PSC-833, a frontier in modulation of P-glycoprotein mediated multidrug resistance.
The expression of drug efflux mechanisms by cancer cells during chemotherapy leads to multidrug resistance (MDR) and constitutes a major obstacle in the effective treatment of cancer. The most widely characterized drug effluxes pump is P-glycoprotein (P-gp) and efforts are being directed towards identifying agents that reverse P-gp mediated drug resistance. PSC-833 is a non-immunosuppressive cyclosporin derivative that potently and specifically inhibits P-gp. The current review focuses on the elucidation of the mechanism of action of PSC-833 as a potential MDR reversing agent, using syngeneic multidrug resistant sublines of MDA435 human breast adenocarcinoma cell line that express increasing levels of P-gp. In vitro experiments indicate that PSC-833 interacts directly with P-gp with high affinity and probably interferes with the ATPase activity of P-gp. Studies in multidrug resistant tumor models confirm P-gp as the in vivo target of PSC-833 and demonstrate the ability of PSC-833 to reverse MDR leukemias and solid tumors in mice. Presently, PSC-833 is being evaluated in the clinic.
Atadja
P
P
Preclinical Research, Novartis Pharmaceutical Corporation, East Hanover, USA.
Watanabe
T
T
Xu
H
H
Cohen
D
D
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D003524:Cyclosporins / Q000494:pharmacology* / Q000627:therapeutic use*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D051381:Rats
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; C070272:valspodar