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Gastrointestinal Oncology Research Laboratory, Division of Solid Tumor Oncology, Department of Medicine, [M. M., G. K. S.] and Program of Molecular Pharmacology and Experimental Therapeutics [F. M. S., Y. S.], Memorial Sloan Kettering Cancer Center, New York, New York 10021, and UPR Centre National de la Recherche Scientifique, Universite Montpellier II, 34095 Montpellier Cedex 05, France [T. C.]
Treatment of the human colon cancer cells Hct116 with SN-38 (an activemetabolite of CPT-11) 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 vector-transfected 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.
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