**4. Anti-proliferative and apoptosis induction role of selenium in HCC**

One of the earlier studies by Baker et al. in the 1990s on human hepatoma Hep3B cell line showed that selenium supplementation restores glutathione peroxidase mRNA expression in selenium-deprived cell culture [53]. Hill et al. investigated in human liver cancer HepG2 cell line showed that in selenium-deprived HepG2 cells, selenoprotein P release decreased to 10% [54]. Further, various studies consistently reported apoptosis induction effect of selenite in human hepatoma cells HepG2 cells, potentially by inducing the release of lactate dehydrogenase (LDH) and decreasing glutathione (GSH) production [55–57]. Another study reported that selenite-induced apoptosis in HepG2 cells was mediated by reactive oxygen species (ROS) that activated JNK to regulate apoptosis [58]. A more recent study on selenium nanoparticle surface decorated with galangin can induce apoptosis through p38 and AKT signaling pathway in HepG2 cells [59]. Similarly, selenium nanoparticles synthesized with extract of hawthorn fruit also induced apoptosis in HepG2 cells [60]. Various mechanisms may be involved in the apoptosis induction

*Selenium in the Prevention and Treatment of Hepatocellular Carcinoma: From Biomedical… DOI: http://dx.doi.org/10.5772/intechopen.88960*

role of selenium and selenium-containing inhibitors for HCC. Tagaram et al. reported a selenium-containing MAPK and PI3 kinase inhibitor, the *Se*, *Se*′-1,4 phenylenebis(1,2-ethanediyl) bisisoselenourea (PBISe), possesses anti-proliferative and pro-apoptotic ability in HCC cell lines *in vitro* and in *in vivo* in a spontaneous murine HCC model [39]. PBISe promoted apoptosis by inhibiting PI3K, MAPK, and STAT3 signaling *in vitro* and with significant reduce tumor sizes *in vivo* (*p* < 0.007) with a significant reduction in tumor survival marker PCNA and angiogenesis markers Vegf-A, Vegf-R3, and CD34 [39]. These results demonstrate the chemotherapeutic effects of selenium by inhibiting tumor proliferation and inducing tumor apoptosis for HCC treatment.
