A direct comparison of butyrate, 4-phenylbutyrate, and β-hydroxybutyrate in an in vitro tumor therapy model.

BACKGROUND

Cancer remains the second leading cause of death worldwide, emphasizing the urgent need for more effective therapies. One promising approach is the use of naturally occurring molecules. The short-chain fatty acid butyrate has attracted attention for its protective and anticancer properties in colorectal cancer. However, the beneficial effects of butyrate are restricted to colonocytes. To determine whether systemically available butyrate derivatives could elicit similar effects in other cell types, we investigated 4-phenylbutyrate and β-hydroxybutyrate treatment regimens in a non-colon BALB/c cell line.

MATERIALS AND

METHODS

The anticarcinogenic potential of butyrate derivatives was evaluated using the BALB/c tumor therapy model, which simulates the early stages of malignant cell transformation. Mechanistic effects were investigated through immunoblotting and flow cytometry.

RESULTS

Initial results revealed that both butyrate and 4-phenylbutyrate exhibited anticancer effects in a time- and dose-dependent manner. Butyrate and 4-phenylbutyrate promoted histone acetylation, activated the tumor suppressor p53 and the expression of p21, leading to cell cycle arrest, with butyrate inducing a G0/1-phase arrest while 4-phenylbutyrate induced an S-phase arrest. Furthermore, butyrate and 4-phenylbutyrate resulted in reduced caspase-3 activation, while simultaneously increasing the number of apoptotic cells. β-hydroxybutyrate did not show measurable effects in the parameters investigated.

CONCLUSION

In summary, this study provides a new comparative insight into both anticancer effects and the underlying mechanisms of action of the three butyrate derivatives in a non-colon cell model. Our findings indicate that 4-phenylbutyrate represents the more promising derivative in the BALB/c tumor therapy model.