Vorinostat Potentiates 5-Fluorouracil/Cisplatin Combination by Inhibiting Chemotherapy-Induced EGFR Nuclear Translocation and Increasing Cisplatin Uptake
Vorinostat Potentiates 5-Fluorouracil/Cisplatin Combination by Inhibiting Chemotherapy-Induced EGFR Nuclear Translocation and Increasing Cisplatin Uptake
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DOI：
10.1158/1535-7163.mct-18-1117
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发表时间：
2019-08-01
影响因子：
5.7
通讯作者：
Di Gennaro，Elena
中科院分区：
文献类型：
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作者：
Piro，Geny;Roca，Maria Serena;Di Gennaro，Elena
5-氟尿嘧啶/顺铂（5 FU/CDDP）组合是几种实体瘤最广泛使用的治疗选择之一。然而，尽管有良好的抗癌反应，这种方案往往与高毒性和治疗耐药性。在我们的研究中，我们评估了组蛋白去乙酰化酶抑制剂（HDACi）伏立诺他是否可以在鳞状细胞癌细胞模型中与5 FU/CDDP联合诱导协同抗肿瘤和促凋亡作用。我们在癌细胞系（包括固有的CDDP抗性Cal 27细胞）中证明，同时暴露于等毒性剂量的伏立诺他加5 FU/CDDP导致与细胞周期扰动和DNA损伤诱导相关的强协同抗增殖和促凋亡作用。这些作用在Cal 27细胞的原位和异位异种移植小鼠模型中得到了体内证实。从机制上讲，伏立诺他逆转了5 FU/CDDP诱导的EGFR磷酸化和核转位，导致细胞核EGFR对胸苷酸合成酶和细胞周期蛋白D1等基因的非经典诱导受损。伏立诺他至少部分通过增加溶酶体介导的EGFR蛋白降解发挥这些作用。此外，伏立诺他通过转录上调CDDP内流通道铜转运蛋白1（CTR 1）增加铂摄取和铂化DNA水平。总体而言，据我们所知，这项研究首次证明伏立诺他能够抑制CDDP耐药的两种众所周知的机制，EGFR核转位和CTR 1过表达，为HDACi和CDDP化疗之间的协同相互作用机制提供了新的见解，并为临床探索这种组合以克服剂量限制性毒性和化疗耐药性提供了理论基础。
The 5-fluorouracil/cisplatin (5FU/CDDP) combination is one of the most widely used treatment options for several solid tumors. However, despite good anticancer responses, this regimen is often associated with high toxicity and treatment resistance. In our study, we evaluated whether the histone deacetylase inhibitor (HDACi), vorinostat, may induce synergistic antitumor and proapoptotic effects in combination with 5FU/CDDP in squamous cancer cell models. We demonstrated in cancer cell lines, including the intrinsic CDDP-resistant Cal27 cells, that simultaneous exposure to equitoxic doses of vorinostat plus 5FU/CDDP results in strong synergistic antiproliferative and proapoptotic effects related to cell-cycle perturbation and DNA damage induction. These effects were confirmedin vivoin both orthotopic and heterotopic xenograft mouse models of Cal27 cells. Mechanistically, vorinostat reverted 5FU/CDDP-induced EGFR phosphorylation and nuclear translocation, leading to the impairment of nuclear EGFR noncanonical induction of genes such as thymidylate synthase and cyclin D1. These effects were exerted by vorinostat, at least in part, by increasing lysosomal-mediated EGFR protein degradation. Moreover, vorinostat increased platinum uptake and platinated DNA levels by transcriptionally upregulating the CDDP influx channel copper transporter 1 (CTR1). Overall, to our knowledge, this study is the first to demonstrate the ability of vorinostat to inhibit two well-known mechanisms of CDDP resistance, EGFR nuclear translocation and CTR1 overexpression, adding new insight into the mechanism of the synergistic interaction between HDACi- and CDDP-based chemotherapy and providing the rationale to clinically explore this combination to overcome dose-limiting toxicity and chemotherapy resistance.