Oncotarget

Research Papers:

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

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

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Oncotarget. 2017; 8:85926-85939. https://doi.org/10.18632/oncotarget.20721

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Abstract

Jingjing Ma1,2,3, Xue Hu1,2,3, Jiao Li1,3, Dandan Wu1,3, Qingzhi Lan1,3, Qian Wang1,2, Shan Tian1,2 and Weiguo Dong1

1Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China

2Key Laboratory of Hubei Province for Digestive System Disease, Wuhan, Hubei Province, China

3Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China

Correspondence to:

Weiguo Dong, email: [email protected]

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.


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