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.

• Authors: Zhao Wang, Jianjun Chen, Jin Wang, Sunjoo Ahn, Chien-Ming Li, Yan Lu, Vivian S Loveless, James T Dalton, Duane D Miller, Wei Li
• Journal: Pharmaceutical research (Pharm Res) Vol. 29 Issue 11 Pg. 3040-52 (Nov 2012) ISSN: 1573-904X [Electronic] United States
• PMID: 22410804 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antimitotic Agents
• Antineoplastic Agents
• Imidazoles
• Tubulin
• Tubulin Modulators
• Colchicine

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Animals
• Animals, Outbred Strains
• Antimitotic Agents (pharmacology)
• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (metabolism, pathology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Colchicine (metabolism)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Endothelial Cells (drug effects, metabolism, pathology)
• Female
• HEK293 Cells
• Humans
• Imidazoles (pharmacology)
• Lung Neoplasms (metabolism, prevention & control, secondary)
• Melanoma (drug therapy, metabolism, pathology, secondary)
• Melanoma, Experimental (metabolism, pathology)
• Mice
• Mice, Hairless
• Mice, Inbred C57BL
• Mice, SCID
• Microtubules (drug effects, metabolism)
• Neoplasm Metastasis
• Tubulin (metabolism)
• Tubulin Modulators (pharmacology)