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Novel Tubulin Polymerization Inhibitors Overcome Multidrug Resistance and Reduce Melanoma Lung Metastasis

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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.

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Abbreviations

μM:

micromolar per liter

ABI:

2-aryl-4-benzoyl-imidazole compounds

BCRP:

breast cancer resistance protein

DAMA-colchicine:

N-deacetyl-N-(2-mercaptoacetyl)-colchicine

DMSO:

dimethyl sulphoxide

DTIC:

dacarbazine

FBS:

fetal bovine serum

HMEC:

human microvascular endothelial cells

MDR:

multidrug resistant

MRP:

MDR associated proteins

MTD:

maximum tolerable dose

nM:

nanomolar per liter

SAR:

structure-activity relationship

SCID:

severe combined immunodeficiency

SHO mice:

double homozygous SCID hairless outbreed mice

SMART:

substituted methoxylbenzoyl-aryl-thiazole

SPA:

scintillation proximity assay

SRB:

sulforhodamine B

TGI:

tumor growth inhibition

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ACKNOWLEDGMENTS & DISCLOSURES

This work was supported by the NIH/NCI Grant R01CA148706-01A1 to WL with additional partial support from GTx, Inc. (SA, CL and JTD). We thank Dr. Christina Barrett for her help in the colchicine site binding assay, Dr. Feng Zhang for capillary network formation assay, Dr. Bob M. Moore II and Dr. Steven Gurley for helping in taking microtubule images, and Dr. David Armbruster for editorial assistance.

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Author notes

  1. Zhao Wang

    Present address: Frontage Laboratories, Inc., Exton, Pennsylvania, USA

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 847 Monroe Ave., Room 327, Memphis, Tennessee, 38163, USA

    Zhao Wang, Jianjun Chen, Jin Wang, Yan Lu, Vivian S. Loveless, Duane D. Miller & Wei Li

  2. Preclinical Research and Development Department, GTx, Inc., Memphis, Tennessee, USA

    Sunjoo Ahn, Chien-Ming Li & James T. Dalton

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  1. Zhao Wang
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Corresponding author

Correspondence to Wei Li.

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Wang, Z., Chen, J., Wang, J. et al. Novel Tubulin Polymerization Inhibitors Overcome Multidrug Resistance and Reduce Melanoma Lung Metastasis. Pharm Res 29, 3040–3052 (2012). https://doi.org/10.1007/s11095-012-0726-4

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  • DOI: https://doi.org/10.1007/s11095-012-0726-4

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