Outcome in these studies demonstrate that combined low-dose therapy of tocotrienol and PPAR antagonists work synergistically to inhibit human breast cancer cell growth, and this effect appears to be mediated by a corresponding reduction in PI3K/Akt mitogenic signaling and substantial reduction in PPAR expression. Although high dose therapy with PPAR agonist also was Oprozomib clinical trial also found to prevent human breast cancer cells growth, it is most likely that these outcomes are mediated through PPAR independent mechanisms because the preponderance of experimental evidence strongly suggest that elevations in PPAR expression can be an indicator of robust breast cancer cell growth and resistance to anticancer therapy, whereas a decrease in PPAR expression can be an indicator of reduced breast cancer proliferation and enhanced responsiveness to chemotherapeutic agents. ese results also demonstrate that combination anticancer therapy does not always result in an additive or synergistic anticancer response, but could result in a paradoxical/antagonistic phytomorphology response as was observed with the combined therapy of tocotrienol with PPAR agonist in MCF 7 and MDA MB 231 human breast cancer cells. e significance of understanding the intracellular mechanism of action of anticancer agents is important for improving therapeutic response. It is also plainly evident that usage of tocotrienol in combination with PPAR antagonist may have potential therapeutic value in treatment of breast cancer in women. The 40S ribosomal protein S6 kinase functions downstream of the mammalian target of rapamycin, which plays essential roles in cell growth, Everolimus clinical trial protein translation and cell survival and is a target for cancer therapy. mTOR inhibitors are, nevertheless, of limited success. Although Akt is thought to act upstream of mTOR, persistent inhibition of p70 S6 kinase or S6K1 may stimulate Akt using a negative feedback loop. S6K exists as two homologs, S6K1 and S6K2 but little is known about the function of S6K2. In the present study, we have examined the results of S6K2 on activation and cell survival. Silencing of S6K1 caused a small decrease whereas knockdown of S6K2 caused a considerable escalation in tumor necrosis factor and TNFrelated apoptosis inducing ligand mediated apoptosis. Contrary to S6K1, depletion of S6K2 by siRNA reduced basal and TNF induced Akt phosphorylation. Ectopic expression of constitutively active Akt in MCF 7 cells repaired cell survival in S6K2 depleted cells. We’ve previously found that activation of Akt induces downregulation of Bid via p53. Knockdown of S6K2 caused an increase in p53 and downregulation of p53 by siRNA reduced Bid level. Silencing of Bid blunted the ability of S6K2 deficiency to boost TNF induced apoptosis.