6-Shogaol has been shown to possess many antitumor properties including inhibition of cancer cell growth, inhibition of cancer metastasis, induction of apoptosis in cancer cells and induction of cancer cell differentiation. Despite its prominent antitumor effects, the direct molecular target of 6-shogaol has remained elusive. To identify the direct targets of 6-shogaol, a comprehensive antitumor profile of 6-shogaol (NSC752389) was tested in the NCI-60 cell line in an in vitro screen. The results show that 6-shogaol is COMPARE negative suggesting that it functions via a mechanism of action distinct from existing classes of therapeutic agents. Further analysis using microarray gene profiling and Connectivity Map analysis showed that MCF-7 cells treated with 6-shogaol display gene expression signatures characteristic of peroxisome proliferator activated receptor c (PPARc) agonists, suggesting that 6-shogaol may activate the PPARc signaling pathway for its antitumor effects. Indeed, treatment of MCF-7 and HT29 cells with 6-shogaol induced PPARc transcriptional activity, suppressed NFjB activity, and induced apoptosis in breast and colon cancer cells in a PPARc-dependent manner. Furthermore, 6-shogaol is capable of binding to PPARc with a binding affinity comparable to 15-delta prostaglandin J2, a natural ligand for PPARc. Together, our findings suggest that the antitumor effects of 6-shogaol are mediated through activation of PPARc and imply that activation of PPARc might be beneficial for breast and colon cancer treatment.

This study was designed to investigate eight herbal active constituents (andrographolide, asiaticoside,asiatic acid, madecassic acid, eupatorin, sinensetin, caffeic acid, and rosmarinic acid) on their potentialinhibitory effects on human cytochrome P450 1A2 (CYP1A2) activity. A fluorescence-based enzyme assaywas performed by co-incubating human cDNA-expressed CYP1A2 with its selective probe substrate, 3-cyano-7-ethoxycoumarin (CEC), in the absence or presence of various concentrations of herbal activeconstituents. The metabolite (cyano-hydroxycoumarin) formed was subsequently measured in order toobtain IC50values. The results indicated that only eupatorin and sinensetin moderately inhibited CYP1A2with IC50values of 50.8 and 40.2 M, while the other active compounds did not significantly affect CYP1A2activity with IC50values more than 100 M. Kivalues further determined for eupatorin and sinensetinwere 46.4 and 35.2 M, respectively. Our data indicated that most of the investigated herbal constituentshave negligible CYP1A2 inhibitory effect. In vivo studies however may be warranted to ascertain theinhibitory effect of eupatorin and sinensetin on CYP1A2 activity in clinical situations

The efficacy of cisplatin for treating nasopharyngeal carcinoma (NPC) is limited by the dose-related toxicities and the development of resistance to cisplatin. Recent studies have shown that B cell lymphoma-2 (BCL-2) is overexpressed and confers chemoresistance in NPC. Thus, targeted therapy against BCL-2 may enhance the antitumour effects of chemotherapy by sensitizing the tumor cells to undergo apoptosis. This study evaluated the combined effects of BCL-2 inhibition and cisplatin in NPC cells. Our results demonstrate that inhibition of BCL-2 by small-hairpin RNA (shRNA) or the BCL-2 inhibitor YC137, synergizes cisplatin sensitivity in NPC cells that overexpress BCL-2. We also show that YC137 enhance cisplatin-induced apoptosis in HK1 and CNE1 cells through suppression of BCL-2 protein expression, induction of mitochondrial depolarization and activation of caspase 9 and caspase 3/7. These findings suggest that the combination of BCL-2 inhibition and cisplatin represents a promising strategy for treating NPC.