The DNA double-stranded break repair protein endo-exonuclease as a therapeutic target for cancer.
DNA repair mechanisms are crucial for the maintenance of genomic stability and are emerging as potential therapeutic targets for cancer. In this study, we report that the endo-exonuclease, a protein involved in the recombination repair process of the DNA double-stranded break pathway, is overexpressed in a variety of cancer cells and could represent an effective target for developing anticancer drugs. We identify a dicationic diarylfuran, pentamidine, which has been used clinically to treat opportunistic infections and is an inhibitor of the endo-exonuclease as determined by enzyme kinetic assay. In clonogenic and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays as well as in the in vivo Lewis lung carcinoma mouse tumor model, pentamidine is shown to possess the ability to selectively kill cancer cells. The LD50 of pentamidine on cancer cells maintained in vitro is correlated with the endo-exonuclease enzyme activity. Tumor cell that has been treated with pentamidine is reduced in the endo-exonuclease as compared with the untreated control. Furthermore, pentamidine synergistically potentiates the cytotoxic effect of DNA strand break and cross-link-inducing agents such as mitomycin C, etoposide, and cisplatin. In addition, we used the small interfering RNA for the mouse homologue of the endo-exonuclease to down-regulate the level of endo-exonuclease in the mouse myeloma cell line B16F10. Down-regulation of the endo-exonuclease sensitizes the cell to 5-fluorouracil. These studies suggested the endo-exonuclease enzyme as a novel potential therapeutic target for cancer.
Department of Oncology, Faculty of Medicine, McGill University Health Centre/Montreal General Hospital, 1650 Avenue Cedar, Room 10-148, Montreal, Quebec, Canada H3G 1A4. tchow@po-box.mcgill.ca
Terry Y-K
TY
Chow
Moulay A
MA
Alaoui-Jamali
Chiaoli
C
Yeh
Leonard
L
Yuen
David
D
Griller
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D004396:Coloring Agents / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D004260:DNA Repair; D015536:Down-Regulation; D004353:Drug Evaluation, Preclinical; D004720:Endonucleases / Q000737:chemistry* / Q000378:metabolism*; D005047:Etoposide / Q000737:chemistry / Q000494:pharmacology; D005092:Exonucleases / Q000737:chemistry* / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology; D009369:Neoplasms / Q000378:metabolism; D010419:Pentamidine / Q000737:chemistry / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D034741:RNA, Small Interfering / Q000737:chemistry / Q000378:metabolism; D011995:Recombination, Genetic; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D034741:RNA, Small Interfering; D013778:Tetrazolium Salts; D013844:Thiazoles; D016685:Mitomycin; D010419:Pentamidine; D005047:Etoposide; D004247:DNA; D004720:Endonucleases; D005092:Exonucleases; C020104:endoexonuclease; C022616:thiazolyl blue; D002945:Cisplatin; D005472:Fluorouracil