveana. However, information regarding its structure, biological activities, and related mechanisms is not entirely available. A series of spectroscopic analyses, structural degradation, interconversion, and crystallography were performed to identify the structure of GB7 acetate. The MTT assay was applied to measure cell proliferation on human colorectal cancer HCT 116 cells. The expressions of the related proteins were measured by Western blotting. Transmission electron microscopy (TEM), acridine orange (AO) and monodansylcadaverine (MDC) staining were used to detect the presence of autophagic vesicles and autolysosomes. A transwell assay was performed to demonstrate metastatic capabilities. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) assays were performed to determine the mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis activity of HCT 116 cells. The data showed that GB7 acetate suppressed the proliferation and colony-forming ability of HCT 116 cells. Pretreatment with GB7 acetate significantly induced the formation of autophagic vesicles and autolysosomes. GB7 acetate upregulated the expressions of LC3 and Thr172 phosphorylated adenosine 5'-monophosphate (AMP)-activated protein kinase α (p-AMPKα), which are key elements of autophagy. In addition, GB7 acetate suppressed the metastatic capabilities of HCT 116 cells. Additionally, the production of matrix metallo-proteinase-2 (MMP-2) and MMP-9 was reduced, whereas the expression of E-cadherin (E-cad) was upregulated. Furthermore, GB7 acetate significantly reduced mitochondrial OXPHOS and glycolysis. In conclusion, the structure of the novel Galbulimima alkaloid GB7 acetate was identified. GB7 acetate was shown to have anti-proliferative, pro-autophagic, anti-metastatic, and anti-metabolite capabilities in HCT 116 cells. This study might provide new insights into cancer treatment efficacy and cancer chemoprevention.

Antitumor Effects of Turmeric on OVCAR-3 Ovarian Cancer Cell Lines.

INTRODUCTION: Ovarian cancer is the deadliest gynecological malignancy, usually not detected until the late stages. In vitro cell culture is a method used to study the behavior of cells in a controlled environment. Turmeric has attracted the attention of scientists due to its anticancer potential. METHODS: OVCAR-3 cells were cultured in RPMI medium with 100 units/mL-100 µg/mL of penicillin-streptomycin and 10% foetal bovine serum in a CO2 incubator. Turmeric extract was diluted in DMSO. Different concentrations of turmeric extract were prepared. Annexin-V staining was performed to test the translocation of phosphatidylserine to the outer side of the cell membrane as a clear indicator of apoptosis. RESULTS: Turmeric extract significantly reduced the viability of OVCAR-3 cells both within 24 and 48 hours of exposure. OVCAR-3 cells were treated with IC50 concentration of turmeric extract for 24 hours. 82.60% of cells were viable. The percentages of the dead, early apoptotic, and late apoptotic cells were detected to be 0.80%, 9.70%, and 6.90%, respectively. Untreated OVCAR-3 cells had migration ability. OVCAR-3 cells exposed to an IC50 concentration of turmeric extract for 24 hours did not close the scratch area. CONCLUSION: In this research, anticancer effects of turmeric have been demonstrated by different analysis methods.

Anti-Cancer Effects of Disulfiram in Cervical Cancer Cell Lines Are Mediated by Both Autophagy and Apoptosis.

Disulfiram (DSF), which is used to treat alcohol dependence, has been reported to have anticancer effects in various malignant tumors. We studied the anti-cancer effects and mechanism of action of DSF on cervical cancer cell lines HeLa and SiHa. The anti-cancer effects of DSF were confirmed in vivo using a xenograft tumor model. The anti-cancer effects of DSF in human head and neck squamous cell carcinoma were found to be copper (Cu)-dependent. The anti-tumor effects of DSF/Cu were time- and dose-dependent and were mediated by both autophagy and apoptosis. DSF/Cu shows stronger cytotoxicity to adenocarcinoma cell lines with higher malignant behavior, and valosin-containing protein (VCP) is its potential target. The cytotoxic effect of DSF/Cu against cervical cancer cell lines in vitro was mediated by apoptosis and autophagy simultaneously. Analysis of the clinical relevance of DSF/Cu on a xenograft animal model showed that DSF markedly stimulated tumor necrosis. DSF may contribute to improved survival of patients with cervical cancer. The antitumor characteristic of DSF can be used in the development of a new drug for advanced and refractory patients with cervical cancer.

