title: Novel tubulin polymerization inhibitors overcome multidrug resistance and reduce melanoma lung metastasis.
abstract: OBJECTIVE
  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.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 847 Monroe Ave., Memphis, Tennessee 38163, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.forename: Sunjoo
authors.initials: S
authors.lastname: Ahn
authors.forename: Chien-Ming
authors.initials: CM
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Vivian S
authors.initials: VS
authors.lastname: Loveless
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D021461:Animals, Outbred Strains; D050256:Antimitotic Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003078:Colchicine / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008812:Mice, Hairless; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D009362:Neoplasm Metastasis; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D007093:Imidazoles; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine