Dataset Information

Novel tubulin polymerization inhibitors overcome multidrug resistance and reduce melanoma lung metastasis.

ABSTRACT:

Purpose

To evaluate abilities of 2-aryl-4-benzoyl-imidazoles (ABI) to overcome multidrug resistance (MDR), define their cellular target, and assess in vivo antimelanoma efficacy.

Methods

MDR cell lines that overexpressed P-glycoprotein, MDR-associated proteins, and breast cancer resistance protein were used to evaluate ABI ability to overcome MDR. Cell cycle analysis, molecular modeling, and microtubule imaging were used to define ABI cellular target. SHO mice bearing A375 human melanoma xenograft were used to evaluate ABI in vivo antitumor activity. B16-F10/C57BL mouse melanoma lung metastasis model was used to test ABI efficacy to inhibit tumor lung metastasis.

Results

ABIs showed similar potency to MDR cells compared to matching parent cells. ABIs were identified to target tubulin on the colchicine binding site. After 31 days of treatment, ABI-288 dosed at 25 mg/kg inhibited melanoma tumor growth by 69%; dacarbazine at 60 mg/kg inhibited growth by 52%. ABI-274 dosed at 25 mg/kg showed better lung metastasis inhibition than dacarbazine at 60 mg/kg.

Conclusions

This new class of antimitotic compounds can overcome several clinically important drug resistant mechanisms in vitro and are effective in inhibiting melanoma lung metastasis in vivo, supporting their further development.

SUBMITTER: Wang Z

PROVIDER: S-EPMC3659804 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Publications

Novel tubulin polymerization inhibitors overcome multidrug resistance and reduce melanoma lung metastasis.

Wang Zhao Z Chen Jianjun J Wang Jin J Ahn Sunjoo S Li Chien-Ming CM Lu Yan Y Loveless Vivian S VS Dalton James T JT Miller Duane D DD Li Wei W

Pharmaceutical research 20120313 11

<h4>Purpose</h4>To evaluate abilities of 2-aryl-4-benzoyl-imidazoles (ABI) to overcome multidrug resistance (MDR), define their cellular target, and assess in vivo antimelanoma efficacy.<h4>Methods</h4>MDR cell lines that overexpressed P-glycoprotein, MDR-associated proteins, and breast cancer resistance protein were used to evaluate ABI ability to overcome MDR. Cell cycle analysis, molecular modeling, and microtubule imaging were used to define ABI cellular target. SHO mice bearing A375 human m ...[more]

PMID: 22410804

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Dataset Information

Novel tubulin polymerization inhibitors overcome multidrug resistance and reduce melanoma lung metastasis.

Purpose

Methods

Results

Conclusions

Publications

Novel tubulin polymerization inhibitors overcome multidrug resistance and reduce melanoma lung metastasis.

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