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

Hakata,Shuko; Terashima,Jun; Shimoyama,Yu; Okada,Kouji; Fujioka,Shiho; Ito,Erika; Habano,Wataru; Ozawa,Shogo

doi:10.3892/ol.2018.7883

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

Authors:
- Shuko Hakata
- Jun Terashima
- Yu Shimoyama
- Kouji Okada
- Shiho Fujioka
- Erika Ito
- Wataru Habano
- Shogo Ozawa
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Affiliations: Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba‑cho, Iwate 028‑3694, Japan, Division of Molecular Microbiology, Iwate Medical University, Yahaba‑cho, Iwate 028‑3694, Japan
Published online on: January 26, 2018 https://doi.org/10.3892/ol.2018.7883
Pages: 4641-4648

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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.

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