Abstract
The folate analogue BGC9331 is a new thymidylate synthase (TS) inhibitor showing a broad spectrum of cyto-toxic activity against several human solid tumors, including colorectal cancer. In this study, we investigated the anticancer activity of BGC9331 either alone or combined with 5-fluorouracil (5-FU), MTA (multi-target antifolate), oxali-platin and SN-38, the active metabolite of the topoisomerase I inhibitor CPT-11. The antiproliferative activity of each drug and BGC9331-based combinations was investigated in the HT-29 human colorectal cancer cell line and its HT-29/5-FU counterparts selected for resistance to 5-FU. BGC9331 combined with MTA or SN-38 induced synergistic responses in HT-29 cells. Treatment of HT-29 cells with either BGC9331 or SN-38 increased caspase-3 activity and the percentage of apoptotic cells from 3 to 13%. Both drugs also augmented the proteolytic cleavage of the Rho-kinase ROCK-1 that was attenuated by the caspase-3 pathway inhibitor z-DEVD-fmk. BGC9331 combined with SN-38 further increased the percentage of apoptotic cells to 25%, and inhibited cell cycle progression and cell proliferation by 65%. This was accompanied by proteolytic activation of ROCK-1, through both caspase-3-dependent and -independent mechanisms, as shown in caspase-3-deficient MCF-7 breast cancer cells. These encouraging results warrant further preclinical investigations and clinical trials on the use of BGC9331 combined with SN-38/CPT-11 in treatment of patients with advanced colorectal or gastric cancers.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Camptothecin / analogs & derivatives*
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Camptothecin / pharmacology
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Caspase 3
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Caspase Inhibitors
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Caspases / metabolism*
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Cell Cycle / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology
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Cysteine Proteinase Inhibitors / pharmacology
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DNA Topoisomerases, Type I / metabolism
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Dose-Response Relationship, Drug
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Drug Synergism
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Enzyme Inhibitors / pharmacology
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Fluorouracil / pharmacology
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Folic Acid Antagonists / pharmacology
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Glutamates / pharmacology
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Guanine / analogs & derivatives
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Guanine / pharmacology
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HT29 Cells
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Humans
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Intracellular Signaling Peptides and Proteins
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Irinotecan
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Oligopeptides / pharmacology
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Organoplatinum Compounds / pharmacology
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Oxaliplatin
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Pemetrexed
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Protein Serine-Threonine Kinases / metabolism*
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Quinazolines / pharmacology*
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Thymidylate Synthase / antagonists & inhibitors
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Thymidylate Synthase / metabolism
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Time Factors
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Topoisomerase I Inhibitors
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rho-Associated Kinases
Substances
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Antineoplastic Agents
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Caspase Inhibitors
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Cysteine Proteinase Inhibitors
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Enzyme Inhibitors
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Folic Acid Antagonists
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Glutamates
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Intracellular Signaling Peptides and Proteins
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Oligopeptides
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Organoplatinum Compounds
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Quinazolines
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Topoisomerase I Inhibitors
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ZD 9331
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benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone
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Pemetrexed
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Oxaliplatin
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Guanine
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Irinotecan
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Thymidylate Synthase
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Protein Serine-Threonine Kinases
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rho-Associated Kinases
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CASP3 protein, human
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Caspase 3
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Caspases
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DNA Topoisomerases, Type I
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Fluorouracil
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Camptothecin