Inactivation of the Reactive Oxygen Species-Dependent PI3K/Akt/Mtor Signaling Pathway by Phloroglucinol Contributes to Cytotoxicity in Hep3B Human Hepatocellular Carcinoma Cells.

Background/aims: Phloroglucinol is a phenolic derivative isolated from brown algae and reportedly has the potential to induce apoptosis in cancer cells, but its mechanism is unclear. This study aimed to elucidate the complete anticancer mechanism of phloroglucinol in Hep3B human hepatocellular carcinoma (HCC) cells.

Methods: We investigated whether phloroglucinol inhibits the proliferation of Hep3B cells by inducing DNA damage and apoptosis, and conducted a study on the mechanism involved. We also explored whether phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway is involved in phloroglucinol-induced apoptosis. In addition, we evaluated whether reactive oxygen species (ROS) was involved in the anticancer activity of phloroglucinol.

Results: Our results revealed that phloroglucinol disrupted mitochondrial integrity and induced caspase-dependent apoptosis by altering the expression of Bcl-2 family proteins and increasing the cytosolic release of cytochrome c . Phloroglucinol also inactivated the PI3K/Akt/mTOR signaling pathway, and pretreatment with a PI3K inhibitor remarkably augmented the phloroglucinol-induced cytotoxic effect in Hep3B cells. In addition, phloroglucinol significantly stimulated generation of ROS and reduced glutathione ratios. However, a ROS scavenger attenuated phloroglucinol-induced oxidative stress, DNA damage, and apoptosis, thus restoring the reduced cellular viability by blockading phloroglucinol-mediated inactivation of PI3K/Akt/mTOR signaling.

Conclusion: Our findings support a mechanism in which phloroglucinol enhances Hep3B cell apoptosis by inactivating the ROS-dependent PI3K/Akt/mTOR pathway, which implies that ROS generation acts as an inducer of phloroglucinol-mediated anticancer activity. Taken together, our findings support further research on the potential of phloroglucinol as a candidate for treating HCC.