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Abstract

Gastric cancer (GC) remains one of the most common malignancies, especially in East Asia. Although surgical resection is the main method in curing cancer, chemotherapy remains an important treatment to avoid tumor recurrence and metastasis. Doxorubicin (DOX) is one of the most effective and widely used chemotherapeutic agents for the treatment of various malignancies. And it is also widely used to treat GC in combination regimens with etoposide, cisplatin and 5-fluorouracil. However, the dose-dependent adverse effects significantly limit its efficacy. Previous researches demonstrated that dysregulation of apoptosis pathway is a fundamental, common aberration adapted by of most cancer cells to survive, proliferate and metastasis. Hence, we have recently proposed a novel synthetic derivative VCPA as a chemosensitive agent, which could enhance the efficacy of DOX and thereby reducing the DOX doses. GC cell lines SGC7901, AGS, MKN28 and MGC803 were used to investigate the cytotoxicity under VCPA treated. The IC50 doses for 48 hours were 19.96 uM, 10.67 uM, 11.30 uM and 14.01 uM, respectively. The inhibition of VCPA was displayed in a dose and time dependent manner. Pretreatment of GC cells with VCPA at IC50 for 24 hours significantly enhanced the inhibition of DOX both in vitro and in vivo. Even the DOX-resistant GC cells displayed apoptosis after pretreatment. This drug combination strategy caused rapid production of ROS in GC cells. And the response of GC cells to the drug correlated with induction of pro-apoptotic protein Bax, inhibition of anti-apoptotic protein Bcl-2, activation of caspase-3 and finally promoting PARP cleavage. Collectively, these results imply that VCPA, a novel synthetic derivative based on �±-tocopheryl succinate, potentiates DOX induced apoptosis in GC cells and is in sight to reduce patient adverse response to DOX. One of the potential mechanisms by which the pretreated combination therapy has synergistic cytotoxic effects against gastric cancer may be through the mitochondrial apoptosis pathway.

Biography

Han Wu is currently pursuing her PhD from Zhongnan Hospital of Wuhan University, Wuhan, China. She has completed her MD in Oncology from the Second Military Medical University, Shanghai, China. She has performed studied on primary hepatocyte isolation and culture, establishment of liver disease model such as DEN-induced hepatocellular carcinogenesis in mouse and rat, DMN-induced acute hepatic failure in rat and tumor metabolism. She has successfully applied for the National Natural Science Foundation of China grant (NO: 31371440) as the principle person. Presently her main research field is the drug resistant in abdominal tumors. She has published two papers as co-author in reputed journals.

Email: wuhan_whu@163.com