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

Abstract

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.

Quercetin Inhibits Breast Cancer Stem Cells via Downregulation of Aldehyde Dehydrogenase 1A1 (ALDH1A1), Chemokine Receptor Type 4 (CXCR4), Mucin 1 (MUC1), and Epithelial Cell Adhesion Molecule (EpCAM)

“…Quercetin, the most common flavonoid, has been shown to act against various cancers, including breast cancer [ 14 – 18 ]. Recent studies have reported that quercetin inhibits breast cancer by inhibiting signal transduction, inducing cancer cell apoptosis, and suppressing proliferation, invasion, and metastases of tumor cells [ 19 – 21 ]. However, the effect of quercetin on breast CSCs has not been described.…”

Myricetin Inhibits Angiogenesis by Inducing Apoptosis and Suppressing PI3K/Akt/mTOR Signaling in Endothelial Cells

“…They exert anticancer activities through their antioxidant, anti-inflammatory, anti-angiogenic, anti-proliferative, and apoptotic actions. 13 – 18 Myricetin has a quercetin backbone with an additional hydroxyl group ( Fig. 1A ).…”

Medicinal Profile, Phytochemistry, and Pharmacological Activities of Murraya koenigii and its Primary Bioactive Compounds

“…Girinimbine, another M. koenigii-derived carbazole alkaloid, showed growth inhibitory activity in human hepatocellular carcinoma and lung cancer cells in vitro [118]. Rutin, quercetin, kaempferol, and apigenin, present in leaf extracts of M. koenigii, showed the dose-dependent inhibition of endogenous 26S proteasome activity in MDA-MB-231 cells [52]. Therefore, M. koenigii contains remarkable anticancer compounds, especially mahanine, which has been reported to show anticancer activity targeting different signaling pathways [46].…”