Different Schedule-Dependent Effects of Epigenetic Modifiers on Cytotoxicity by Anticancer Drugs in Colorectal Cancer Cells

Abstract

Limited information is currently available on how to apply epigenetic modifiers to current colorectal cancer (CRC) chemotherapy. The purpose of this study is to clarify the schedule-dependent effects of combined treatment with conventional anticancer drugs and epigenetic modifiers in human CRC cells. Cytotoxicity in 4 CRC cell lines (SW480, HT29, SW48, and HCT116) was measured using the WST-8 assay. As epigenetic modifiers, 3 DNA methyltransferase (DNMT) inhibitors such as decitabine (DAC), azacytidine (AC), and zebularine (Zeb), and 3 histone deacetylase (HDAC) inhibitors including trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), and valproic acid (VPA) were used. Combination effects were analyzed by the isobologram method. SW480 cells showed the lowest sensitivity to the anticancer drugs 5-fluorouracil, SN-38 (the active form of irinotecan), and oxaliplatin. In SW480 cells, epigenetic modifiers other than VPA showed the most significant synergistic effects when used before anticancer drugs, while VPA showed synergistic effects in co-or post-treatment. In the 3 other CRC cells, synergistic effects were less frequent and weaker. The dose of anticancer drugs may be reduced by combining epigenetic modifiers in SW480 cells, which are less sensitive to anticancer drugs, unlike the more sensitive HT29, SW48, and HCT116 cell lines. These results provide useful information for understanding how to incorporate epigenetic modifiers into current CRC chemotherapy.Key words schedule-dependent treatment; epigenetic therapy; colorectal cancer; DNA methyltransferase inhibitor; histone deacetylase inhibitor Epigenetic alterations such as DNA methylation and histone modifications have been identified as a crucial driving force in the initiation and progression of cancer.1) Since epigenetic alterations are reversible, epigenetic modifiers may be beneficial in chemotherapy.2) Several epigenetic modifiers including DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors have been approved by U.S. Food and Drug Administration (FDA) for the treatment of cancer.Combined chemotherapy, including 5-fluorouracil (5-FU) and either irinotecan (CPT-11) or oxaliplatin (L-OHP), has improved the survival period of metastatic colorectal cancer (CRC). However, resistance to these anticancer drugs, which limits the effectiveness of chemotherapy, has been reported. 3,4) In order to overcome this issue, novel combination therapy using epigenetic modifiers is expected. Clinical trials on combination therapy have been performed using solid tumors including CRC.5,6) However, there is not enough integrated information on how to apply epigenetic modifiers to current CRC chemotherapy. We previously reported that a co-treatment with decitabine (DAC, 5-aza-2′-deoxycytidine), a DNMT inhibitor, and L-OHP exerted the most potent synergistic effects among the combinations tested using 5 epigenetic modifiers and 5-FU, CPT-11, or L-OHP in 4 different CRC cell lines. 7)The treatment schedule is important for effective cancer ...

Correlation Analysis of Protein Expression of 10 HDAC/Sirtuin Isoenzymes with Sensitivities of 23 Anticancer Drugs in 17 Cancer Cell Lines and Potentiation of Drug Activity by Co-Treatment with HDAC Inhibitors

“…Moreover, no significant positive correlation between the toxicity mediated by 5-fluorouracil and expression of Sirt2 was detected. Combination studies of unspecific zinc dependent HDAC inhibitors as well as sirtuin inhibitors have been performed by several groups, who found a positive combination effect between 5-fluorouracil and various HDACs [ 30 , 31 ]. Similarly, significant positive correlations were found between the topoisomerase inhibitor etoposide and Sirt2 protein expression with Sirt5, and an inverse correlation of the vinca alkaloid vinblastine with HDAC6.…”

Perspective Chapter: Topoisomerase 1 and Colo Rectal Carcinoma

“…These transformers include DNA methyl transferase, decitabine, azacytidine, and zebularine. The study also used drugs that were considered histone deacetylase inhibitors including the well-known mood stabilizer valproic acid with promising results [68]. During the process of cancer evolution, cancer cells have different strategies to survive.…”

IFI6 Downregulation Reverses Oxaliplatin Resistance of Colorectal Cancer Cells by Activating the ROS-Induced p38MAPK Signaling Pathway

“…9,10) But the frequent application of OXA has led to drug resistance of tumor cells, which has brought great limitations to the treatment of CRC. [11][12][13][14] To date, drug resistance remains one of the barriers of CRC patient's treatment, which leads to the poor outcomes in patients. 15,16) Therefore, finding new strategies to overcome OXA resistance is of great significance to change the low survival rate of CRC patients.…”