title: I-387, a novel antimitotic indole, displays a potent in vitro and in vivo antitumor activity with less neurotoxicity.
abstract: (3-(1H-indol-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone (I-387) is a novel synthetic compound that inhibits tubulin action and exhibits potent antitumor activity in various preclinical models. I-387 inhibited the in vitro growth of several human cancer cell lines with IC₅₀ values in the range of 15 to 39 nmol/L. Nanomolar concentrations of the compound induced apoptosis and caused phosphorylation of the antiapoptotic protein Bcl-2. I-387 induced a strong and concentration-dependent G₂-M arrest in PC-3 cells by constitutive activation of Cdc2/cyclin B1 complex and destabilized polymerization of purified tubulin in vitro by binding to the colchicine-binding site. In vivo, I-387 treatment effectively inhibited tumor growth in mice bearing PC-3 tumor xenografts. In vitro studies of nerve growth factor-dependent neurite outgrowth in PC12 pheochromocytoma cells and in vivo studies of mouse behavior showed that I-387 was less neurotoxic than vinblastine and vincristine, tubulin destabilizers with known neurotoxicity. Interestingly, multidrug-resistant cell lines that overexpressed P-glycoprotein (P-gp), multidrug resistance-associated proteins, and breast cancer resistance protein were rendered resistant to docetaxel, vinblastine, SN-38, and doxorubicin, but not to I-387. I-387 dosed at 10 mg/kg was equally effective with 76% tumor growth inhibition in xenograft models using MES-SA uterine sarcoma cells and MES-SA/DX5 cells overexpressing P-gp. In contrast, docetaxel and vinblastine were not effective in MES-SA/DX5 xenograft models. The potent in vitro and in vivo antitumor activity of I-387 suggests that it may represent a new antimitotic agent for management of various malignancies, particularly for patients with drug-resistant cancer.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Sunjoo
authors.initials: S
authors.lastname: Ahn
authors.forename: Charles B
authors.initials: CB
authors.lastname: Duke
authors.forename: Christina M
authors.initials: CM
authors.lastname: Barrett
authors.forename: Dong Jin
authors.initials: DJ
authors.lastname: Hwang
authors.forename: Chien-Ming
authors.initials: CM
authors.lastname: Li
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
mesh_terms: D000818:Animals; D050256:Antimitotic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001577:Benzophenones / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D019073:HT29 Cells; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D020014:K562 Cells; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D020258:Neurotoxicity Syndromes / Q000453:epidemiology / Q000473:pathology; D016716:PC12 Cells; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: C556166:(3-(1H-indol-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone; D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D001577:Benzophenones; D007211:Indoles