BPR0L075, a novel synthetic indole compound with antimitotic activity in human cancer cells, exerts effective antitumoral activity in vivo

Ching Chuan Kuo, Hsing Pang Hsieh, Wen Yu Pan, Ching Ping Chen, Jing Ping Liou, Shiow Ju Lee, Yi Ling Chang, Li Tzong Chen, Chiung Tong Chen, Jang Yang Chang

Research output: Contribution to journalArticle

181 Citations (Scopus)

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 BPROL075 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 BPROL075-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.

Original languageEnglish
Pages (from-to)4621-4628
Number of pages8
JournalCancer Research
Volume64
Issue number13
DOIs
Publication statusPublished - Jul 1 2004
Externally publishedYes

Fingerprint

Antimitotic Agents
Human Activities
KB Cells
Neoplasms
Colchicine
Tubulin
Carcinoma
Cell Death
Cyclin B1
DNA Nucleotidylexotransferase
Mitochondrial Membrane Potential
G2 Phase
Vincristine
Paclitaxel
Cell Cycle Checkpoints
Tumor Cell Line
Mitosis
Drug Resistance
Heterografts
Nude Mice

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

BPR0L075, a novel synthetic indole compound with antimitotic activity in human cancer cells, exerts effective antitumoral activity in vivo. / Kuo, Ching Chuan; Hsieh, Hsing Pang; Pan, Wen Yu; Chen, Ching Ping; Liou, Jing Ping; Lee, Shiow Ju; Chang, Yi Ling; Chen, Li Tzong; Chen, Chiung Tong; Chang, Jang Yang.

In: Cancer Research, Vol. 64, No. 13, 01.07.2004, p. 4621-4628.

Research output: Contribution to journalArticle

Kuo, Ching Chuan ; Hsieh, Hsing Pang ; Pan, Wen Yu ; Chen, Ching Ping ; Liou, Jing Ping ; Lee, Shiow Ju ; Chang, Yi Ling ; Chen, Li Tzong ; Chen, Chiung Tong ; Chang, Jang Yang. / BPR0L075, a novel synthetic indole compound with antimitotic activity in human cancer cells, exerts effective antitumoral activity in vivo. In: Cancer Research. 2004 ; Vol. 64, No. 13. pp. 4621-4628.
@article{6bb38180f8b84318b9ef704496c9af8c,
title = "BPR0L075, a novel synthetic indole compound with antimitotic activity in human cancer cells, exerts effective antitumoral activity in vivo",
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 BPROL075 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 BPROL075-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.",
author = "Kuo, {Ching Chuan} and Hsieh, {Hsing Pang} and Pan, {Wen Yu} and Chen, {Ching Ping} and Liou, {Jing Ping} and Lee, {Shiow Ju} and Chang, {Yi Ling} and Chen, {Li Tzong} and Chen, {Chiung Tong} and Chang, {Jang Yang}",
year = "2004",
month = "7",
day = "1",
doi = "10.1158/0008-5472.CAN-03-3474",
language = "English",
volume = "64",
pages = "4621--4628",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "13",

}

TY - JOUR

T1 - BPR0L075, a novel synthetic indole compound with antimitotic activity in human cancer cells, exerts effective antitumoral activity in vivo

AU - Kuo, Ching Chuan

AU - Hsieh, Hsing Pang

AU - Pan, Wen Yu

AU - Chen, Ching Ping

AU - Liou, Jing Ping

AU - Lee, Shiow Ju

AU - Chang, Yi Ling

AU - Chen, Li Tzong

AU - Chen, Chiung Tong

AU - Chang, Jang Yang

PY - 2004/7/1

Y1 - 2004/7/1

N2 - 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 BPROL075 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 BPROL075-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.

AB - 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 BPROL075 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 BPROL075-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.

UR - http://www.scopus.com/inward/record.url?scp=3042740981&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=3042740981&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-03-3474

DO - 10.1158/0008-5472.CAN-03-3474

M3 - Article

C2 - 15231674

AN - SCOPUS:3042740981

VL - 64

SP - 4621

EP - 4628

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 13

ER -