Gamma delta (γδ) T cells in cancer immunotherapy; where it comes from, where it will go?

Cancer immunotherapy is a field of interest in the recent treatment approaches against cancer cells, as it could use the assets of the host's immune system against the invading tumor cells. In cancer immunotherapy, for a while, αßT cells play fundamental roles; however, their dependence on major histocompatibility complex (MHC), their ability to only recognize mutated peptides, as well as their low tropism to the tumor sites, especially in solid tumors, have put an obstacle on their way into the clinical settings. Currently, a renewed interest has focused on γδT cells -cells that act as a bridge between the innate and adaptive arm of the immune system- in cancer immunotherapy. γδT cells have been shown to induce anti-tumor effects in cancer cells, but not in normal cells. Their genetic structure also allows easy manipulation for therapeutic interventions. γδT cells could recognize a wide range of antigens, such as lipids, phospho-antigens, and peptides, in MHC-dependent and -independent manner; suggesting that these cells could also exert anti-tumor effects against tumors with low mutational burdens and downregulated MHC. Although seems promising, it should not be forgotten that the application of γδT cells in cancer research is relatively at its infancy and many challenges and hurdles are yet to be identified. In the present review, we discuss the advantages as well as the challenges of γδT cells-based immunotherapies in human cancer and propose how new technologies could solve these limitations.

Anti-Cancer Effects of Epigenetics Drugs Scriptaid and Zebularine in Human Breast Adenocarcinoma Cells.

BACKGROUND: High relapse and metastasis progression in breast cancer patients have prompted the need to explore alternative treatments. Epigenetic therapy has emerged as an attractive therapeutic strategy due to the reversibility of epigenome structures. OBJECTIVE: This study investigated the anti-cancer effects of epigenetic drugs scriptaid and zebularine in human breast adenocarcinoma MDA-MB-231 and MCF-7 cells. METHODS: First, the half maximal Inhibitory Concentration (IC50) of scriptaid and zebularine, and the combination of both drugs on human breast adenocarcinoma MDA-MB-231 cells were determined. Next, MDA-MB-231 and MCF-7 cells were treated with IC50 of scriptaid, zebularine and the combination of both. After IC50 treatments, the anti-cancer effects were evaluated via cell migration assay, cell cycle analysis and apoptotic studies which included histochemical staining and reverse-transcriptase polymerase chain reaction (RT-PCR) of the apoptotic genes. RESULTS: Both epigenetic drugs inhibited cell viability in a dose-dependent manner with IC50 of 2 nM scriptaid, 8 µM zebularine and a combination of 2 nM scriptaid and 2 µM zebularine. Both MDA-MB-231 and MCF-7 cells exhibited a reduction in cell migration after the treatments. In particular, MDA-MB-231 cells exhibited a significant reduction in cell migration (p < 0.05) after the treatments of zebularine and the combination of scriptaid and zebularine. Besides, cell cycle analysis demonstrated that scriptaid and the combination of both drugs could induce cell cycle arrest at the G0/G1 phase in both MDA-MB-231 and MCF-7 cells. Furthermore, histochemical staining allowed the observation of apoptotic features, such as nuclear chromatin condensation, cell shrinkage, membrane blebbing, nuclear chromatin fragmentation and cytoplasmic extension, in both MDA-MB-231 and MCF-7 cells after the treatments. Further, apoptotic studies revealed the upregulation of pro-apoptotic Bax, downregulation of anti-apoptotic Bcl-2 and elevation of Bax/Bcl-2 ratio in MDA-MB-231 cells treated with zebularine and MCF-7 cells treated with all drug regimens. CONCLUSION: Collectively, these findings suggest that scriptaid and zebularine are potential anti-cancer drugs, either single or in combination, for the therapy of breast cancer. Further investigations of the gene regulatory pathways directed by scriptaid and zebularine are definitely warranted in the future.

