Differential sensitization of two human colon cancer cell lines to the antitumor effects of irinotecan combined with 5-aza-2'-deoxycytidine

Abstract

Abstract. Irinotecan (CPT-11) is a key therapeutic drug used in the treatment of colorectal cancer, although acquired or constitutive resistance to CPT-11 (and its activated metabolite SN-38) can lead to tumor progression. Since the acquisition of drug resistance can result from DNA hypermethylation, the antitumor activity of CPT-11 and SN-38 was assessed in combination with a known DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, also known as decitabine (DAC). DAC potentiated the antitumor activity of CPT-11 additively, and that of SN-38 synergistically, as measured by colony formation in the human colorectal cancer HCT116 cell line. No DAC potentiation of these antitumor effects was observed with another human colorectal cancer HT29 cell line. Anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein expression was reduced to 50-67% of the control following a single treatment with CPT-11, SN-38, or DAC, and was markedly reduced to 7-8% following the combination of CPT-11/SN-38 with DAC. By contrast, Bcl-2 protein expression was barely detected in HT29. Wilms' tumor protein (WT1), which has been shown to be a positive regulator of Bcl-2 in HCT116 cells through WT1-kncokdown experiments, was downregulated in HCT116 and HT29 cells when treated with CPT-11/SN-38 combined with DAC, with decreases greater than any single administration of CPT-11, SN-38, or DAC. The extent of CPT-11/SN-38 potentiation by DAC may depend on Bcl-2 expression levels in human colorectal cancer cells.

Chemomodulatory Effect of the Marine-Derived Metabolite “Terrein” on the Anticancer Properties of Gemcitabine in Colorectal Cancer Cells

“…The anti-apoptotic gene, BCL2, which plays a role in programmed cell death as an antiapoptotic protein [ 47 ], was over-expressed when HCT-116 cells were treated with Terr alone under normoxic conditions; however, it was significantly downregulated when the cells were treated with the combination treatment (GCB + Terr). This observation is supported by similar combination studies that showed the downregulation of BCL2 when HCT-116 was treated with combination treatment [ 48 ].…”

Cellular irinotecan resistance in colorectal cancer and overcoming irinotecan refractoriness through various combination trials including DNA methyltransferase inhibitors: a review

“…Several studies have reported that a combination of DNMT inhibitors, such as 5-aza-2’ deoxycytidine (DAC), with irinotecan could overcome irinotecan resistance by different mechanisms in human colon cancer cell models. We found that enhanced apoptosis by irinotecan was achieved in combination with DAC, through the downregulation of the anti-apoptotic gene Bcl-2 [ 67 ] . Bcl-2/adenovirus E1B 19 kDa protein-interacting protein (BNIP3), a pro-apoptotic gene, was methylated in human colon cancer cell lines.…”

Epigenetic modulations in cancer: predictive biomarkers and potential targets for overcoming the resistance to topoisomerase I inhibitors

“…Indeed, another hypomethylating cytidine analogue, 5-aza-2′-deoxycytidine (DAC), enhanced the anticancer efficacy of CPT-11, the prodrug of irinotecan, additively and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), synergistically. The extent to which DAC potentiates CPT-11 or SN-38 might be dependent on the expression level of anti-apoptotic Bcl-2 protein in human colorectal cancer cells, as the higher intracellular protein levels of Bcl-2 were shown to be associated with the resistance of cancer cells to CPT-11 and SN-38 [ 67–70 ]. Treatment with DAC before irinotecan significantly improved tumor suppression in a xenograft model with OCUM2 M/SN38 irinotecan-resistant gastric cancer cells.…”