The combination therapy of HIF1α inhibitor LW6 and cisplatin plays an effective role on anti-tumor function in A549 cells

Abstract

Hypoxia-inducible factor 1α (HIF1α) has been demonstrated to be involved in the resistance of various human cancer cells to chemotherapies. However, correlation between HIF1α and sensitivity of human non-small cell lung cancer (NSCLC) cells to cisplatin has not been illuminated. The aim of present study was to investigate the effects of HIF1α on drug resistance in NSCLC cells. A549 cells were incubated in 21% or 0.5% O 2 followed by the assessment of HIF1α level with qRT-PCR and western blot, and ROS levels by DCFH-DA assays. Effects of hypoxia or HIF1α inhibitor LW6 on the proliferation and apoptosis of A549 cells were evaluated via CCK-8 and flow cytometry assays. IC 50 of A549 cells to cisplatin was determined by MTT assay. The mitochondrial membrane potential (MMP) was measured via JC-1 staining. Moreover, the expression of apoptosis related protein (Bcl-2, Bax) and drug resistance related proteins (MDR1, MRP1) were measured by western blotting. Exposure of A549 cells to 1% O 2 significantly upregulated HIF1α expression, maintained cell viability to cisplatin but decreased the ROS level, which promoted chemoresistance to cisplatin. LW6-treated A549 cells showed an increase in ROS level that blocked the hypoxia induced resistance to cisplatin and in addition, decreased expression of MDR1 and MRP1 in cisplatin-treated cells. This study revealed that hypoxia-improved cisplatin chemoresistance of NSCLC cells by regulated MDR1 and MRP1 expression via HIF1α/ROS pathway is reversed by LW6, suggesting that LW6 may act as effective sensitizer in chemotherapy for NSCLC.

Identification of Proteins Deregulated by Platinum-Based Chemotherapy as Novel Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer

“…Cisplatin, cis-Diammineplatinum (II) dichloride, is the most widely studied platinum agent (9)(10)(11)(12)(13), and is currently one of the most effective chemotherapeutic agents available for treating NSCLC. However, objective response rates for patients with advanced NSCLC remain poor at 40%-50% (14,15).…”

Multidrug Resistance in Cancer: Understanding Molecular Mechanisms, Immunoprevention and Therapeutic Approaches

“…HIF-1a also contributes to the DNA repair mechanism and counteracts the activities of several chemotherapeutic agents (173,174). Furthermore, HIF-1a can increase mitophagy and protect cancer cells from several drugs, including cisplatin (175), 5-FU (176), and GEM (163).…”

“…HIF-1α also contributes to the DNA repair mechanism and counteracts the activities of several chemotherapeutic agents ( 173 , 174 ). Furthermore, HIF-1α can increase mitophagy and protect cancer cells from several drugs, including cisplatin ( 175 ), 5-FU ( 176 ), and GEM ( 163 ). Mitophagy also helps cancer cells to replenish ATP, metabolites, and building blocks that have been damaged by drugs.…”

Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

“…Chemotherapeutic drugs as 5-fluorouracil and cisplatin increase ROS generation [110]. The lower levels of OXPHOS detected in hypoxic cells or in cells with high levels of HIF-1α may explain the lower generation of ROS and the reduced oxidative damages induced by chemotherapy in these conditions [123]. Moreover, the reductive catabolism of glutaminei.e.…”

“…Mitophagy allows cancer cells to recover ATP, redox metabolites and building blocks, that can be used to re-synthesize biomolecules damaged by chemotherapeutic drugs, providing an additional mechanism by which the altered mitochondrial metabolism induced by HIF-1α determines chemoresistance. For instance, HIF-1α triggers a protective mitophagic response and at the same time confers resistance to 5-fluorouracil [126], gemcitabine [94] and cisplatin in ovarian cancer [123]. Indeed the increased rate of mitophagy [121,122], favored by the up-regulation of the mitophagic Bcl-2/ adenovirus E1B 19-kDa interacting protein 3 (BNIP3) by HIF-1α [127], compensates the lower ATP produced by OXPHOS.…”