Wang Cong, Guo Liubin, Wang Saiqi, Wang Junwei, Li Yongmei, Dou Yinhui, Wang Ran, Shi Hongge, Ke Yu, Liu Hongmin
Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou, Henan 450001, P.R. China.
Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China.
Int J Mol Med. 2017 Mar;39(3):645-653. doi: 10.3892/ijmm.2017.2867. Epub 2017 Jan 24.
Chemoresistance to anticancer drugs is a major obstacle in the efforts to develop a successful treatment strategy for esophageal squamous carcinoma (ESCC). Thus, the exploration of new drugs and treatment strategies for combating resistance are of utmost importance. In this study, we investigated the antitumor drug resistance activity of Jesridonin, a new ent-kaurene diterpenoid, and its possible mechanisms of action using the resistant cancer cell line, EC109/Taxol. MTT assay revealed that Jesridonin had similar IC50 values against EC109 paclitaxel-sensitive cells and drug-resistant EC109/Taxol cells in vitro. In mice, Jesridonin effectively prevented the growth of EC109/Taxol tumor xenografts without exerting any significant toxicity. In addition, Jesridonin significantly inhibited the proliferation of EC109/Taxol cells, induced apoptosis and arrested the cell cycle at the G2/M phase. Furthermore, western blot analysis revealed that Jesridonin upregulated the expression of p53, p53 upregulated modulator of apoptosis (PUMA), cleaved-caspase-9 and cleaved-caspase-3 in EC109/Taxol cells, and downregulated the expression of procaspase-3, procaspase-9 and Bcl-2 in the EC109/Taxol cells in a concentration-dependent manner. Overall, our results demonstrate that Jesridonin may have potential for use in the treatment of paclitaxel-resistant ESCC. The data of the present study may lead to the development of novel treatment strategies for paclitaxel-resistant tumors.
对抗癌药物的化学抗性是为食管鳞状细胞癌(ESCC)制定成功治疗策略的主要障碍。因此,探索对抗抗性的新药和治疗策略至关重要。在本研究中,我们使用耐药癌细胞系EC109/Taxol研究了一种新的对映-贝壳杉烯二萜类化合物Jesridonin的抗肿瘤耐药活性及其可能的作用机制。MTT分析显示,Jesridonin在体外对EC109紫杉醇敏感细胞和耐药的EC109/Taxol细胞具有相似的IC50值。在小鼠中,Jesridonin有效地抑制了EC109/Taxol肿瘤异种移植瘤的生长,且未产生任何明显毒性。此外,Jesridonin显著抑制EC109/Taxol细胞的增殖,诱导细胞凋亡并使细胞周期停滞在G2/M期。此外,蛋白质印迹分析显示,Jesridonin上调了EC109/Taxol细胞中p53、p53上调的凋亡调节因子(PUMA)、裂解的半胱天冬酶-9和裂解的半胱天冬酶-3的表达,并以浓度依赖性方式下调了EC109/Taxol细胞中前半胱天冬酶-3、前半胱天冬酶-9和Bcl-2的表达。总体而言,我们的结果表明Jesridonin可能具有用于治疗紫杉醇耐药性ESCC的潜力。本研究的数据可能会导致开发针对紫杉醇耐药性肿瘤的新治疗策略。