Kidoikhammouan Sonexai, Seubwai Wunchana, Silsirivanit Atit, Wongkham Sopit, Sawanyawisuth Kanlayanee, Wongkham Chaisiri
Department of Biochemistry, Faculty of Medicine, Khon Kaen University; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand.
Cholangiocarcinoma Research Institute, Khon Kaen University; Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
J Cancer Res Ther. 2019 Jan-Mar;15(1):148-152. doi: 10.4103/jcrt.JCRT_250_17.
Resistance of cancer cells to chemotherapeutic drugs is a major pitfall of the failure of chemotherapy treatment for cholangiocarcinoma (CCA). A new therapeutic strategy that can improve treatment efficacy is mandatory for CCA patients. Our previous findings demonstrated the overexpression of methionine aminopeptidase-2 (MetAP2) in CCA patients. In addition, supplementation of TNP-470, a MetAP2 inhibitor, significantly inhibited the growth and metastatic activities of CCA cell lines. However, the molecular mechanism of antitumor activity of TNP-470 and the synergistic antitumor activity of TNP-470 combined with chemotherapeutic drugs are still unknown.
The aim of this study is to evaluate the molecular mechanism of anticancer activity and the potential use of TNP-470 as a chemosensitizing agent in CCA cell lines.
Cell cycle and apoptosis of CCA cell lines were evaluated using flow cytometry with propidium iodide staining. Expression of apoptosis regulatory proteins was measured by Western blotting. The chemosensitizing effect of TNP-470 was determined using combination index.
TNP-470 inhibited the growth of CCA cells via induction of apoptosis through activation of the p38-phosphorylation and up- and down-regulation of Bax and Bcl-xL, respectively. Furthermore, TNP-470 significantly enhanced the antitumor activity of 5-fluorouracil, cisplatin, doxorubicin, and gemcitabine.
The present results show that TNP-470 could be a potential therapeutic or adjuvant agent for CCA.
癌细胞对化疗药物的耐药性是胆管癌（CCA）化疗失败的主要障碍。对于CCA患者而言，一种能够提高治疗效果的新治疗策略是必不可少的。我们之前的研究结果表明，CCA患者体内甲硫氨酸氨肽酶-2（MetAP2）过表达。此外，补充MetAP2抑制剂TNP-470可显著抑制CCA细胞系的生长和转移活性。然而，TNP-470的抗肿瘤活性分子机制以及TNP-470与化疗药物联合使用的协同抗肿瘤活性仍不清楚。
本研究旨在评估TNP-470在CCA细胞系中的抗癌活性分子机制及其作为化学增敏剂的潜在用途。
采用碘化丙啶染色的流式细胞术评估CCA细胞系的细胞周期和凋亡情况。通过蛋白质免疫印迹法检测凋亡调节蛋白的表达。使用联合指数测定TNP-470的化学增敏作用。
TNP-470通过激活p38磷酸化诱导凋亡，分别上调和下调Bax和Bcl-xL，从而抑制CCA细胞的生长。此外，TNP-470显著增强了5-氟尿嘧啶、顺铂、阿霉素和吉西他滨的抗肿瘤活性。
目前的结果表明，TNP-470可能是CCA的一种潜在治疗药物或辅助药物。
