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Garcinol, obtained from Garcinia indica, has exhibited some promising anticancer activity. In particular, our earlier work has demonstrated its ability to inhibit cell proliferation and induction of apoptosis in multiple cancer cell lines representative of breast, prostate, as well as pancreatic cancers. However, its exact mechanism of action remains largely unclear. Here we show that garcinol also targets signal transducer and activator of transcription-3 (STAT-3) signaling pathway. STAT-3 is frequently found to be activated in many cancer types and this is the first report on such action of garcinol leading to its anticancer effects. Garcinol inhibited total, as well as phosphorylated, STAT-3 in breast, prostate and pancreatic cancer cell lines and was also found to inhibit cell invasion of all the cancer cell lines tested. STAT-3 phosphorylation was inhibited by garcinol in a dose-dependent manner. We also observed an inhibitory effect of garcinol on IL-6-induced STAT-3 phosphorylation and production of urokinase-type plasminogen activator, vascular endothelial growth factor and matrix metalloproteinase-9, which might explain the reduced invasion and aggressiveness of cells treated with garcinol. The results were further verified in vivo using MDA-MB-231 breast cancer mouse xenograft model where administration of garcinol significantly inhibited tumor growth, and western blot analysis of remnant tumor lysates showed reduced STAT-3 expression and activation. These results suggest that garcinol may have translational potential as chemopreventive or therapeutic agent against multiple cancers and inhibition of STAT-3 signaling pathway is one of the mechanisms by which garcinol exerts its anticancer effects. [ABSTRACT FROM PUBLISHER]

Abstract: Cisplatin resistance is a major problem in the successful treatment of squamous cell carcinoma (SCC). In the present study we showed, for the first time, that the constitutive activation of NF-κB partly contributes to cisplatin resistance and that the inactivation of NF-κB by natural agents [G2535 (isoflavone mixture containing genistein and diadzein), 3,3′-diindolylmethane (Bioresponse BR-DIM referred to as B-DIM)] could overcome this resistance, resulting in the inhibition of cell growth and induction of apoptosis, which might be an useful strategy for achieving better treatment outcome in patients diagnosed with cisplatin-resistant tumors of SCC. [Copyright &y& Elsevier]

Abstract: Aims: The protein kinase C (PKC) family of enzymes has been implicated in cellular proliferation, differentiation, and apoptosis. However, the distribution of specific PKC isoforms with varying functions in normal and malignant human tissues remains to be determined. The objective of this study was to investigate the expression of certain PKC isoforms (α, βI, βII, ε) in human breast cancer specimens relative to adjacent uninvolved tissue (n =24) and in the normal breast tissue obtained from patients undergoing reduction mammoplasty (n =12). Main methods: Western blot analysis using PKC isoform specific antibodies was performed on tissue extracts from breast tumors, adjacent uninvolved tissues, and reduction mammoplasty tissues. Key findings: Mean levels of cytosolic and membrane PKC-α, PKC-βI, and PKC-βII were significantly higher in the cancer specimens than in the adjacent uninvolved breast tissues (Wilcoxon signed-ranks test; P <0.05 for each, after adjustment for multiple comparisons). There was a notably higher mean level of membrane PKC-βII isozyme in Her-2 positive and in poorly differentiated tumors. No significant differences were observed when normal tissue adjacent to tumor was compared to breast tissue obtained from reduction mammoplasty specimens. Significance: Higher level of PKC-α, PKC-βI, and PKC-βII in cancer specimens and higher level of PKC-βII in Her-2 positive tumors require further exploration of the intracellular pathways involving PKC-α and -β isoforms in breast cancer because both could be specific targets for the development of new therapies and for the prevention and treatment of this disease. [Copyright &y& Elsevier]

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated clinical benefit in patients with nonsmall cell lung cancer (NSCLC), particularly those with tumors that have EGFR-TK domain mutations. Moreover, the EGFR and cyclooxygenase (COX)-2 pathways are known to enhance the procarcinogenic effects of each other in different tumor types. Therefore, it was hypothesized that tumor EGFR mutation status may influence the effectiveness of simultaneous EGFR and COX-2 inhibition in patients with NSCLC.Methods: Three NSCLC cell lines with varying EGFR mutation status and sensitivities to EGFR-TKIs were selected: H3255 (L858R), H1650 (del E746-A750), and H1781 (wild-type EGFR). Cells were treated with erlotinib, gefitinib, or celecoxib alone, and the combination of both EGFR-TKI inhibitors with celecoxib. Cell survival and apoptosis was assessed and correlated with the expression of COX-2, EGFR, pEGFR, Akt, pAkt, expression, and derived prostaglandin E2 (PGE(2)).Results: Celecoxib by itself was found to have no effects on cell growth or apoptosis in any of the cell lines. Erlotinib and gefitinib inhibited cell growth and induced apoptosis in both mutant cell lines and did so in H1781 cells at 10-fold higher concentrations. Celecoxib when added to erlotinib or gefitinib significantly enhanced the antiproliferative and proapoptotic effects in both mutant cell lines but had no additional effects in H1781 cells. Greater down-regulation of COX-2, EGFR, pEGFR, Akt, pAkt, and PGE(2) was found when H3255 cells were treated with the combination compared with any of the single agents alone.Conclusions: The results of the current study demonstrate that the effectiveness of the addition of celecoxib to an EGFR-TKI is significantly greater in NSCLC cells with EGFR mutations, which is likely due to more complete inhibition of both pathways. [ABSTRACT FROM AUTHOR]

Chemoresistance to 5-fluorouracil (5-Fu)-based chemotherapy is a leading obstacle in achieving effective treatment for colorectal cancer (CRC). Typically, NF-κB activation induced by the chemotherapeutics themselves is an important cause resulting in chemoresistance. Specifically, NF-κB activation can inhibit tumor cell apoptosis and induce chemoresistance. Drugs that can prevent NF-κB activation induced by chemotherapeutics are urgently needed to overcome chemoresistance. Obviously, aspirin is one of these agents, which has been demonstrated to possess antitumor activities and as an inhibitor of NF-κB. The current study aimed to investigate whether aspirin was able to overcome the chemoresistance to 5-Fu in CRC, together with the potential synergistic mechanisms. Our results suggested that aspirin remarkably potentiated the inhibitory effect of 5-Fu on the growth and invasion of resistant cells in vitro. In vivo, aspirin markedly enhanced the antitumor activity of 5-Fu in suppressing tumor growth and metastasis, and down-regulating the expression of NF-κB-regulated genes in the 5-Fu-resistant cells. Obviously, aspirin completely eradicated the 5-Fu-induced NF-κB activation, without inducing pronounced adverse effects. Taken together, findings in this study suggest that aspirin can reverse chemoresistance and potentiate the antitumor effect of 5-Fu, which is achieved through abolishing the 5-Fu-induced NF-κB activation, suggesting that aspirin may be a promising adjuvant therapeutic agent for CRC. [ABSTRACT FROM AUTHOR]