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Enhancing conventional chemotherapy drug cisplatin-induced anti-tumor effects on human gastric cancer cells both in vitro and in vivo by Thymoquinone targeting PTEN gene

2017; Impact Journals LLC; Volume: 8; Issue: 49 Linguagem: Inglês

10.18632/oncotarget.20721

1949-2553

Jingjing Ma, Xue Hu, Jiao Li, Dandan Wu, Qingzhi Lan, Qian Wang, Shan Tian, Weiguo Dong,

Drug Transport and Resistance Mechanisms

// Jingjing Ma 1, 2, 3 , Xue Hu 1, 2, 3 , Jiao Li 1, 3 , Dandan Wu 1, 3 , Qingzhi Lan 1, 3 , Qian Wang 1, 2 , Shan Tian 1, 2 and Weiguo Dong 1 1 Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China 2 Key Laboratory of Hubei Province for Digestive System Disease, Wuhan, Hubei Province, China 3 Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China Correspondence to: Weiguo Dong, email: dongweiguo@whu.edu.cn Keywords: thymoquinone, cisplatin, gastric cancer, PTEN, drug sensitivity Abbreviations: GC: gastric cancer; TQ: Thymoquinone; P-gp: P-glycoprotein; NC: negative control Received: May 18, 2017 Accepted: August 09, 2017 Published: September 08, 2017 ABSTRACT Combination chemotherapy regimen with several anti-tumor drugs is a strategy to improve outcome. Thymoquinone (TQ) has been reported to exert biological activity on various types of human cancers without obvious toxicity. However, only few studies showed the anti-tumor effects of TQ combination with cisplatin on gastric cancer (GC). Here, we showed pretreatment with 5μM TQ significantly increased the apoptotic effects induced by cisplatin on GC cell lines. Combined treatment of cisplatin with TQ represented a significantly superior tumor suppression effect than either agent alone in a xenograft tumor mouse model. Interestingly, TQ pretreatment following cisplatin caused a significant increase in the levels of PTEN, an obvious decrease in p-AKT, CyclinD1, P-glycoprotein (P-gp), meanwhile, TQ and cisplatin also led to an increase in Bax, Cyt C, AIF, cleaved caspase 9, and cleaved caspase 3, and a decrease in Bcl-2, procaspase-9, procaspase-3. Moreover, results in vitro , showed that a combination of TQ and cisplatin represents a more effective anti-tumor agent than either agent alone in a xenograft tumor mouse model. In conclusion, TQ significantly augments cisplatin-induced anti-tumor effects on gastric cancer both in vitro and in vivo , through inhibiting PI3K/AKT signaling pathway, activating the mitochondrial pathway, and down-regulating P-glycoprotein by up-regulating PTEN gene. TQ might be as a promising candidate as a cancer chemopreventive or chemotherapeutic agent for antineoplastic combination therapy and merits further clinical investigation.