Abstract
Aberrant DNA methylation, especially hypermethylation of tumor suppressor genes, has been associated with many cancers' progression. 5-Aza-2′-deoxycytidine (DAC) can reverse hypermethylation-induced gene silencing via regulating DNA methyltransferases (DNMTs) activity, In addition, low-dose of DAC was proved to exert durable antitumor effects against solid tumor cells. Nevertheless, no clinical effect of DAC has been made when fighting against pancreatic cancer. Hence, it is necessary to raise a novel therapeutic strategy that further enhance the efficacy of DAC but not increase side effect, which impede the utilization of DAC. In the present study, we have discovered that C188-9, a novel signal transduction activator of transcription (STAT) inhibitor, could improve the antitumor effects of low-dose DAC in vivo and in vitro. Further study demonstrated that such improvement was attributed to re-expression of Ras association domain family member 1A (RASSF1A), a well-known tumor suppressor gene. Bisulfite sequencing PCR (BSP) assay showed that C188-9 combined with DAC treatment could significantly reverse the hypermethylation status of RASSF1A promoter, which indicated that C188-9 could enhance the demethylation efficacy of DAC. Our data demonstrated that DNA methyltransferase 1 (DNMT1) was the underlying mechanism that C188-9 regulates the demethylation efficacy of DAC. Overall, these findings provide a novel therapeutic strategy combining low-dose DAC and C188-9 to improve therapeutic efficacy by inhibiting DNMT1-inducing promoter methylation.
Highlights
Pancreatic ductal adenocarcinoma is highly lethal, for which the 5-year relative survival is currently 8% [1], and it is predicted to become the second leading cause of cancer-related deaths by 2030 in the United States [2]
In order to study the effect of C188-9 in enhancing sensitivity of pancreatic cancer cells to low-dose DAC treatment, Cell Counting Kit-8 (CCK-8) assay and clonogenic assay were performed to test the effect of different doses of DAC in growth of pancreatic cancer cells in vitro
Through CCK-8 assay, we found that 1 μM DAC treatment for 72 h cannot significantly suppress proliferation of pancreatic cancer cells
Summary
Pancreatic ductal adenocarcinoma is highly lethal, for which the 5-year relative survival is currently 8% [1], and it is predicted to become the second leading cause of cancer-related deaths by 2030 in the United States [2]. The clinical effectiveness of DAC therapy in solid tumors has been demonstrated in recent years [4, 5]; most of the clinical trials investigating DAC alone or in combination with other agents have shown relatively disappointing results [6]. Low-dose DAC was proved to be relatively well tolerated in both hematological malignancies and solid tumors. Pancreatic cancer cells are sensitive to monotherapy of DAC, there were limited evidence for the optimal strategy of appropriate doses and combination therapies with DAC. A novel therapeutic strategy that reduces toxicity while enhancing demethylation efficiency of DAC is essential
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