Effect of abemaciclib (LY2835219) on enhancement of chemotherapeutic agents in ABCB1 and ABCG2 overexpressing cells in vitro and in vivo.
Multidrug resistance (MDR) is the major obstacle of the success in cancer chemotherapy. The overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1 and ABCG2, play a significant role in mediating MDR by pumping anticancer drugs out of cancer cells. Abemaciclib (LY2835219) is an orally bioavailable CDK4/6 inhibitor under phase III clinical trials. Here, we found that LY2835219 remarkably enhanced the efficacy of chemotherapeutic drugs in ABCB1 or ABCG2 over-expressing cancer cells in vitro and in vivo. Furthermore, LY2835219 significantly increased the intracellular accumulation of doxorubicin (DOX) and rhodamine 123 (Rho 123) by inhibiting ABCB1 or ABCG2-mediated drug efflux in the transporters-overexpressing cells. Mechanistically, LY2835219 is likely a competitive inhibitor of ABCB1 and ABCG2 for its competition with [125I]-iodoarylazidoprazosin for photo affinity labeling of the transporters. On the other hand, at the transporters-inhibiting concentrations, LY2835219 did not alter the expression level of ABCB1 and ABCG2, and the phosphorylation status of retinoblastoma (Rb) pathway in both parental and their resistant cells. In conclusion, these findings revealed a novel role of LY2835219 in reversing ABCB1 or ABCG2-mediated MDR, which may be benefit to the patients with MDR cancer for combinational therapy.
Department of Oral Medicine, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Tong
T
Wu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Zhen
Z
Chen
School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
Kenneth K W
KKW
To
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Xiaona
X
Fang
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Fang
F
Wang
Department of Oral Medicine, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, China. Electronic address: chengbin@mail.sysu.edu.cn.
Bin
B
Cheng
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-Sen University Cancer Center, Guangzhou, China. Electronic address: Fulw@mail.sysu.edu.cn.
Liwu
L
Fu
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism*; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D020112:Rhodamine 123 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000631:Aminopyridines; D000903:Antibiotics, Antineoplastic; D001562:Benzimidazoles; D009363:Neoplasm Proteins; D020112:Rhodamine 123; C000590451:abemaciclib; D004317:Doxorubicin
ABCB1; ABCG2; ATP-binding cassette transporters; LY2835219; Multidrug resistance