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.
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.
Coudray
Anne-Marie
AM
INSERM U482, Signal Transduction and Cellular Functions in Diabetes and Digestive Cancers, Paris, France.
Louvet
Christophe
C
Kornprobst
Michel
M
Raymond
Eric
E
André
Thierry
T
Tournigand
Christophe
C
Faivre
Sandrine
S
De Gramont
Aimery
A
Larsen
Annette K
AK
Gespach
Christian
C
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000494:pharmacology; D005971:Glutamates / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D000077146:Irinotecan; D009842:Oligopeptides / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D000068437:Pemetrexed; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D059004:Topoisomerase I Inhibitors; D054460:rho-Associated Kinases
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D005971:Glutamates; D047908:Intracellular Signaling Peptides and Proteins; D009842:Oligopeptides; D009944:Organoplatinum Compounds; D011799:Quinazolines; D059004:Topoisomerase I Inhibitors; C094299:ZD 9331; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D000068437:Pemetrexed; D000077150:Oxaliplatin; D006147:Guanine; D000077146:Irinotecan; D013940:Thymidylate Synthase; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D004264:DNA Topoisomerases, Type I; D005472:Fluorouracil; D002166:Camptothecin