ABSTRACT
Probiotic roles of Clostridium butyricum (C.B) are involved in regulating disease and cancers, yet the mechanistic basis for these regulatory roles remains largely unknown. Here, we demonstrate that C.B reprograms the proliferation, migration, stemness, and tumor growth in CRC by regulating pivotal signal molecules including MYC. Destabilization of MYC by C.B supplementation suppresses cancer cell proliferation/metastasis, sensitizes 5-FU treatment, and boosts responsiveness of anti-PD1 therapy. MYC is a transcriptional regulator of Thymidylate synthase (TYMS), a key target of the 5-FU. Also MYC is known to impact on PD-1 expression. Mechanistically, C.B treatment of CRC cells results in MYC degradation by enhancing proteasome-mediated ubiquitination, thereby mitigating MYC-mediated 5-FU resistance and boosting anti-PD1 immunotherapeutic efficacy. Together, our findings uncover previously unappreciated links between C.B and CRC cell signaling, providing insight into the tumorigenesis modulating mechanisms of C.B in boosting chemo/immune therapies.
Subject(s)
Clostridium butyricum , Colorectal Neoplasms , Gastrointestinal Microbiome , Humans , Colorectal Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation , Fluorouracil/pharmacology , Fluorouracil/therapeutic useABSTRACT
This study evaluated the antitumor activity of the extracts of green husks of Juglans sigillata Dode on esophageal cancer. KYSE150 EC9706 cells were treated with different concentrations of six components of the extracts of J. sigillata green husks. Cell viability was measured by MTT. Cell migration and cell invasion were measured by wound-healing assays and transwell assays, respectively. Cell apoptosis and cycle were measured by flow cytometry. The expression of cell migration, cell cycle and cell apoptosis regulatory proteins was analyzed by Western blotting. Only the three constituents, including EtOH extractives, EtOAc soluble fraction and gallic acid (GA), exhibited inhibitory effects on the cell viability, migration and invasion by decreasing MMP2 and MMP9 expression (all P < 0.05). Flow cytometry revealed that these three constituents also induced cell apoptosis by increasing Bax and cleaved caspase-3 but decreasing Bcl-2 in KYSE150 and EC9706 cells. Furthermore, these constituents arrested the cell cycle at G0/G1 by downregulating the expression of Cyclin D1 but upregulating p53 and phospho-p53 expression in KYSE150 cells. In conclusion, the green husks of J. sigillata may act as a potential inhibitor on esophageal cancer growth. GA was the major single active constituent of the extracts.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Esophageal Neoplasms/drug therapy , Juglans , Plant Extracts/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Esophageal Neoplasms/pathology , Gallic Acid/pharmacology , HumansABSTRACT
Metformin is derived from galegine, a natural ingredient, and recent studies have suggested that metformin could enhance the antitumor effects of hormone ablative therapy or chemotherapy and reduce prostate cancer-specific mortality. Zyflamend is a combination of herbal extracts that reduces inflammation and comprises turmeric, holy basil, green tea, oregano, ginger, rosemary, Chinese goldthread, hu zhang, barberry, and basil skullcap. We propose a maintenance regimen with metformin and/or Zyflamend that targets cancer stem cells and the tumor microenvironment to keep the cancer dormant and prevent it from activation from dormancy. Herein, we report the clinical course of four patients who experienced a clinical response after treatment with metformin and/or Zyflamend.