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Abstract

Backgorund: Many studies have reported the anticancer effects of cucurbitacins. However, related molecular events need to be described. The current study aims at evaluating the impact of cucurbitacins D, E, and I on death and survival pthways in colorectal cancer (CRC).

Methods: Cell viability was determined by MTT assay in both SW-480 and HT-29 (only cucurbitacin-E). Total RNA was extracted, and the expression of mRNA was quantified by real-time RT-PCR analysis.

Results: The MTT results for SW-480 revealed that cucurbitacins E and I had almost similar potency in different doses, but cucurbitacin-D only had up to almost 50% lethality as a function of dose. Cucurbitacin-E reached IC50 in a very lower dosage at 6 micromolar in HT-29. The expression levels of BAX mRNA were significantly decreased or remained almost unaltered (HT-29) and that of BCL-2 mRNA witnessed a considerable increase (p˂0.05), which is a non-canonical paradigm. What is more, while the expression levels of p53 and AIF mRNA was increased in all treatments of cucurbitacins in SW-480, they were suppressed in HT-29 cells treated with cucurbitacin-E. Caspase-3 expression increased in both colon cell lines. According to expression patern, only cucurbitacin-I had the possibility of suppressing the AKT-mTOR pathway. While autophagy genes were increased in cucurbitacins, cucurbitacin-I decreased the ATG5 expression level.

Conclusion: We noticed that cucurbitacins have the potential to reveal more about both non-canonical interactions of death pathway and BAX/BAk independent apoptosis. These results indicate that cucurbitacins might contribute to BAX/BCL-2-independent cell death in CRC cells.