Hypoxia can impair doxorubicin resistance of non-small cell lung cancer cells by inhibiting MRP1 and P-gp expression and boosting the chemosensitizing effects of MRP1 and P-gp blockers.
BACKGROUND
Non-small cell lung cancers (NSCLCs) frequently exhibit resistance to therapeutic drugs, which seriously hampers their treatment. Here, we set out to assess the roles of the multidrug resistance protein 1 (MRP1) and P-glycoprotein (P-gp) in the doxorubicin (DOX) resistance of NSCLC cells, as well as the putative therapeutic efficacy of MRP1 and P-gp blockers on DOX-treated NSCLC cells.


METHODS
The impact of DOX on cell survival, DOX efflux and MRP1 and P-gp expression was assessed in 5 different NSCLC-derived cell lines (parental CH27, A549, H1299, H460, and DOX resistant CH27) in the absence or presence of MK571 (MRP1 inhibitor) or Verapamil (P-gp inhibitor), under both normoxic and hypoxic conditions.


RESULTS
We found that in response to DOX treatment, NSCLC cells that express high levels of MRP1 and P-gp (such as CH27) showed a better DOX efflux and a higher DOX resistance. MK571 and Verapamil were found to abolish DOX resistance and to act as chemosensitizers for DOX therapy in all cell lines tested. We also found that hypoxia could inhibit MRP1 and P-gp expression in a HIF-1α-dependent manner, abolish DOX resistance and boost the chemosensitizer effect of MK571 and Verapamil on DOX treatment of all the NSCLC cells tested, except the DOX-resistant CH27 cells.


CONCLUSIONS
From our data we conclude that MRP1 and P-gp play critical roles in the DOX resistance of the NSCLC cells tested. MRP1 and P-gp targeted therapy using MK571, Verapamil, CoCl2or ambient hypoxia appeared to be promising in abolishing the DOX efflux and DOX resistance of the NSCLC cells. The putative therapeutic efficacies of MRP1 and/or P-gp blockers on NSCLC cells are worthy of note.
Department of Life Sciences, National Chung Hsing University, 145, Hsing-Da Rd, Taichung, 40227, Taiwan.
Yu-Lun
YL
Chen
Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
Tsung-Ying
TY
Yang
Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
Kun-Chieh
KC
Chen
Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.|Center for Quality Management, Taichung Veterans General Hospital, Taichung, Taiwan.
Chieh-Liang
CL
Wu
Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan.
Shih-Lan
SL
Hsu
Department of Life Sciences, National Chung Hsing University, 145, Hsing-Da Rd, Taichung, 40227, Taiwan. cmhsueh@dragon.nchu.edu.tw.|Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan. cmhsueh@dragon.nchu.edu.tw.
Chi-Mei
CM
Hsueh
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011422:Propionates; D011804:Quinolines; D014700:Verapamil; C059141:verlukast; C421109:multidrug resistance-associated protein 1
Doxorubicin resistance; HIF-1α; Hypoxia; MRP1; NSCLC; P-gp