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.
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).