Hypothesizing that histone deacetylase inhibitors can be used to reverse multiple drug resistance.
It is well known that the mechanism of action of chemotherapeutic drugs and their ability to induce multidrug resistance (MDR) are of relevance to cancer treatment. Although MDR is a multifactorial process, the main obstacle is the expression of multidrug-efflux pumps that lowers the intracellular drug levels. P-glycoprotein (P-gp) is the longest identified efflux pump. Thus, P-gp has been looked as a well established mediator of MDR and it became a therapeutic target for circumventing multidrug resistance. However, the mechanism of adjusting the expression of P-gp is not clear yet. The results of the effect of genetic polymorphism on P-gp expression and function remain conflicting. More recently, studies on the regulation of MDR1 has widened to examine the role of epigenetics and some new results were found to support the effect of epigenetic variance in vitro. It is hence hypothesized that epigenetic variants play more important roles than genetic polymorphism, thus adjusting the epigenetic factors could alter the expression of MDR, leading to the reverse of MDR. And it is further hypothesized that histone deacetylase inhibitors could be another strategy to overcome MDR. The mechanism may include a bidirectional modulation of P-gp by histone deacetylase inhibitors.
Jiang
Zhi-Ping
ZP
Laboratory of Clinical Pharmacology, Department of Hematology, Xiang-Ya Hospital, Central-South University, Changsha 410008, People's Republic of China.
Xu
Ping
P
Wang
Guan-Ping
GP
Zhao
Xie-Lan
XL
Chen
Fang-Ping
FP
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D044127:Epigenesis, Genetic; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D008957:Models, Genetic; D008962:Models, Theoretical; D011110:Polymorphism, Genetic
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D056572:Histone Deacetylase Inhibitors