Sonia Abou Najem, Ghada Khawaja, Mohammad Hassan Hodroj and Sandra Rizk* Pages 1 - 19 ( 19 )
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.
apoptosis, epigenetics, colon cancer, decitabine, suberoylanilide hydroxamic acid
Department of Biological Sciences, Faculty of Science, Beirut Arab University, Department of Biological Sciences, Faculty of Science, Beirut Arab University, Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut, Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut