No abstract

Resveratrol (Res; 3,4′,5-trihydroxy-trans-stilbene), which is a polyphenol found in grapes, can block cell proliferation and induce growth arrest and/or cell death in several types of cancer cells. However, the precise mechanisms by which Res exerts anticancer effects remain poorly understood. Res blocked both anchorage-dependent and -independent growth of HT-29 and COLO 201 human colon cancer cells in a dose- and time-dependent manner. Annexin V staining and Western blot analysis revealed that Res induced apoptosis accompanied by an increase in Caspase-8 and Caspase-3 cleavage. In HT-29 cells, Res caused autophagy as characterized by the appearance of autophagic vacuoles by electron microscopy and elevation of microtubule-associated protein 1 light chain 3 (LC3)-II by immunoblotting, which was associated with the punctuate pattern of LC3 detected by fluorescein microscopy. Inhibition of Res-induced autophagy by the autophagy inhibitor 3-methyladenine caused a significant decrease in apoptosis accompanied by decreased cleavage of Casapse-8 and Caspase-3, indicating that Res-induced autophagy was cytotoxic. However, inhibition of Res-induced apoptosis by the pan-caspase inhibitor Z-VAD(OMe)-FMK did not decrease autophagy but elevated LC3-II levels. Interestingly, Res increased the intracellular reactive oxygen species (ROS) level, which correlated to the induction of Casapse-8 and Caspase-3 cleavage and the elevation of LC3-II; treatment with ROS scavenger N-acetyl cysteine diminished this effect. Therefore, the effect of Res on the induction of apoptosis via autophagy is mediated through ROS in human colon cancer cells.

p63 expression may be a marker of basal/progenitor cells in tumors of epidermis and epidermal appendages, and may be a diagnostic marker of these tumors.

We compared the effects of identical amounts but different proportions of dietary n-3 polyunsaturated fatty acids (PUFAs) on N-methyl-N-nitrosourea (MNU)-induced mammary cancer in a rat model. The ability of dietary docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to suppress mammary cancer was evaluated. Female Sprague-Dawley rats were randomly assigned to three groups and maintained on diets containing 10% fatty acid consisting of EPA, a 1:1 mixture of EPA-plus-DHA, or DHA. The experimental diet was started after administration of MNU at 49 days of age, and the rats were maintained on the respective diets until the largest mammary tumor reached >1 cm in diameter or until the end of the study period (20 wk after MNU). All histologically detected mammary carcinomas were evaluated, irrespective of size. The DHA diet was associated with significant suppression of the carcinogenic effect of MNU compared with the EPA and EPA-plus-DHA diets: tumor incidence decreased to 23% (3/13) compared with 73% (11/15) and 65% (12/17) (P < 0.01 and P < 0.05, respectively); tumor multiplicity decreased to 0.23 compared with 1.67 and 1.59 (P < 0.01 and P < 0.05, respectively). There was no significant difference in tumor latency among the DHA, EPA, and EPA-plus-DHA groups (119, 105, and 117 days, respectively). Over 20 wk, the fatty acid composition of serum and mammary fat tissue reflected differences in the dietary n-3 PUFAs. Although DHA suppressed MNU-induced mammary carcinogenesis more effectively than EPA, generalized steatosis including mammary fat tissue appeared in all three groups.

The effect of monoterpene perillyl alcohol (POH) on cell growth, cell cycle progression, and expression of cell cycle-regulatory proteins in estrogen receptor (ER)-positive (KPL-1 and MCF-7) and ER-negative (MKL-F and MDA-MB-231) human breast cancer cell lines was examined. POH inhibited cell proliferation in a dose-dependent manner in all cell lines tested. POH at a dose of 500 micro M had a cytostatic effect, in which growth inhibition was due to accumulation of cells in G1-phase. Cell cycle progression was preceded by a decrease in G1 cyclins (cyclin D1 and E), followed by an increase in p21(Cip1/Waf1) and a decrease in proliferating cell nuclear antigen level. Levels of p53 and cyclin A were unchanged. POH at a dose of 75 mg/kg administered intraperitoneally three times a week throughout the entire 6-week experimental period suppressed orthotopically transplanted KPL-1 tumor cell growth and regional lymph node metastasis in a nude mouse system. POH inhibited both ER-positive and -negative human breast cancer cell growth in vitro, and suppressed growth and metastasis in vivo.