Histone deacetylase inhibitor apicidin-mediated drug resistance: involvement of P-glycoprotein.
Multidrug resistance (MDR), which is a significant impediment to the success of cancer chemotherapy, is attributable to the overexpression of membrane transport proteins, such as P-glycoprotein (P-gp), resulting in an increased drug efflux. In this study, we show that the histone deacetylase (HDAC) inhibitor apicidin leads to resistance of HeLa cells to paclitaxel through the induction of P-gp expression. Furthermore, apicidin dramatically increases the release of a fluorescent P-gp substrate, rhodamine 123, from cells. In parallel, apicidin resistance to the apoptotic potential of paclitaxel is associated with induction of P-gp expression in HeLa cells, as evidenced by specific inhibition of P-gp function using either the pharmacological inhibitor verapamil or RNA silencing. We also demonstrate the contribution of apicidin-induced functional P-gp expression to drug resistance using KB cells. Failure of P-gp induction by apicidin does not reverse paclitaxel-induced cytotoxicity in the cells. Although HDAC inhibitors are widely appreciated as a new class of anti-tumor agent, our findings clearly demonstrate that apicidin treatment may lead to P-gp-mediated resistance to other anti-tumor agents, suggesting a need for careful design of clinical applications using HDAC inhibitors.
Kim
Yong Kee
YK
Department of Pharmacology, Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea.
Kim
Nam Hyun
NH
Hwang
Jee Won
JW
Song
Yong-Jin
YJ
Park
Yeon-Suk
YS
Seo
Dong-Wan
DW
Lee
Hoi Young
HY
Choi
Wahn Soo
WS
Han
Jeung-Whan
JW
Kim
Su-Nam
SN
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000502:physiology*; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D017239:Paclitaxel / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C102351:apicidin; D020112:Rhodamine 123; D017239:Paclitaxel