c-Myc is a novel target of cell cycle arrest by honokiol in prostate cancer cells.

Honokiol (HNK), a highly promising phytochemical derived from Magnolia officinalis plant, exhibits in vitro and in vivo anticancer activity against prostate cancer but the underlying mechanism is not fully clear. This study was undertaken to delineate the role of c-Myc in anticancer effects of HNK. Exposure of prostate cancer cells to plasma achievable doses of HNK resulted in a marked decrease in levels of total and/or phosphorylated c-Myc protein as well as its mRNA expression. We also observed suppression of c-Myc protein in PC-3 xenografts upon oral HNK administration. Stable overexpression of c-Myc in PC-3 and 22Rv1 cells conferred significant protection against HNK-mediated growth inhibition and G0-G1 phase cell cycle arrest. HNK treatment decreased expression of c-Myc downstream targets including Cyclin D1 and Enhancer of Zeste Homolog 2 (EZH2), and these effects were partially restored upon c-Myc overexpression. In addition, PC-3 and DU145 cells with stable knockdown of EZH2 were relatively more sensitive to growth inhibition by HNK compared with control cells. Finally, androgen receptor overexpression abrogated HNK-mediated downregulation of c-Myc and its targets particularly EZH2. The present study indicates that c-Myc, which is often overexpressed in early and late stages of human prostate cancer, is a novel target of prostate cancer growth inhibition by HNK.

Sulforaphane Inhibits c-Myc-Mediated Prostate Cancer Stem-Like Traits.

Preventive and therapeutic efficiencies of dietary sulforaphane (SFN) against human prostate cancer have been demonstrated in vivo, but the underlying mechanism(s) by which this occurs is poorly understood. Here, we show that the prostate cancer stem cell (pCSC)-like traits, such as accelerated activity of aldehyde dehydrogenase 1 (ALDH1), enrichment of CD49f+ fraction, and sphere forming efficiency, are attenuated by SFN treatment. Interestingly, the expression of c-Myc, an oncogenic transcription factor that is frequently deregulated in prostate cancer cells, was markedly suppressed by SFN both in vitro and in vivo. This is biologically relevant, because the lessening of pCSC-like phenotypes mediated by SFN was attenuated when c-Myc was overexpressed. Naturally occurring thio, sulfinyl, and sulfonyl analogs of SFN were also effective in causing suppression of c-Myc protein level. However, basal glycolysis, a basic metabolic pathway that can also be promoted by c-Myc overexpression, was not largely suppressed by SFN, implying that, in addition to c-Myc, there might be another SFN-sensitive cellular factor, which is not directly involved in basal glycolysis, but cooperates with c-Myc to sustain pCSC-like phenotypes. Our study suggests that oncogenic c-Myc is a target of SFN to prevent and eliminate the onset of human prostate cancer. J. Cell. Biochem. 117: 2482-2495, 2016. © 2016 Wiley Periodicals, Inc.

Activation of oxidative stress and inflammatory factors could account for histopathological progression of aflatoxin-B1 induced hepatocarcinogenesis in rat.

Aflatoxin-B1 (AFB1) intoxication is known to develop hepatocellular carcinoma (HCC). However, pathogenesis and diagnosis of AFB1-induced HCC remain undefined. This article describes histopathological progression versus kinetics of the placental glutathione S-transferase (GST-pi) expression and profiles of the antioxidant enzymes, pro-inflammatory cytokines, and proliferative cell nuclear antigen (PCNA) in the liver from the rats administered with two doses of 1 mg AFB1/kg b.w. Histopathologically, hepatocytes necrosis could be observed after 4 weeks of the AFB1 treatment, which subsequently developed into the well-defined foci of altered hepatocytes (FAH) at 10 weeks post-treatment stage. This was consistent with an increasing trend of GST-pi immunostaining especially in the liver foci as a function of FAH progression and thus, suggesting that GST-pi over expression may serve as a marker for AFB1-induced hepatocarcinogenesis. The liver from AFB1-treated rats showed significantly enhanced level of reactive oxygen species coinciding with the declined immunostaining for superoxide dismutase-1, a committed enzyme of the antioxidant pathway, in the FAH regions and also with declined activity of the other antioxidant enzymes. Concordantly, the liver from the AFB1-treated rats showed over expression of pro-inflammatory cytokines; TNF-α & IL-1α and a cell proliferative marker PCNA. These findings present histological characterization of AFB1-induced HCC development and provide evidence for activation of oxidative stress-pro-inflammatory pathway during hepatocarcinogenesis induced by AFB1 toxicity.

Apoptosis of Dalton's lymphoma due to in vivo treatment with emodin is associated with modulations of hydrogen peroxide metabolizing antioxidant enzymes.

The evolving concept of pro-oxidative mechanism-based antitumor activity of emodin (1,3,8-trihydroxy-6-methyl anthraquinone), derived mainly from in vitro studies, needs to be defined for in vivo tumor models. The present article describes apoptosis and regression of Dalton's lymphoma (DL) in mice by emodin vis a vis modulations of hydrogen peroxide (H2O2) metabolizing antioxidant enzymes in the tumor cells in vivo. A non-toxic dose (40 mg/kg bw) of emodin, given intraperitoneally to the DL bearing mice daily up to 12th post DL transplantation day, caused a significant decline (P < 0.05) in the number of viable DL cells and could significantly increase life span of the DL mice (P < 0.01). A significant decline in Bcl2/Bax ratio consistent with the release of mitochondrial cytochrome c release in DL cells from emodin-treated DL mice suggested that emodin could induce mitochondrial pathway of apoptosis in the DL cells in vivo. Apoptosis of DL cells by emodin was further confirmed by the appearance of smaller DNA fragments on DNA ladder analysis. Over activation of both, the Cu-Zn-superoxide dismutases (SOD1) and Mn-SOD (SOD2), has been found correlated with the tumor suppression. Emodin caused significant increases in the expression and activity of SOD1 and SOD2 in the DL cells. H2O2 produced by SODs is degraded by catalase and glutathione peroxidase in the cells. Both these enzymes were observed to be declined significantly with a concomitant increment in H2O2 concentration (P < 0.01) in the DL cells from emodin-treated DL mice. It is concluded that emodin is able to induce mitochondrial pathway of apoptosis in the DL cells in vivo via reciprocal modulations of H2O2 producing and degrading antioxidant enzymes.