Aspirin Overcomes Cisplatin Resistance In Lung Cancer By Inhibiting Cancer Cell Stemness

Background Lung cancer is the leading cause of cancer death with a less than 20%five-year survival rate.Resistance to clinical integrated treatment is reported as one major reason for treatment failure.The standard treatment of lung cancer is plain-based combination chemotherapy.Cisplatin occupies a leading position in platinum anticancer drugs in clinical chemotherapy and integrated treatment of lung cancer.Therefore,exploring the causes and solutions to cisplatin resistance is crucial for improving treatment outcome of lung cancer.Despite the lack of a clear underlying mechanism for lung cancer cisplatin resistance,it is widely accepted that cancer stem cell hypothesis could be one potential mechanism that causes treatment failure and leads to recurrence.On the one hand,the stem cell-related mechanisms could influence the resistance,including the apoptotic mechanism of cell damage,enhanced DNA repair mechanism,upregulation of multidrug resistance proteins,and extramembrane transport proteins.On the other hand,as a stem cell-related factor,CD 133-positive lung cancer patients have a shorter progression-free survival than CD133-negative patients.In cisplatin-resistant cell lines,the increased activation of ALDH1 is related to the expression of tumor stem cell markers.Lung cancer cells expressing CD44 are enriched for stem-like properties.CD44-positive cells show a higher level of expression for pluripotency markers,among which CD24-/CD44+cancer cells show more significant stemness and resistance than CD24+/CD44+cancer cells.The rapid growth of tumors leads to insufficient oxygen supply in the microenvironment,which results in the upregulation of HIF-1?.HIF-1? activates the COX-2 signaling axis and is crucial in cancer cell stemness.Aspirin,a non selective COX inhibitor,has been shown reduced risk of lung cancer and to help reverse the sensitivity of recurrent human ovarian cancer cells to cisplatin in epidemiological and clinical studies.Therefore,we speculate that aspirin may reduce the up regulation of stem cell related proteins,which may help to overcome the increase of drug resistance related proteins.This study observed the influences of aspirin in lung cancer cisplatin-resistant cells using cisplatin-resistant tumor-bearing node mice.In this study,we used cisplatin resistant strains and cisplatin sensitive strains to prove that aspirin can alleviate cisplatin resistance of lung cancer in vivo and in vitro.Objective To observe the effect of aspirin on the stemness of cisplatin-resistant lung cancer cell lines and the expression of resistance related proteins,and prove that aspirin can alleviate drug resistance by reducing the stemness of tumor cells.Methods1.NCBI-GEO is a free public database of microarray/gene profile,and we obtained the gene expression profile of GSE21656 in H460 cisplatin-sensitive cells(H460S)and H460 cisplatin-negative cells(H460R).2.H460S and H460R were selected for cell experiment.Grouping:H460S;H460R;H460rR+aspirin;H460R+cisplatin;H460rR+aspirin+cisplatin.The expressions of stem cell related protein,drug resistance related protein,and apoptosis related protein were observed.3.H460R was subcutaneously injected into nod BALB/c mice and divided into different treatment groups:control group;aspirin group;cisplatin group;aspirin+cisplatin group.The tumor sizes,stem cell-related protein,and apoptosis were tested.Results GSE21656 analysis showed that the difference between cisplatin-resistant and cisplatin-sensitive lung cancer cells was in the stem cell-related genes.That most of the apoptosis related proteins,resistance and stemness related proteins showed significant differences after 72 hours of treatment according to the groups in vitro.That is to say,when H460R was treated with aspirin,its sensitivity to cisplatin was increased,showing increased apoptosis,decreased drug resistance and stemness in vitro.The results of in vivo experiments showed that the tumor size of aspirin combined cisplatin group was the smallest,and that of the control group was the largest.The combination of aspirin and cisplatin group had the lowest proportion of CD 133+cells and CD24-/CD44+cells.ConclusionIn vitro,lung cancer H460 cisplatin-resistant cells showed stronger drug resistance and stemness than lung cancer H460 cisplatin-sensitive cells.Aspirin can reduce the stemness and resistance,and increase apoptosis in H460R.In vivo,aspirin combined with cisplatin showed significant anti-tumor effect in lung cancer cisplatin-resistant tumors.