Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib in vitro by altering cell bioenergetics
Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib in vitro by altering cell bioenergetics
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DOI：
10.20892/j.issn.2095-3941.2018.0375
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发表时间：
2019-05-01
影响因子：
5.5
通讯作者：
Radulovic, Sinisa
中科院分区：
文献类型：
--
作者：
Grahovac, Jelena;Srdic-Rajic, Tatjana;Radulovic, Sinisa
目的：尽管最近在靶向治疗和免疫治疗方面取得了进展，但转移性黑色素瘤患者的预后仍然非常差。对先前有效治疗的耐药性的发展提出了严重的挑战，迫切需要新的黑色素瘤治疗方法。本研究的目的是研究替米沙坦，AGTR 1抑制剂和部分激动剂的过氧化物酶体增殖物激活物受体γ，对黑色素瘤细胞作为一个潜在的代理人在黑色素瘤treatment.Methods：黑色素瘤患者肿瘤样本中的AGTR 1和过氧化物酶体增殖物激活物受体γ mRNA的表达进行了检查，在公开的数据集，并确认在黑色素瘤细胞系通过qRT-PCR。在存在替米沙坦的情况下，通过流式细胞术和免疫细胞化学，对一组黑色素瘤细胞系进行了活力、凋亡和代谢试验。替米沙坦和靶向治疗vemurafenib的组合的细胞毒性作用进行了检查使用Chou-Talalay组合指数methods.Results：AGTR 1和PPAR γ mRNA在黑色素瘤患者的肿瘤样品中表达，并降低相比，在健康皮肤中的表达。在体外，我们发现替米沙坦通过诱导细胞凋亡降低黑色素瘤细胞的活力。在存在替米沙坦的情况下，葡萄糖摄取增加，但利用率未增加，导致线粒体分裂和活性氧释放。替米沙坦改变了细胞的生物能量学，从而协同vemurafenib在体外，甚至敏感的vemurafenib耐药细胞的treatment.Conclusions：鉴于在我们的研究中检查的有效剂量的替米沙坦可以给患者和替米沙坦是一种广泛使用的和安全的抗高血压药物，我们的研究结果提供了科学的理由来测试其疗效在治疗黑色素瘤进展。
Objective: Despite recent advancements in targeted therapy and immunotherapies, prognosis for metastatic melanoma patients remains extremely poor. Development of resistance to previously effective treatments presents a serious challenge and new approaches for melanoma treatment are urgently needed. The objective of this study was to examine the effects of telmisartan, an AGTR1 inhibitor and a partial agonist of PPAR gamma, on melanoma cells as a potential agent for repurposing in melanoma treatment.Methods: Expression of AGTR1 and PPAR gamma mRNA in melanoma patient tumor samples was examined in publicly available datasets and confirmed in melanoma cell lines by qRT-PCR. A panel of melanoma cell lines was tested in viability, apoptosis and metabolic assays in presence of telmisartan by flow cytometry and immunocytochemistry. A cytotoxic effect of combinations of telmisartan and targeted therapy vemurafenib was examined using the Chou-Talalay combination index method.Results: Both AGTR1 and PPAR gamma mRNA were expressed in melanoma patient tumor samples and decreased compared to the expression in the healthy skin. In vitro, we found that telmisartan decreased melanoma cell viability by inducing cell apoptosis. Increased glucose uptake, but not utilization, in the presence of telmisartan caused the fission of mitochondria and release of reactive oxygen species. Telmisartan altered the cell bioenergetics, thereby synergizing with vemurafenib in vitro, and even sensitized vemurafenib-resistant cells to the treatment.Conclusions: Given that the effective doses of telmisartan examined in our study can be administered to patients and that telmisartan is a widely used and safe antihypertensive drug, our findings provide the scientific rationale for testing its efficacy in treatment of melanoma progression.