The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action.
Combination therapy has proven successful in treating a wide variety of aggressive human cancers. Historically, combination treatments have been discovered through serendipity or lengthy trials using known anticancer agents with similar indications. We have used combination high-throughput screening to discover the unexpected synergistic combination of an antiparasitic agent, pentamidine, and a phenothiazine antipsychotic, chlorpromazine. This combination, CRx-026, inhibits the growth of tumor cell lines in vivo more effectively than either pentamidine or chlorpromazine alone. Here, we report that CRx-026 exerts its antiproliferative effect through synergistic dual mitotic action. Chlorpromazine is a potent and specific inhibitor of the mitotic kinesin KSP/Eg5 and inhibits tumor cell proliferation through mitotic arrest and accumulation of monopolar spindles. Pentamidine treatment results in chromosomal segregation defects and delayed progression through mitosis, consistent with inhibition of the phosphatase of regenerating liver family of phosphatases. We also show that CRx-026 synergizes in vitro and in vivo with the microtubule-binding agents paclitaxel and vinorelbine. These data support a model where dual action of pentamidine and chlorpromazine in mitosis results in synergistic antitumor effects and show the importance of systematic screening for combinations of targeted agents.
Lee
Margaret S
MS
CombinatoRx, Incorporated, 245 First Street, 16th Floor, Cambridge, MA 02142, USA. mlee@combinatorx.com
Johansen
Lisa
L
Zhang
Yanzhen
Y
Wilson
Amy
A
Keegan
Mitchell
M
Avery
William
W
Elliott
Peter
P
Borisy
Alexis A
AA
Keith
Curtis T
CT
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002746:Chlorpromazine / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005455:Fluorescent Antibody Technique; D045325:HCT116 Cells / Q000187:drug effects; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects*; D017239:Paclitaxel / Q000008:administration & dosage; D010419:Pentamidine / Q000494:pharmacology*; D008941:Spindle Apparatus; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine; D023041:Xenograft Model Antitumor Assays
D000981:Antiprotozoal Agents; D014150:Antipsychotic Agents; D014747:Vinblastine; D010419:Pentamidine; D016547:Kinesins; D017239:Paclitaxel; D000077235:Vinorelbine; D002746:Chlorpromazine