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Roscovitine synergizes with conventional chemo-therapeutic drugs to induce efficient apoptosis of human colorectal cancer cells

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World journal of Gastroenterology 2008年第33期14卷 5162-5175页

作者： Mohamed Salah I Abaza Abdul-Majeed A Bahman rajaa j al-attiyah Molecular Biology Program Department of Biological Sciences Faculty of Science Kuwait UniversitySafaat 13006 Kuwait Department of Microbiology Faculty of Medicine Kuwait UniversitySafaat 13006 Kuwait

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 treat-ed, individually and in combination, with Rosco, taxol, 5-Fluorouracil (5-FU), doxorubicine or vinblastine. The antiproliferative effects and the type of interaction of Rosco with tested chemotherapeutic drugs were de-termined. Cell cycle alterations were investigated by fluorescence-activated cell sorter FACS analysis. Apop-tosis was determined by DNA fragmentation assay. RESULTS: Rosco inhibited the proliferation of tumor cells in a time-and dose-dependent manner. The ef-ficacies 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, re-spectively. The combination of Rosco and chemothera-peutic 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 chemothera-peutic drugs to induce efficient apoptosis in human colorectal cancer cells. Sequential, inverted sequential and simultaneous treatment of cancer cells with combi-nations 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 eff icacy of many anticancer drugs depends on their ability to induce apoptotic cell death, modulation of this parameter by cell cycle inhibi-tors may provide a novel chemo-preventive and chemo-therapeutic strategy for human colorectal cancer.

关键词： Human colorectal cancer cell lines Cyclindependent kinase inhibition Chemosensitization Synergy Apoptosis Cell cycle

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