Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest

Abstract

The efficacy of cisplatin-based chemotherapy in cancer is limited by the occurrence of innate and acquired drug resistance. In order to better understand the mechanisms underlying acquired cisplatin resistance, we have compared the adenocarcinoma-derived non-small cell lung cancer (NSCLC) cell line A549 and its cisplatin-resistant sub-line A549rCDDP2000 with regard to cisplatin resistance mechanisms including cellular platinum accumulation, DNA-adduct formation, cell cycle alterations, apoptosis induction and activation of key players of DNA damage response. In A549rCDDP2000 cells, a cisplatin-induced G2/M cell cycle arrest was lacking and apoptosis was reduced compared to A549 cells, although equitoxic cisplatin concentrations resulted in comparable platinum-DNA adduct levels. These differences were accompanied by changes in the expression of proteins involved in DNA damage response. In A549 cells, cisplatin exposure led to a significantly higher expression of genes coding for proteins mediating G2/M arrest and apoptosis (mouse double minute 2 homolog (MDM2), xeroderma pigmentosum complementation group C (XPC), stress inducible protein (SIP) and p21) compared to resistant cells. This was underlined by significantly higher protein levels of phosphorylated Ataxia telangiectasia mutated (pAtm) and p53 in A549 cells compared to their respective untreated control. The results were compiled in a preliminary model of resistance-associated signaling alterations. In conclusion, these findings suggest that acquired resistance of NSCLC cells against cisplatin is the consequence of altered signaling leading to reduced G2/M cell cycle arrest and apoptosis.

Luminescent PtII and PtIV Platinacycles with Anticancer Activity Against Multiplatinum‐Resistant Metastatic CRC and CRPC Cell Models

“…For that, we studied the effect of 3a' on the cell cycle phase distribution ( Figure 3) and apoptosis (Figure4)ofS W620-O and SW620-MPR cells. Moreover,w hereas cisplatin appeared to inducea significant G2/M arrest, consistent with previouso bservations, [23] 3a' only occasioned am inor reorganizationb etween the Sand G2/M subpopulations, with no effect on the percentage of cells at G0/G1. Moreover,w hereas cisplatin appeared to inducea significant G2/M arrest, consistent with previouso bservations, [23] 3a' only occasioned am inor reorganizationb etween the Sand G2/M subpopulations, with no effect on the percentage of cells at G0/G1.…”

A Non-genetic Mechanism for Chemoresistance in Lung Cancer: The Role of Integrin β4/Paxillin Axis

“…However, the exact mechanism(s) underlying the emergence of drug resistance remains poorly understood and a bewildering plethora of targets have been implicated in different cancer types. For example, in NSCLC alone, dysregulation of genes involved in cell cycle arrest and apoptosis namely, mouse double minute 2 homolog (MDM2), xeroderma pigmentosum complementation group C, stress inducible protein and p21 (Sarin et al, 2017), cytoplasmic RAP1 that alters NF-κB signaling, upregulation of antiapoptotic factor BCL-2 (Xiao et al, 2017), enhanced Stat3 and Akt phosphorylation, high expression of survivin (Hu et al, 2016), hypoxia factor HIF-1α and mutant p53 (Deben et al, 2018), have been implicated in cisplatin resistance. Furthermore, although changes in administration schedules, choice of methods, and frequency of toxicity monitoring have all contributed to incremental improvements, chemoresistance limits the clinical utility of cisplatin (Fennell et al, 2016).…”

Thermosensitive Polypeptide Hydrogels Co‐Loaded with Two Anti‐Tumor Agents to Reduce Multi‐Drug Resistance and Enhance Local Tumor Treatment

“…These results confirmed that the combination of DOX and CDDP effectively inhibited MDR development in A549 tumors, consistent with the cell test results in vitro (Figures 2F and 3F). [ 51,52 ]…”