Sensitization of ABCG2-overexpressing cells to conventional chemotherapeutic agent by sunitinib was associated with inhibiting the function of ABCG2

• Published in: Cancer letters 2009-06, Vol.279 (1), p.74-83
• Main Authors: Dai, Chun-ling, Liang, Yong-ju, Wang, Yan-sheng, Tiwari, Amit K, Yan, Yan-yan, Wang, Fang, Chen, Zhe-sheng, Tong, Xiu-zhen, Fu, Li-wu
• Format: Article
• Language: English
• Subjects: ABC transporters; ABCG2/BCRP; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; ATP Binding Cassette Transporter, Sub-Family B; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - antagonists & inhibitors; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Binding sites; Breast cancer; Cancer therapies; Cell culture; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cytotoxicity; Dose-Response Relationship, Drug; Doxorubicin - pharmacology; Drug resistance; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Hematology, Oncology and Palliative Medicine; Humans; Indoles - pharmacology; Inhibitory Concentration 50; Kinases; Methotrexate - pharmacology; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Multidrug resistance; Multidrug Resistance-Associated Proteins - metabolism; Mutation; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Phosphorylation; Placenta; Protein Kinase Inhibitors - pharmacology; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Pyrroles - pharmacology; RNA, Messenger - metabolism; Sunitinib; Time Factors; Topotecan - pharmacology; Transfection; Tyrosine kinase inhibitor; Up-Regulation; Vincristine - pharmacology
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2009.01.027

Abstract Sunitinib is an ATP-competitive multi-targeted tyrosine kinase inhibitor. In this study, we evaluated the possible interaction of sunitinib with P-glycoprotein (P-gp, ABCB1), multidrug resistance protein 1 (MRP1, ABCC1), breast cancer resistance protein (BCRP, ABCG2) and lung-resistance protein (LRP) in vitro . Our results showed that sunitinib completely reverse drug resistance mediated by ABCG2 at a non-toxic concentration of 2.5 μM and has no significant reversal effect on ABCB1-, ABCC1- and LRP-mediated drug resistance, although a small synergetic effect was observed in combining sunitinib and conventional chemotherapeutic agents in ABCB1 overexpressing MCF-7/adr and parental sensitive MCF-7 cells, ABCC1 overexpressing C-A120 and parental sensitive KB-3-1 cells. Sunitinib significantly increased intracellular accumulation of rhodamine 123 and doxorubicin and remarkably inhibited the efflux of rhodamine 123 and methotrexate by ABCG2 in ABCG2-overexpressing cells, and also profoundly inhibited the transport of [3 H]-methotrexate by ABCG2. However, sunitinib did not affect the expression of ABCG2 at mRNA or protein levels. In addition, sunitinib did not block the phosphorylation of Akt and Erk1/2 in ABCG2-overexpressing or parental sensitive cells. Overall, we conclude that sunitinib reverses ABCG2-mediated MDR through inhibiting the drug efflux function of ABCG2. These findings may be useful for cancer combinational therapy with sunitinib in the clinic.