This Article Full Text Full Text (PDF) All Versions of this Article: 0008-5472.CAN-08-0877v1 69/5/1910    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Arora, S. Articles by Welsh, W. J. Search for Related Content PubMed PubMed Citation Articles by Arora, S. Articles by Welsh, W. J.

Novel Microtubule Polymerization Inhibitor with Potent Antiproliferative and Antitumor Activity

Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School and the Informatics Institute of University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey

Requests for reprints: William J. Welsh, Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 661 Hoes Lane, Piscataway, NJ 08854. Phone: 732-235-3234; Fax: 732-235-3475; E-mail: welshwj{at}umdnj.edu.

Key Words: microtubule • multidrug resistance

Microtubule-stabilizing and microtubule-destabilizing agents are commonly used as anticancer agents. Although highly effective, success with these agents has been limited due to their relative insolubility, cumbersome synthesis/purification, toxic side effects, and development of multidrug resistance. Hence, the identification of improved agents that circumvent one or more of these problems is warranted. We recently described the rational design of a series of triazole-based compounds as antimitotic agents. Members of this N-substituted 1,2,4-triazole family of compounds exhibit potent tubulin polymerization inhibition and broad spectrum cellular cytotoxicity. Here, we extensively characterize the in vitro and in vivo effects of our lead compound from the series 1-methyl-5-(3-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole-4-yl)-1H-indole, designated T115. We show that T115 competes with colchicine for its binding pocket in tubulin, produces robust inhibition of tubulin polymerization, and disrupts the microtubule network system inside the cells. In addition, T115 arrests human cancer cells in the G₂-M phase of cell cycling, a hallmark of microtubule destabilizing drugs. T115 also inhibits cell viability of several cancer cell lines, including multidrug-resistant cell lines, in the low nanomolar range. No cytotoxicity was observed by T115 against normal human skin fibroblasts cell lines, and acute toxicity studies in normal nontumor-bearing mice indicated that T115 is well-tolerated in vivo (maximum total tolerated dose, 400 mg/kg). In a mouse xenograft model using human colorectal (HT-29) and prostate (PC3) cancer cells, T115 significantly inhibited tumor growth when administered i.p. Taken together, our results suggest that T115 is a potential drug candidate for cancer chemotherapy. [Cancer Res 2009;69(5):1910–5]