BPR1K653, a novel aurora kinase inhibitor, exhibits potent anti-proliferative activity in MDR1 (P-gp170)-mediated multidrug-resistant cancer cells

Chun-Hei Cheung, Wen Hsing Lin, John Tsu An HsuJohn, Tzyh Chyuan Hour, Teng Kuang Yeh, Shengkai Ko, Tzu Wen Lien, Mohane Selvaraj Coumar, Jin Fen Liu, Wen Yang Lai, Hui Yi Shiao, Tian Ren Lee, Hsing Pang Hsieh, Jang-Yang Chang

Research output: Contribution to journalArticle

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Abstract

Background: Over-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells. Principal Findings: BPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats. Conclusions and Significance: BPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments.

Original languageEnglish
Article numbere23485
JournalPloS one
Volume6
Issue number8
DOIs
Publication statusPublished - 2011 Aug 24

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Aurora Kinases
phosphotransferases (kinases)
Cells
neoplasms
Neoplasms
cell lines
drugs
uterine cervical neoplasms
drug resistance
carcinogenesis
pharmacokinetics
transporters
Aurora Kinase B
Pharmaceutical Preparations
apoptosis
neoplasm cells
BPR1K653
cells
Pharmacokinetics
therapeutics

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Cheung, Chun-Hei ; Lin, Wen Hsing ; HsuJohn, John Tsu An ; Hour, Tzyh Chyuan ; Yeh, Teng Kuang ; Ko, Shengkai ; Lien, Tzu Wen ; Coumar, Mohane Selvaraj ; Liu, Jin Fen ; Lai, Wen Yang ; Shiao, Hui Yi ; Lee, Tian Ren ; Hsieh, Hsing Pang ; Chang, Jang-Yang. / BPR1K653, a novel aurora kinase inhibitor, exhibits potent anti-proliferative activity in MDR1 (P-gp170)-mediated multidrug-resistant cancer cells. In: PloS one. 2011 ; Vol. 6, No. 8.
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title = "BPR1K653, a novel aurora kinase inhibitor, exhibits potent anti-proliferative activity in MDR1 (P-gp170)-mediated multidrug-resistant cancer cells",
abstract = "Background: Over-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells. Principal Findings: BPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats. Conclusions and Significance: BPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments.",
author = "Chun-Hei Cheung and Lin, {Wen Hsing} and HsuJohn, {John Tsu An} and Hour, {Tzyh Chyuan} and Yeh, {Teng Kuang} and Shengkai Ko and Lien, {Tzu Wen} and Coumar, {Mohane Selvaraj} and Liu, {Jin Fen} and Lai, {Wen Yang} and Shiao, {Hui Yi} and Lee, {Tian Ren} and Hsieh, {Hsing Pang} and Jang-Yang Chang",
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Cheung, C-H, Lin, WH, HsuJohn, JTA, Hour, TC, Yeh, TK, Ko, S, Lien, TW, Coumar, MS, Liu, JF, Lai, WY, Shiao, HY, Lee, TR, Hsieh, HP & Chang, J-Y 2011, 'BPR1K653, a novel aurora kinase inhibitor, exhibits potent anti-proliferative activity in MDR1 (P-gp170)-mediated multidrug-resistant cancer cells', PloS one, vol. 6, no. 8, e23485. https://doi.org/10.1371/journal.pone.0023485

BPR1K653, a novel aurora kinase inhibitor, exhibits potent anti-proliferative activity in MDR1 (P-gp170)-mediated multidrug-resistant cancer cells. / Cheung, Chun-Hei; Lin, Wen Hsing; HsuJohn, John Tsu An; Hour, Tzyh Chyuan; Yeh, Teng Kuang; Ko, Shengkai; Lien, Tzu Wen; Coumar, Mohane Selvaraj; Liu, Jin Fen; Lai, Wen Yang; Shiao, Hui Yi; Lee, Tian Ren; Hsieh, Hsing Pang; Chang, Jang-Yang.

In: PloS one, Vol. 6, No. 8, e23485, 24.08.2011.

Research output: Contribution to journalArticle

TY - JOUR

T1 - BPR1K653, a novel aurora kinase inhibitor, exhibits potent anti-proliferative activity in MDR1 (P-gp170)-mediated multidrug-resistant cancer cells

AU - Cheung, Chun-Hei

AU - Lin, Wen Hsing

AU - HsuJohn, John Tsu An

AU - Hour, Tzyh Chyuan

AU - Yeh, Teng Kuang

AU - Ko, Shengkai

AU - Lien, Tzu Wen

AU - Coumar, Mohane Selvaraj

AU - Liu, Jin Fen

AU - Lai, Wen Yang

AU - Shiao, Hui Yi

AU - Lee, Tian Ren

AU - Hsieh, Hsing Pang

AU - Chang, Jang-Yang

PY - 2011/8/24

Y1 - 2011/8/24

N2 - Background: Over-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells. Principal Findings: BPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats. Conclusions and Significance: BPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments.

AB - Background: Over-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells. Principal Findings: BPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats. Conclusions and Significance: BPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments.

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