Cytotoxic Effects of Hellebrigenin and Arenobufagin Against Human Breast Cancer Cells

Abstract

Development of new therapeutic strategies for breast cancer is urgently needed due to the sustained emergence of drug resistance, tumor recurrence and metastasis. To gain a novel insight into therapeutic approaches to fight against breast cancer, the cytocidal effects of hellebrigenin (Helle) and arenobufagin (Areno) were investigated in human estrogen receptor (ER)-positive breast cancer cell line MCF-7 and triple-negative breast cancer cell line MDA-MB-231. Helle exhibited more potent cytotoxicity than Areno in both cancer cells, and MCF-7 cells were more susceptible to both drugs in comparison with MDA-MB-231 cells. Apoptotic-like morphological characteristics, along with the downregulation of the expression level of Bcl-2 and Bcl-xL and the upregulation of the expression level of Bad, were observed in Helle-treated MCF-7 cells. Helle also caused the activation of caspase-8, caspase-9, along with the cleavage of poly(ADP-ribose) polymerase in MCF-7 cells. Helle-mediated necrosis-like phenotype, as evidenced by the increased propidium iodide (PI)-positive cells was further observed. G2/M cell cycle arrest was also induced by Helle in the cells. Upregulation of the expression level of p21 and downregulation of the expression level of cyclin D1, cyclin E1, cdc25C and survivin were observed in MCF-7 cells treated with Helle and occurred in parallel with G2/M arrest. Autophagy was triggered in MCF-7 cells and the addition of wortmannin or 3-MA, two well-known autophagy inhibitors, slightly but significantly rescued the cells. Furthermore, similar alterations of some key molecules associated with the aforementioned biological phenomena were observed in MDA-MB-231 cells. Intriguingly, the numbers of PI-positive cells in Helle-treated MCF-7 cells were significantly reduced by wortmannin and 3-MA, respectively. In addition, Helle-triggered G2/M arrest was significantly corrected by wortmannin, suggesting autophagy induction contributed to Helle-induced cytotoxicity of breast cancer cells by modulating necrosis and cell cycle arrest. Collectively, our results suggested potential usefulness of both Helle and Areno in developing therapeutic strategies to treat patients with different types of breast cancer, especially ER-positive breast cancer.

Hellebrigenin induces oral cancer cell apoptosis by modulating MAPK signalling and XIAP expression

“…Previous studies conducted on oestrogen receptor (ER)-positive and triple-negative breast cancer cells have demonstrated that hellebrigenin prevents cancer cell proliferation through cell cycle arrest at the G2/M phase, suppressing cell cycle regulators and inducing caspase-mediated apoptosis. 21 Similar findings have been observed in pancreatic and hepatic cancer cells following treatment with hellebrigenin. 15,20 Previous studies investigating the anticancer mode of action of hellebrigenin have shown that both hellebrin and hellebrigenin bind to and inhibit Na+/K+ ATPase with equal potency, leading to activation of caspase-mediated apoptosis of cancer cells.…”

Diphenyl disulfide potentiates the apoptosis of breast cancer cells through Bax proteolytic activation with accompanying autophagy

“…Furthermore, the lack of corresponding receptor targets means that triple-negative breast cancer (TNBC) does not respond to traditional ER-, epidermal growth factor receptor-2 (EGFR)-, and PR-targeted therapies. 21,22 Diphenyl disulfide has two phenyl groups that are connected with a disulfide bond. 13 DPDS derivatives, such as bis[2-(acylamino)phenyl] disulfide, 1,2-bis(4-chlorophenyl) disulfide, 1,2-bis (4-methoxyphenyl) disulfide and 1,2-bis(4-nitrophenyl) disulfide, have been shown to have anticancer effects.…”

“…Due to the developing and continuing problems of drug resistance, tumor recurrence, and metastasis, there is a critical need for the development of innovative breast cancer treatment strategies. Furthermore, the lack of corresponding receptor targets means that triple‐negative breast cancer (TNBC) does not respond to traditional ER‐, epidermal growth factor receptor‐2 (EGFR)‐, and PR‐targeted therapies 21,22 . Diphenyl disulfide has two phenyl groups that are connected with a disulfide bond 13 .…”

Comparative Evaluation of the Potential Antitumor of Helleborus purpurascens in Skin and Breast Cancer

“…Probably one of the most important cardiotonic glycosides found in the composition of Helleborus species is hellebrin, which is found in the largest amount in the species of H. purpurascens [17]. Studies on the antitumor effect of natural compounds, highlighted the role played by hellebrin and its deglycosylated form, hellebrigenin, possesses cytotoxic activity on melanoma [52], pancreatic cancer [53], breast cancer [54], and others. The successful use of these compounds in antitumor treatment is due to the inhibitory activity of the Na+/K+-ATPase complex, which prevents the development of cancer cells' resistance to treatment [52].…”