Sujan K Mondal, Chang-Sook Hong, Jie Han, Brenda Diergaarde, Dan P Zandberg, Theresa L Whiteside
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引用次数: 0
Abstract
Tumor cells produce/release tumor-derived exosomes (TEX) which promote tumor growth, drive immune suppression, and interfere with immune therapies. Amlodipine, a calcium flux inhibitor may block TEX release by tumor cells. Amlodipine's potential as a drug blocking TEX release was evaluated. We measured tumor growth, TEX numbers, phenotype, and molecular content in murine SCCVII and human cancer cell lines. Cell lysates and TEX were tested for expression of autophagy-related proteins by Western blots (WBs). Tumor growth in mice, histopathology, T-cell infiltrations, and TEX production by SCCVII treated with amlodipine were measured. Numbers and protein content of TEX eluted from tumor explants were studied by flow cytometry and WBs. Amlodipine used in vitro at 0.5-5µM was nontoxic, did not impair tumor cell viability, reduced cell proliferation and decreased TEX production. It reduced PD-L1 and Rab11 content of TEX, altered tumor cell size/shape, induced vesicle accumulations in the cytosol and up-regulated expression levels of autophagy-related proteins, ATG7, Beclin-1 and LC3. In vivo, daily treatment of established SCCVII with amlodipine (10mg/kg) inhibited tumor growth (P<0.001), increased CD8+T cell infiltration into tumor, decreased TEX production and altered PD-L1, Rab11 and FasL content of TEX. Amlodipine delivered in vitro to tumor cells or in vivo to tumor-bearing mice interferes with tumor growth and TEX production, induces tumor autophagy, reduces circulating TEX numbers, and alters the TEX immunosuppressive signature. Amlodipine emerges as a potentially promising drug for removing immunosuppressive TEX in cancer subjects who are candidates for immune therapies.
肿瘤细胞产生/释放肿瘤源性外泌体(TEX),其促进肿瘤生长,驱动免疫抑制,并干扰免疫治疗。氨氯地平是一种钙通量抑制剂,可阻断肿瘤细胞释放TEX。评价氨氯地平作为阻断特克斯释放药物的潜力。我们测量了小鼠SCCVII和人类癌细胞系的肿瘤生长、TEX数量、表型和分子含量。Western blots (WBs)检测细胞裂解液和TEX中自噬相关蛋白的表达。测量小鼠肿瘤生长、组织病理学、t细胞浸润和氨氯地平处理SCCVII产生的TEX。用流式细胞术和WBs研究了肿瘤外植体中TEX的数量和蛋白含量。氨氯地平在体外0.5-5µM浓度下无毒,不损害肿瘤细胞活力,降低细胞增殖,减少TEX的产生。它降低了TEX的PD-L1和Rab11含量,改变了肿瘤细胞的大小/形状,诱导细胞质中囊泡积聚,上调自噬相关蛋白ATG7、Beclin-1和LC3的表达水平。在体内,每天用氨氯地平(10mg/kg)治疗已建立的SCCVII可抑制肿瘤生长(P
期刊介绍:
Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).