Abstract
Platinum-based chemotherapy is the first-line treatment for non-small cell lung cancer, but recurrence occurs in most patients. Recent evidence suggests that CD133(+) cells are the cause of drug resistance and tumor recurrence. However, the correlation between chemotherapy and regulation of CD133(+) cells has not been investigated methodically. In this study, we revealed that CD133(+) lung cancer cells labeled by a human CD133 promoter-driven GFP reporter exhibited drug resistance and stem cell characteristics. Treatment of H460 and H661 cell lines with low-dose cisplatin (IC(20)) was sufficient to enrich CD133(+) cells, to induce DNA damage responses, and to upregulate ABCG2 and ABCB1 expression, which therefore increased the cross-resistance to doxorubicin and paclitaxel. This cisplatin-induced enrichment of CD133(+) cells was mediated through Notch signaling as judged by increased levels of cleaved Notch1 (NICD1). Pretreatment with the γ-secretase inhibitor, N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butyl ester (DAPT), or Notch1 short hairpin RNAs (shRNA) remarkably reduced the cisplatin-induced enrichment of CD133(+) cells and increased the sensitivity to doxorubicin and paclitaxel. Ectopic expression of NICD1 reversed the action of DAPT on drug sensitivity. Immunohistochemistry showed that CD133(+) cells were significantly increased in the relapsed tumors in three of six patients with lung cancer who have received cisplatin treatment. A similar effect was observed in animal experiments as cisplatin treatment increased Notch1 cleavage and the ratio of CD133(+) cells in engrafted tumors. Intratumoral injection of DAPT with cisplatin treatment significantly reduced CD133(+) cell number. Together, our results showed that cisplatin induces the enrichment of CD133(+) cells, leading to multidrug resistance by the activation of Notch signaling.
Highlights
Non–small cell lung cancer (NSCLC) represents approximately 80% of all lung cancers, and platinum-based chemotherapy is the standard first-line therapeutic approach to treat patients with NSCLCs
The most cited mechanism for the acquisition of drug resistance is the active efflux of chemotherapeutic agents via ATP-binding cassette (ABC) transporters, such as P-glycoprotein P-gp/MDR1/ABCB1, breast cancer resistance protein BCRP/ABCG2, and multidrug resistance proteins
Pretreatment with 5 mmol/L verapamil, a pan-inhibitor for ABC transporters, completely inhibited cisplatin-induced doxorubicin resistance of H460 cells (Fig. 3C). These results suggested that cisplatininduced ABCG2, but not ABCB1, expression in CD133þ -enriched cultures leads to drug resistance to doxorubicin treatment
Summary
Non–small cell lung cancer (NSCLC) represents approximately 80% of all lung cancers, and platinum-based chemotherapy is the standard first-line therapeutic approach to treat patients with NSCLCs. The overall median survival of the patients who received platinumbased therapy has reached 9 to 12 months [2], the chemoresistance of tumor cells continues to be a considerable challenge in the management of NSCLCs. Tumor cells often show initial sensitivity to chemotherapeutic drugs, but acquired resistance develops during the treatment, leading to tumor recurrence and further tumor progression. The most cited mechanism for the acquisition of drug resistance is the active efflux of chemotherapeutic agents via ATP-binding cassette (ABC) transporters, such as P-glycoprotein P-gp/MDR1/ABCB1, breast cancer resistance protein BCRP/ABCG2, and multidrug resistance proteins Several receptor-mediated survival signaling pathways, including mitogen-activated protein kinase (MAPK), Akt, mTOR, NF-kB, and Notch pathways, have been linked to the drug resistance of conventional chemotherapy [4,5,6]
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