title: Lapatinib enhances the cytotoxic effects of doxorubicin in MCF-7 tumorspheres by inhibiting the drug efflux function of ABC transporters.
abstract: Increasing evidences indicate that cancer stem cells are resistant to chemotherapy due to their cell quiescence and the expression of ATP-binding cassette (ABC) transporters. In this study, we utilized tumorsphere cultures to seek better strategies to overcome chemoresistance since tumorsphere cultures have been used widely for the enrichment of cancer stem cells. We found that tumorspheres generated from MCF-7 human breast cancer cells exhibited high proportions of quiescent cells and expressed MDR-1 at elevated levels, leading to resistance to 5-fluorouracil, paclitaxel, and doxorubicin. Because the expression of EGFR/HER2 was increased in MCF-7 tumorspheres, we assessed the combinational effect of the dual ErbB1/ErbB2 inhibitor, lapatinib, with doxorubicin in tumorspheres. The results showed that inhibition of EGFR/HER2 signaling by lapatinib sensitized MCF-7 tumorspheres to doxorubicin by inhibiting the expression of the ABC transporters, MDR-1 and BCRP, and thus, enhancing the intracellular accumulation of doxorubicin. These findings suggest that combinations of lapatinib and cytotoxic anticancer drugs may offer an advantage for treating the drug-resistant cancers.
authors.affiliation: Department of Pharmacology, School of Medicine and Intractable Disease Research Center, Dongguk University, 87 Dongdae-ro, Gyeongju-si, Gyeongsangbuk-do 780-350, Republic of Korea.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Chun
authors.affiliation: Department of Pharmacology, School of Medicine and Intractable Disease Research Center, Dongguk University, 87 Dongdae-ro, Gyeongju-si, Gyeongsangbuk-do 780-350, Republic of Korea.
authors.forename: Yun-Suk
authors.initials: YS
authors.lastname: Kwon
authors.affiliation: Department of Pharmacology, School of Medicine and Intractable Disease Research Center, Dongguk University, 87 Dongdae-ro, Gyeongju-si, Gyeongsangbuk-do 780-350, Republic of Korea. Electronic address: namks@dongguk.ac.kr.
authors.forename: Kyung-Soo
authors.initials: KS
authors.lastname: Nam
authors.affiliation: Department of Pharmacology, School of Medicine and Intractable Disease Research Center, Dongguk University, 87 Dongdae-ro, Gyeongju-si, Gyeongsangbuk-do 780-350, Republic of Korea. Electronic address: soyoungkim@dongguk.ac.kr.
authors.forename: Soyoung
authors.initials: S
authors.lastname: Kim
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077341:Lapatinib; D061986:MCF-7 Cells; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D011799:Quinazolines; D000077341:Lapatinib; D004317:Doxorubicin; D066246:ErbB Receptors
keywords: ATP-binding cassette (ABC) drug transporters; Chemoresistance; Lapatinib; MCF-7 breast cancer cells; Tumorsphere