The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action.

The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action. Research Abstract Details 

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The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action. Abstract Text:

Margaret S Lee,Lisa Johansen,Yanzhen Zhang,Amy Wilson,Mitchell Keegan,William Avery,Peter Elliott,Alexis A Borisy,Curtis T Keith,Margaret S Lee,Lisa Johansen,Yanzhen Zhang,Amy Wilson,Mitchell Keegan,William Avery,Peter Elliott,Alexis A Borisy,Curtis T Keith,

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.

The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action. Publishing Authors By Initials

MS Lee,L Johansen,Y Zhang,A Wilson,M Keegan,W Avery,P Elliott,AA Borisy,CT Keith,MS Lee,L Johansen,Y Zhang,A Wilson,M Keegan,W Avery,P Elliott,AA Borisy,CT Keith,

For similar xenograft model antitumor assays research abstracts see: xenograft model antitumor assays research

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The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Cancer research

VOLUME: 67

Page Numbers: 11359-67

Journal Abbreviation: Cancer Res.

ISSN: 1538-7445

DAY: 1

MONTH: Dec

YEAR: 2007

The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action. Information

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LANGUAGE: eng

NlmUniqueID: 2984705

The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action. Keywords Mesh Terms:

KEYWORDS: Xenograft Model Antitumor Assays

MESH TERMS: analogs & derivatives

Chemical & Substance for Abstract: The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action. Information

Substance Name: Kinesin

Registry Number: EC 3.6.1.-

Grant and Affiliation Information for The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action.

AFFILIATION: CombinatoRx, Incorporated, 245 First Street, 16th Floor, Cambridge, MA 02142, USA. mlee@combinatorx.com

Country: United States

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MEDLINETA: Cancer Res

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