Journal
PHARMACOLOGICAL REPORTS
Volume 71, Issue 2, Pages 289-298Publisher
SPRINGER HEIDELBERG
DOI: 10.1016/j.pharep.2019.01.001
Keywords
Breast cancer; Nor-wogonin; Apoptosis; Cell cycle arrest; Multi-target flavone
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Funding
- NCI NIH HHS [R01 CA195558, T32 CA121938, R01 CA238042, R01 CA160911] Funding Source: Medline
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Background: Nor-wogonin, a polyhydroxy flavone, has been shown to possess antitumor activity. However, the mechanisms responsible for its antitumor activity are poorly studied. Herein, we investigated the mechanisms of nor-wogonin actions in triple-negative breast cancer (TNBC) cells. Methods: Effects of nor-wogonin on cell proliferation and viability of four TNBC cell lines (MDA-MB-231, BT-549, HCC70, and HCC1806) and two non-tumorigenic breast cell lines (MCF-10A and AG11132) were assessed by BrdU incorporation assays and trypan blue dye exclusion tests. Cell cycle and apoptosis analyses were carried out by flow cytometry. Protein expression was analyzed by immunoblotting. Results: Nor-wogonin significantly inhibited the growth and decreased the viability of TNBC cells; however, it exhibited no or minimal effects in non-tumorigenic breast cells. Nor-wogonin (40 mu M) was a more potent anti-proliferative and cytotoxic agent than wogonin (100 mu M) and wogonoside (100 mu M), which are structurally related to nor-wogonin. The antitumor effects of nor-wogonin can be attributed to cell cycle arrest via reduction of the expression of cyclin D1, cyclin B1, and CDK1. Furthermore, norwogonin induced mitochondrial apoptosis, (as evidenced by the increase in % of cells that are apoptotic), decreases in the mitochondrial membrane potential (Delta Psi m), increases in Bax/Bcl-2 ratio, and caspase-3 cleavage. Moreover, nor-wogonin attenuated the expression of the nuclear factor kappa-B and activation of signal transducer and activator of transcription 3 pathways, which can be correlated with suppression of transforming growth factor-beta-activated kinase 1 in TNBC cells. Conclusion: These results showed that nor-wogonin might be a potential multi-target agent for TNBC treatment. (C) 2019 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.
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