摘要
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.
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）, doxorubicine 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 × 10^3 and 130-5.28 × 10^3 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 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.
基金
Kuwait University, Research Project No. SL01/05
关键词
直肠癌
化学敏感作用
细胞凋亡
细胞周期
协同作用
Human colorectal cancer cell lines
Cyclindependent kinase inhibition
Chemosensitization
Synergy
Apoptosis
Cell cycle
