Drg1, a novel target for modulating sensitivity to CPT-11 in colon cancer cells

Monica Motwani, Francis M. Sirotnak, Yuhong She, Therese Commes, Gary K. Schwartz

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


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.

Original languageEnglish
Pages (from-to)3950-3955
Number of pages6
JournalCancer Research
Issue number14
StatePublished - 15 Jul 2002
Externally publishedYes


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