Colorectal Cancer
Copyright ©2008 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Sep 7, 2008; 14(33): 5162-5175
Published online Sep 7, 2008. doi: 10.3748/wjg.14.5162
Roscovitine synergizes with conventional chemo-therapeutic drugs to induce efficient apoptosis of human colorectal cancer cells
Mohamed Salah I Abaza, Abdul-Majeed A Bahman, Rajaa J Al-Attiyah
Mohamed Salah I Abaza, Abdul-Majeed A Bahman, Molecular Biology Program, Department of Biological Sciences, Faculty of Science, Kuwait University, Safaat 13006, Kuwait
Rajaa J Al-Attiyah, Department of Microbiology, Faculty of Medicine, Kuwait University, Safaat 13006, Kuwait
Author contributions: Abaza MSI designed research; Abaza MSI and Bahman AMA contributed equally to the experimental work execution, writing and revising the paper; and Al-Attiyah RJ carried out cell cycle analysis by fluorescence activated cell sorter.
Supported by Kuwait University, Research Project No. SL01/05
Correspondence to: Dr. Mohamed-Salah I Abaza, Molecular Biology Program, Department of Biological Sciences, Faculty of Science, Kuwait University, PO Box 5696, Safaat 13006, Kuwait. abaza@kuc01.kuniv.edu.kw
Telephone: +965-9-835274 Fax: +965-4-847054
Received: April 10, 2008
Revised: July 7, 2008
Accepted: July 14, 2008
Published online: September 7, 2008
Abstract

AIM: To examine the ability of cyclin-dependent kinase inhibitor (CDKI) roscovitine (Rosco) to enhance the antitumor effects of conventional chemotherapeutic agents acting by different mechanisms against human colorectal cancer.

METHODS: Human colorectal cancer cells were treated, individually and in combination, with Rosco, taxol, 5-Fluorouracil (5-FU), doxorubicin or vinblastine. The antiproliferative effects and the type of interaction of Rosco with tested chemotherapeutic drugs were determined. Cell cycle alterations were investigated by fluorescence-activated cell sorter FACS analysis. Apoptosis was determined by DNA fragmentation assay.

RESULTS: Rosco inhibited the proliferation of tumor cells in a time- and dose-dependent manner. The efficacies of all tested chemotherapeutic drugs were markedly enhanced 3.0-8.42 × 103 and 130-5.28 × 103 fold in combination with 5 and 10 μg/mL Rosco, respectively. The combination of Rosco and chemotherapeutic drugs inhibited the growth of human colorectal cancer cells in an additive or synergistic fashion, and in a time and dose dependent manner. Rosco induced apoptosis and synergized with tested chemotherapeutic drugs to induce efficient apoptosis in human colorectal cancer cells. Sequential, inverted sequential and simultaneous treatment of cancer cells with combinations of chemotherapeutic drugs and Rosco arrested the growth of human colorectal cancer cells at various phases of the cell cycle as follows: Taxol/Rosco (G2/M- and S-phases), 5-FU/Rosco (S-phase), Dox/Rosco (S-phase) and Vinb/Rosco (G2/M- and S-phases).

CONCLUSION: Since the efficacy of many anticancer drugs depends on their ability to induce apoptotic cell death, modulation of this parameter by cell cycle inhibitors may provide a novel chemo-preventive and chemotherapeutic strategy for human colorectal cancer.

Keywords: Human colorectal cancer cell lines; Cyclin dependent kinase inhibition; Chemosensitization; Synergy; Apoptosis; Cell cycle