Background: Colorectal Cancer (CRC) is a common cause of oncological deaths worldwide.
Alterations of the epigenetic landscape constitute a well-documented hallmark of CRC phenotype. The
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 panhistone
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 a
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, downregulates the expression of antiapoptotic
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 the CRC cell line and offer new insights into the corresponding
underlined molecular mechanism.