Drg1, a novel target for modulating sensitivity to CPT-11 in colon cancer cells Journal Article
| Authors: | Motwani, M.; Sirotnak, F. M.; She, Y.; Commes, T.; Schwartz, G. K. |
| Article Title: | Drg1, a novel target for modulating sensitivity to CPT-11 in colon cancer cells |
| Abstract: | Treatment of the human colon cancer cells Hct116 with SN-38 (an active metabolite of CPT-II) resulted in G2 cell cycle arrest without Induction of apoptosis. However, subsequent treatment of SN-38-treated Hct116 cells with flavopiridol Induced apoptosis. One of the genes markedly up-regulated during cell cycle arrest by SN-38 and suppressed during apoptosis by SN-38 followed by flavopiridol in Hct116 cells is Drg1. We found that Drg1 had profound effects on SN-38 sensitivity. Inhibition of endogenous Drg1 expression in Hct116 cells by stable expression of an antisense (AS) Drg1 cDNA increased the sensitivity of cells to undergo apoptosis by SN-38. Clonogenic and apoptosis assays with AS Drg1-expressing cells showed a 2-fold decrease in the IC50 and a 4-5-fold increase in induction of apoptosis with SN-38. Conversely, the forced expression of Drg1 in SW620 cells increased the resistance of these cells to SN-38-induced apoptosis by 2-5-fold. Moreover, when xenografted in mice, AS Drg1-expressing Hct116 cells were 3-fold more sensitive to CPT-11 as compared with vector transfected Hct116 cells. Similarly, tumors established from Drg1 overexpressing SW620 cells were more resistant to CPT-11 as compared with tumors established from vectortransfected SW620 cells in mice. Taken together, our data suggest that Drg1 is a novel gene that plays a direct role in resistance to CPT-11. Inhibition of Drg1 may provide a new means to increase the sensitivity of colon cancer cells to CPT-11. |
| Keywords: | controlled study; human cell; animals; mice; gene overexpression; apoptosis; antineoplastic combined chemotherapy protocols; 7 ethyl 10 hydroxycamptothecin; camptothecin; colonic neoplasms; dna, antisense; gtp-binding proteins; tumor cells, cultured; xenograft model antitumor assays; irinotecan; drug synergism; gene expression regulation; drug mechanism; xenograft; mice, nude; colon cancer; inhibition kinetics; cell cycle g2 phase; flavonoids; flavopiridol; piperidines; drug metabolism; ic 50; drug sensitivity; marker gene; complementary dna; clonogenesis; dna, complementary; prodrugs; molecular stability; mitosis inhibition; genetic resistance; humans; human; male; priority journal; article; drg1 gene |
| Journal Title: | Cancer Research |
| Volume: | 62 |
| Issue: | 14 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2002-07-01 |
| Start Page: | 3950 |
| End Page: | 3955 |
| Language: | English |
| PUBMED: | 12124325 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 14 November 2014 -- Source: Scopus |
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