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Increased anticancer activity of the thymidylate synthase inhibitor BGC9331 combined with the topoisomerase I inhibitor SN-38 in human colorectal and breast cancer cells: induction of apoptosis and ROCK cleavage through caspase-3-dependent and -independent mechanisms.

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.
AuthorsAnne-Marie Coudray, Christophe Louvet, Michel Kornprobst, Eric Raymond, Thierry André, Christophe Tournigand, Sandrine Faivre, Aimery De Gramont, Annette K Larsen, Christian Gespach
JournalInternational journal of oncology (Int J Oncol) Vol. 27 Issue 2 Pg. 553-61 (Aug 2005) ISSN: 1019-6439 [Print] Greece
PMID16010439 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • Enzyme Inhibitors
  • Folic Acid Antagonists
  • Glutamates
  • Intracellular Signaling Peptides and Proteins
  • Oligopeptides
  • Organoplatinum Compounds
  • Quinazolines
  • Topoisomerase I Inhibitors
  • ZD 9331
  • benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone
  • Pemetrexed
  • Oxaliplatin
  • Guanine
  • Irinotecan
  • Thymidylate Synthase
  • Protein Serine-Threonine Kinases
  • rho-Associated Kinases
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • DNA Topoisomerases, Type I
  • Fluorouracil
  • Camptothecin
Topics
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Breast Neoplasms (metabolism, pathology)
  • Camptothecin (analogs & derivatives, pharmacology)
  • Caspase 3
  • Caspase Inhibitors
  • Caspases (metabolism)
  • Cell Cycle (drug effects)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Colorectal Neoplasms (metabolism, pathology)
  • Cysteine Proteinase Inhibitors (pharmacology)
  • DNA Topoisomerases, Type I (metabolism)
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Enzyme Inhibitors (pharmacology)
  • Fluorouracil (pharmacology)
  • Folic Acid Antagonists (pharmacology)
  • Glutamates (pharmacology)
  • Guanine (analogs & derivatives, pharmacology)
  • HT29 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Irinotecan
  • Oligopeptides (pharmacology)
  • Organoplatinum Compounds (pharmacology)
  • Oxaliplatin
  • Pemetrexed
  • Protein Serine-Threonine Kinases (metabolism)
  • Quinazolines (pharmacology)
  • Thymidylate Synthase (antagonists & inhibitors, metabolism)
  • Time Factors
  • Topoisomerase I Inhibitors
  • rho-Associated Kinases

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