Abstract
Resistance is a major concern when administering chemotherapy to patients with non-small cell lung cancer (NSCLC). Chemosensitizer are agents that can reverse resistance to chemotherapeutic drugs, thereby enhancing the chemosensitivity of tumor cells. Thus, their development will improve therapeutic efficacy in cancer. However, few effective chemosensitizer have been identified to date. Piperlongumine (PL) has been shown to effectively reverse resistance to chemotherapeutic drugs in several types of cancers. However, the mechanisms associated with the chemotherapy resistance reversal effect of PL and its regulation of target factors in chemotherapy resistance cells are still unclear. This study investigated the reversal effect of PL both in vitro and in vivo, and provided evidence that PL inhibited the phosphorylation of Akt via the accumulation of reactive oxygen species in chemotherapy resistance cells. Consequently, various Akt activation-dependent genes caused a reduction of drug efflux and induction of apoptosis in cisplatin-resistant A549 NSCLC cells. Our results indicate that Akt phosphorylation may play a functional role in the reversal effect of PL and contribute, at least in part, to the treatment outcomes of patients with chemotherapy resistance.
Highlights
Most cancer-related death is caused by non-small cell lung cancer (NSCLC) in China (Bray et al, 2018)
The results indicated that reactive oxygen species (ROS) suppressed phosphorylation of Akt may play a critical role in the chemotherapy resistance reversal effect of PL by reducing drug efflux and promoting the apoptosis of nonsmall cell lung cancer (NSCLC) cells
PL was purchased from Selleck Chemicals (Houston, TX, USA; purity: 99.33%); dimethyl sulfoxide (DMSO), 3-[4,5-dimethyl2-thiazol]-2,5-diphenyltetrazolium bromide (MTT), and N-Acetyl-L-cysteine (NAC) were purchased from SigmaAldrich (Darmstadt, Germany); cisplatin (Cis) was from Hansoh Pharmaceutical Group (Lianyungang, Jiangsu, China); rabbit polyclonal anti-Akt, anti-phosphorylated Akt (p-Akt, Ser-473), anti-p-forkhead box O3 (p-FoxO3a, Ser-318/Ser-321), anti-pmTOR (p-mTOR, Ser-2448), anti-p-PTEN (p-PTEN, Ser-280) and rabbit monoclonal anti-p-Bcl-2-associated death promoter (p-BAD; Ser-136 and Ser-112), anti-mTOR, and anti-PTEN antibodies were from Cell Signaling Technology (9272, 4060, 9465, 2971, 9551, 2983, 9559, 5286, and 5284, respectively; Danvers, MA, USA)
Summary
Most cancer-related death is caused by non-small cell lung cancer (NSCLC) in China (Bray et al, 2018). The identification of effective chemosensitizer that are able to reverse chemotherapy resistance and work with anticancer drugs is a promising strategy for increasing the success rate of chemotherapy (Fennell et al, 2016). Most of chemosensitizers displayed unacceptable levels of toxicity even if administered at effective doses in clinical trials (Kim et al, 1993; Ferry et al, 1996; Thomas and Coley, 2003), leading to restriction of Piperlongumine Reverses Resistance to Cisplatin their application in clinical settings.
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