Chemopreventive Effect of Cinnamon and Its Bioactive Compounds in a Rat Model of Premalignant Prostate Carcinogenesis.

Cinnamon and its bioactive compounds inhibit prostate cancer cell proliferation in vitro. The aim of the current study was to assess the chemopreventive efficacy of cinnamon (CN) and its bioactive compounds in vivo using N-methyl-N-nitrosourea (MNU) and testosterone (T) to induce prostate carcinogenesis in male Wistar/National Institute of Nutrition rats. Cancer-induced (CI) rats (n = 10) developed prostatic hyperplasia and prostatic intraepithelial neoplasia. These histopathologic changes were diminished in CI rats fed for 4 months with diets supplemented with either CN (n = 20) or its bioactive compounds (cinnamaldehyde, n = 10 and procyanidin B2, n = 10). Androgen receptor (AR) expression was lower in the prostates of CI rats than in control, but the AR target gene, probasin, was robustly upregulated. Treatment of CI rats with CN or its bioactive compounds upregulated AR expression but inhibited the expression of the 5-alpha reductase genes (Srd5a1 and Srd5a2) and did not further increase probasin expression, suggesting blunted transcriptional activity of AR due to the limited availability of dihydrotestosterone. MNU+T induced an altered oxidant status in rat prostate, which was reflected by an increase in lipid peroxidation and DNA oxidation. These changes were completely or partially corrected by treatment with CN or the bioactive compounds. CN and its active components increased the activity of the apoptotic enzymes caspase-8 and caspase-3 in the prostates of CI rats. In conclusion, our data demonstrate that CN and its bioactive compounds have inhibitory effects on premalignant prostate lesions induced by MNU + T and, therefore, may be considered for the chemoprevention of prostate cancer. PREVENTION RELEVANCE: The research work presented in this article demonstrates the chemopreventive efficacy of CN and its bioactive compounds in a rat model of premalignant prostate cancer.

Cytotoxicity and Proteasome Inhibition by Alkaloid Extract from Murraya koenigii Leaves in Breast Cancer Cells-Molecular Docking Studies.

Murraya koenigii (curry tree) leaves are rich in bioactive compounds such as flavonoids, alkaloids, and coumarins. Alkaloids from M. koenigii leaves have antianalgesic, antiulcerogenic, antiobesity, and antitumor activities. In this study, we tested the cytotoxic and proteasome-inhibitory potential of a total alkaloid extract (TAE) from M. koenigii leaves in the breast cancer cell line MDA-MB-231. The TAE decreased cell viability with an IC50 of 14.4 µg/mL and altered growth kinetics of breast cancer cells. TAE (32 µg/mL) arrested cells (35%) in the "S" phase of the cell cycle and induced apoptosis. The 26S proteasome, a multicatalytic protease complex, promotes tumor cell proliferation and protects tumor cells from apoptosis. The TAE and mahanine, a carbazole alkaloid present in M. koenigii leaves, preferentially inhibited the trypsin-like, but not the chymotrypsin-like proteolytic activity of the proteasome with an IC50 of 162 µg/mL and 287 µM, respectively. In silico analysis of 26 compounds from M. koenigii leaves revealed significant docking scores for mahanine and two other carbazole alkaloids with the ß2 and ß5 subunits of the catalytic 20S proteasome. Taken together, this study demonstrates that inhibition of the proteasome is an important biological activity of M. koenigii alkaloids, which may lead to cancer cell death.

In Vivo Inhibition of Proteasome Activity and Tumour Growth by Murraya koenigii Leaf Extract in Breast Cancer Xenografts and by Its Active Flavonoids in Breast Cancer Cells.

Inhibition of the 26S proteasome is an attractive approach for anticancer therapy. Proteasome inhibitors are known to selectively target cancer cells and make them more sensitive to chemotherapeutic agents. Murraya koenigii is a medicinally important herb of Asian origin and a rich source of bioactive compounds such as flavonoids and alkaloids. In the present study, we investigated the proteasome inhibitory and apoptotic effect of M. koenigii leaf extract in vivo in a xenograft tumor mouse model, and also assessed the toxicity if any in normal mice. M. koenigii extract did not lead to any toxicity in mice. Analysis of extract revealed the presence of flavonoid compounds which act as proteasome inhibitors. Quercetin treatment led to the decrease in the cell viability and arrest of cells in G2/M phase. Quercetin, Apigenin, Kaempferol and Rutin; flavonoids present in the leaf extract, dose-dependently inhibited the endogenous 26S proteasome activity in MDA-MB-231 cells. Reduction in tumor growth was associated with a decrease in proteasomal enzyme activities in the treated groups. Increased caspase-3 activity and TUNEL-positive cells indicated enhanced apoptosis with Murraya leaf extract treatment. Decreased expression of angiogenic and anti-apoptotic gene markers is indicative of inhibition of angiogenesis and promotion of apoptosis in the leaf extract treated tumors.