Metformin partially reverses the carboplatin-resistance in NSCLC by inhibiting glucose metabolism
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Yong Liu1, Chunxi He1 and Xianping Huang1
1Department of Cardiothoracic Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China
Xianping Huang, email: firstname.lastname@example.org
Keywords: NSCLC, carboplatin resistance, metformin, PKM2, glucose metabolism
Received: March 21, 2017 Accepted: July 12, 2017 Published: September 06, 2017
Platinum-based chemotherapeutic drugs are irreplaceable for the treatment of advanced non-small cell lung cancer (NSCLC). However, acquired drug resistance has become a major obstacle for the clinical application of chemotherapy on NSCLC. In the present study, we established carboplatin-resistant NSCLC models on A549 and PC9 cell lines, which were named A549/R and PC9/R. Besides the low sensitivity of A549/R and PC9/R to carboplatin treatment, they exhibited higher metabolism rate of glucose compared to their parental A549 and PC9 cells, respectively. Mechanically, we confirmed that overexpression of PKM2 in A549/R and PC9/R was responsible for the high glucose metabolism and carboplatin resistance. Metformin, an antidiabetic drug, was observed to increase the sensitivity of carboplatin-resistant NSCLC cells to carboplatin treatment in vitro and in vivo. Mechanically, metformin decreased expression of PKM2 and subsequently inhibited the glucose uptake, lactate generation and ATP production in A549/R and PC9/R. Therefore, metformin promoted carboplatin-induced apoptosis through the mitochondria pathway. In addition, we demonstrated that metformin treatment also impaired the cross-resistance of A549/R and PC9/R to cisplatin, etoposide and 5-fluorouracil.
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