This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Kuo, C.-C. Articles by Chang, J.-Y. Search for Related Content PubMed PubMed Citation Articles by Kuo, C.-C. Articles by Chang, J.-Y.

BPR0L075, a Novel Synthetic Indole Compound with Antimitotic Activity in Human Cancer Cells, Exerts Effective Antitumoral Activity in Vivo

Divisions of ¹ Cancer Research and ² Biotechnology and Pharmaceutical Research, National Health Research Institutes, Taipei, Taiwan, ROC

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 article has been cited by other articles:

				L.-C. Ma, C.-C. Kuo, J.-F. Liu, L.-T. Chen, and J.-Y. Chang Transcriptional Repression of O6-Methylguanine DNA Methyltransferase Gene Rendering Cells Hypersensitive to N,N'-Bis(2-chloroethyl)-N-nitrosurea in Camptothecin-Resistant Cells Mol. Pharmacol., August 1, 2008; 74(2): 517 - 526. [Abstract] [Full Text] [PDF]

				S.-F. Chang, C. A. Chang, D.-Y. Lee, P.-L. Lee, Y.-M. Yeh, C.-R. Yeh, C.-K. Cheng, S. Chien, and J.-J. Chiu Tumor cell cycle arrest induced by shear stress: Roles of integrins and Smad PNAS, March 11, 2008; 105(10): 3927 - 3932. [Abstract] [Full Text] [PDF]

				S. H. Hwang, A. Rait, K. F. Pirollo, Q. Zhou, V. M. Yenugonda, G. M. Chinigo, M. L. Brown, and E. H. Chang Tumor-targeting nanodelivery enhances the anticancer activity of a novel quinazolinone analogue Mol. Cancer Ther., March 1, 2008; 7(3): 559 - 568. [Abstract] [Full Text] [PDF]

				J.-S. Kim, Y.-C. Lee, H.-T. Nam, G. Li, E.-J. Yun, K.-S. Song, K.-S. Seo, J.-H. Park, J.-W. Ahn, O. Zee, et al. Apicularen A Induces Cell Death through Fas Ligand Up-Regulation and Microtubule Disruption by Tubulin Down-Regulation in HM7 Human Colon Cancer Cells Clin. Cancer Res., November 1, 2007; 13(21): 6509 - 6517. [Abstract] [Full Text] [PDF]

				J.-P. Liou, K.-S. Hsu, C.-C. Kuo, C.-Y. Chang, and J.-Y. Chang A Novel Oral Indoline-Sulfonamide Agent, N-[1-(4-Methoxybenzenesulfonyl)-2,3-dihydro-1H-indol-7-yl]-Isonicotinamide (J30), Exhibits Potent Activity against Human Cancer Cells in Vitro and in Vivo through the Disruption of Microtubule J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 398 - 405. [Abstract] [Full Text] [PDF]

				H.-T. Yao, Y.-S. Wu, Y.-W. Chang, H.-P. Hsieh, W.-C. Chen, S.-J. Lan, C.-T. Chen, Y.-S. Chao, L. Chang, H.-Y. Sun, et al. Biotransformation of 6-Methoxy-3-(3',4',5'-trimethoxy-benzoyl)-1H-indole (BPR0L075), a Novel Antimicrotubule Agent, by Mouse, Rat, Dog, and Human Liver Microsomes Drug Metab. Dispos., July 1, 2007; 35(7): 1042 - 1049. [Abstract] [Full Text] [PDF]

				S.-H. Juang, C.-C. Lung, P.-C. Hsu, K.-S. Hsu, Y.-C. Li, P.-C. Hong, H.-S. Shiah, C.-C. Kuo, C.-W. Huang, Y.-C. Wang, et al. D-501036, a novel selenophene-based triheterocycle derivative, exhibits potent in vitro and in vivo antitumoral activity which involves DNA damage and ataxia telangiectasia-mutated nuclear protein kinase activation Mol. Cancer Ther., January 1, 2007; 6(1): 193 - 202. [Abstract] [Full Text] [PDF]

				T. L. Gururaja, D. Goff, T. Kinoshita, E. Goldstein, S. Yung, J. McLaughlin, E. Pali, J. Huang, R. Singh, S. Daniel-Issakani, et al. R-253 disrupts microtubule networks in multiple tumor cell lines. Clin. Cancer Res., June 15, 2006; 12(12): 3831 - 3842. [Abstract] [Full Text] [PDF]

				C.-C. Kuo, J.-F. Liu, and J.-Y. Chang DNA Repair Enzyme, O6-Methylguanine DNA Methyltransferase, Modulates Cytotoxicity of Camptothecin-Derived Topoisomerase I Inhibitors J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 946 - 954. [Abstract] [Full Text] [PDF]

				T. Hosono, T. Fukao, J. Ogihara, Y. Ito, H. Shiba, T. Seki, and T. Ariga Diallyl Trisulfide Suppresses the Proliferation and Induces Apoptosis of Human Colon Cancer Cells through Oxidative Modification of {beta}-Tubulin J. Biol. Chem., December 16, 2005; 280(50): 41487 - 41493. [Abstract] [Full Text] [PDF]

				Z. Chen, P. J. Merta, N.-H. Lin, S. K. Tahir, P. Kovar, H. L. Sham, and H. Zhang A-432411, a novel indolinone compound that disrupts spindle pole formation and inhibits human cancer cell growth Mol. Cancer Ther., April 1, 2005; 4(4): 562 - 568. [Abstract] [Full Text] [PDF]