GB7 acetate,a galbulimima alkaloid from Galbulimima belgraveana,possesses anticancer effects in colorectal cancer cells / 药物分析学报

GB7 acetate is a galbulimima alkaloid obtained from Galbulimima belgraveana.However,information regarding its structure,biological activities,and related mechanisms is not entirely available.A series of spectroscopic analyses,structural degradation,interconversion,and crystallography were performed to identify the structure of GB7 acetate.The MTT assay was applied to measure cell proliferation on human colorectal cancer HCT 116 cells.The expressions of the related proteins were measured by Western blotting.Transmission electron microscopy(TEM),acridine orange(AO)and monodansylcadaverine(MDC)staining were used to detect the presence of autophagic vesicles and autolysosomes.A transwell assay was performed to demonstrate metastatic capabilities.Oxygen consumption rate(OCR)and extracellular acidification rate(ECAR)assays were performed to determine the mitochondrial oxidative phosphorylation(OXPHOS)and glycolysis activity of HCT 116 cells.The data showed that GB7 acetate suppressed the proliferation and colony-forming ability of HCT 116 cells.Pretreatment with GB7 acetate significantly induced the formation of autophagic vesicles and autolysosomes.GB7 acetate upregulated the expressions of LC3 and Thr172 phosphorylated adenosine 5'-monophosphate(AMP)-activated pro-tein kinase α(p-AMPKα),which are key elements of autophagy.In addition,GB7 acetate suppressed the metastatic capabilities of HCT 116 cells.Additionally,the production of matrix metallo-proteinase-2(MMP-2)and MMP-9 was reduced,whereas the expression of E-cadherin(E-cad)was upregulated.Furthermore,GB7 acetate significantly reduced mitochondrial OXPHOS and glycolysis.In conclusion,the structure of the novel Galbulimima alkaloid GB7 acetate was identified.GB7 acetate was shown to have anti-proliferative,pro-autophagic,anti-metastatic,and anti-metabolite capabilities in HCT 116 cells.This study might provide new insights into cancer treatment efficacy and cancer chemoprevention.

Intravenous Administration of Dehydroxymethylepoxyquinomicin With Polymer Enhances the Inhibition of Pancreatic Carcinoma Growth in Mice.

BACKGROUND/AIM: Pancreatic cancer, which exhibits resistance to cytotoxic and molecular targeted drugs, has an extremely poor prognosis. Nuclear factor-κB (NF-κB) is constitutively activated in many pancreatic cancer cases. Although the NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) has exhibited anti-cancer effects in pancreatic cancer models, its poor solubility limits its use to intraperitoneal administration. MATERIALS AND METHODS: Poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) (PMB) forms stable polymer aggregates with DHMEQ. The stability of DHMEQ aggregated with PMB in the human blood was measured by high-performance liquid chromatography-mass spectrometry (HPLC-MS) ex vivo. Anti-pancreatic cancer effects in AsPC-1 and MIA PaCa-2 pancreatic cancer cells were evaluated by cell growth inhibition assay in vitro and tumor growth inhibition assay in vivo. RESULTS: DHMEQ aggregated with PMB (PMB-DHMEQ) remained detectable after 60 min of incubation in the human blood, whereas DHMEQ aggregated with carboxymethyl cellulose (CMC-DHMEQ) was barely detectable. PMB-DHMEQ significantly inhibited AsPC-1 and MIA PaCa-2 cell growth in vitro compared to CMC-DHMEQ. Intravenous administration of PMB-DHMEQ reduced the tumor volume and liver metastasis compared to untreated or CMC-DHMEQ-treated mice. CONCLUSION: Aggregation with PMB improved the solubility of DHMEQ, and effectively inhibited pancreatic cancer cell growth both in vitro and in vivo.