Abstract
IntroductionProteasome inhibition is an attractive approach to anticancer therapy and may have relevancy in breast cancer treatment. Natural products, such as dietary flavonoids, have been suggested as natural proteasome inhibitors with potential use for cancer prevention and therapeutics. We previously reported that apigenin, a flavonoid widely distributed in many fruits and vegetables, can inhibit proteasome activity and can induce apoptosis in cultured leukemia Jurkat T cells. Whether apigenin has proteasome-inhibitory activity in the highly metastatic human breast MDA-MB-231 cells and xenografts, however, is unknown.MethodsMDA-MB-231 breast cancer cell cultures and xenografts were treated with apigenin, followed by measurement of reduced cellular viability/proliferation, proteasome inhibition, and apoptosis induction. Inhibition of the proteasome was determined by levels of the proteasomal chymotrypsin-like activity, by ubiquitinated proteins, and by accumulation of proteasome target proteins in extracts of the treated cells or tumors. Apoptotic cell death was measured by capase-3/caspase-7 activation, poly(ADP-ribose) polymerase cleavage, and immunohistochemistry for terminal nucleotidyl transferase-mediated nick end labeling positivity.ResultsWe report for the first time that apigenin inhibits the proteasomal chymotrypsin-like activity and induces apoptosis not only in cultured MDA-MB-231 cells but also in MDA-MB-231 xenografts. Furthermore, while apigenin has antibreast tumor activity, no apparent toxicity to the tested animals was observed.ConclusionWe have shown that apigenin is an effective proteasome inhibitor in cultured breast cancer cells and in breast cancer xenografts. Furthermore, apigenin induces apoptotic cell death in human breast cancer cells and exhibits anticancer activities in tumors. The results suggest its potential benefits in breast cancer prevention and treatment.
Highlights
Proteasome inhibition is an attractive approach to anticancer therapy and may have relevancy in breast cancer treatment
We report for the first time that apigenin inhibits the proteasomal chymotrypsin-like activity and induces apoptosis in cultured MDA-MB-231 cells and in MDA-MB231 xenografts
We have shown that apigenin is an effective proteasome inhibitor in cultured breast cancer cells and in breast cancer xenografts
Summary
Proteasome inhibition is an attractive approach to anticancer therapy and may have relevancy in breast cancer treatment. We previously reported that apigenin, a flavonoid widely distributed in many fruits and vegetables, can inhibit proteasome activity and can induce apoptosis in cultured leukemia Jurkat T cells. By examining a broad range of cell culture models, it has been found that proteasome inhibitors rapidly induce tumor cell apoptosis, selectively activate the cell death program in cancer or oncogene-transformed cells, but not in normal or untransformed cells, and are able to trigger apoptotic death in human cancer cells that are resistant to various anticancer agents [9,11,13,14,15,16,17,18]
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