BPR0L075, a Novel Synthetic Indole Compound with Antimitotic Activity in Human Cancer Cells, Exerts Effective Antitumoral Activityin Vivo
Open Access
- 1 July 2004
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 64 (13), 4621-4628
- https://doi.org/10.1158/0008-5472.can-03-3474
Abstract
BPR0L075 is a novel synthetic compound discovered through research to identify new microtubule inhibitors. BPR0L075 inhibits tubulin polymerization through binding to the colchicine-binding site of tubulin. Cytotoxic activity of BPR0L075 in a variety of human tumor cell lines has been ascertained, with IC50 values in single-digit nanomolar ranges. As determined by flow cytometry, human cervical carcinoma KB cells are arrested in G2-M phases in a time-dependent manner before cell death occurs. Terminal deoxynucleotidyl transferase-mediated nick end labeling assay indicates that cell death proceeds through an apoptotic pathway. Additional studies indicate that the effect of BPR0L075 on cell cycle arrest is associated with an increase in cyclin B1 levels and a mobility shift of Cdc2 and Cdc25C. The changes in Cdc2 and Cdc25C coincide with the appearance of phosphoepitopes recognized by a marker of mitosis, MPM-2. Furthermore, phosphorylated forms of Bcl-2, perturbed mitochondrial membrane potential, and activation of the caspase-3 cascade may be involved in BPR0L075-induced apoptosis. Notably, several KB-derived multidrug-resistant cell lines overexpressing P-gp170/MDR and MRP are resistant to vincristine, paclitaxel, and colchicine but not to BPR0L075. Moreover, BPR0L075 shows potent activity against the growth of xenograft tumors of the gastric carcinoma MKN-45, human cervical carcinoma KB, and KB-derived P-gp170/MDR-overexpressing KB-VIN10 cells at i.v. doses of 50 mg/kg in nude mice. These findings indicate BPR0L075 is a promising anticancer compound with antimitotic activity that has potential for management of various malignancies, particularly for patients with drug resistance.This publication has 34 references indexed in Scilit:
- Novel sulfonate analogues of combretastatin A-4: potent antimitotic agentsBioorganic & Medicinal Chemistry Letters, 2001
- Focusing-in on microtubulesCurrent Opinion in Structural Biology, 2000
- The Release of Cytochrome c from Mitochondria: A Primary Site for Bcl-2 Regulation of ApoptosisScience, 1997
- Cell cycle and apoptosis: Common pathways to life and deathJournal of Cellular Biochemistry, 1995
- Antineoplastic Agents. 291. Isolation and Synthesis of Combretastatins A-4, A-5, and A-6Journal of Medicinal Chemistry, 1995
- Chapter 2 Identification of Dying Cells—In Situ StainingPublished by Elsevier BV ,1995
- Dephosphorylation and activation of a p34cdc2/cyclin B complex in vitro by human CDC25 proteinNature, 1991
- The cdc25 protein controls tyrosine dephosphorylation of the cdc2 protein in a cell-free systemCell, 1991
- A semiautomated microculture method for investigating growth inhibitory effects of cytotoxic compounds on exponentially growing carcinoma cellsAnalytical Biochemistry, 1984
- Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reactionBiochemical Pharmacology, 1973