Background: Colorectal cancer (CRC) is a common cause of oncological deaths worldwide. Alterations of the epigenetic landscape constitute are a well-documented hallmark of CRC phenotype. Accumulation of aberrant DNA methylation and histone acetylation plays a major role in altering gene activity and driving tumor onset, progression and metastasis.
Objective: In this study we evaluated the effect of suberoylanilide hydroxamic acid (SAHA), a pan histone deacetylase inhibitor, and decitabine (DAC), a DNA methyltransferase inhibitor, either alone or in combination, on Caco-2 human colon cancer cell line in vitro.
Results: Our results showed that SAHA and DAC, separately, significantly decreased cell proliferation, induced apoptosis and cell cycle arrest of Caco-2 cell line. On the other hand, the sequential treatment of Caco-2 cells, first with DAC and then with SAHA, induced a synergistic anti-tumor effect with as significant enhancement of growth inhibition and apoptosis induction in Caco-2 cell line as compared to cells treated with either drug alone. Furthermore, the combination therapy upregulates protein expression levels of pro-apoptotic proteins Bax, p53 and cytochrome c, down regulates the expression of anti-apoptotic Bcl-2 protein and increases the cleavage of procaspases 8 and 9; this suggests that the combination activates apoptosis via both the intrinsic and extrinsic pathways. Mechanistically, we demonstrated that the synergistic anti-neoplastic activity of combined SAHA and DAC involves an effect on PI3K/AKT and Wnt/β-catenin signaling.
Conclusion: In conclusion, our results provide evidence for the profound anti-tumorigenic effect of sequentially combined SAHA and DAC in CRC cell line and offer new insights into the corresponding underlined molecular mechanism.