Caffeic acid phenethyl ester (CAPE), derived from a honeybee product propolis, exhibits a diversity of anti-tumor effects in pre-clinical models of human breast cancer

Abstract

Breast cancer (BC) patients use alternative and natural remedies more than patients with other malignancies. Specifically, 63%–83% use at least one type of alternative medicine and 25%–63% use herbals and vitamins. Propolis is a naturopathic honeybee product, and CAPE (caffeic acid phenethyl ester), is a major medicinal component of propolis. CAPE, in a concentration dependent fashion, inhibits MCF-7 (hormone receptor positive, HR+) and MDA-231 (a model of triple-negative BC (TNBC) tumor growth, both in vitro and in vivo without much effect on normal mammary cells and strongly influences gene and protein expression. It induces cell cycle arrest, apoptosis and reduces expression of growth and transcription factors, including NF-κB. Notably, CAPE down-regulates mdr-1 gene, considered responsible for the resistance of cancer cells to chemotherapeutic agents. Further, CAPE dose-dependently suppresses VEGF formation by MDA-231 cells and formation of capillary-like tubes by endothelial cells, implicating inhibitory effects on angiogenesis. In conclusion, our results strongly suggest that CAPE inhibits MDA-231 and MCF-7 human breast cancer growth via its apoptotic effects, and modulation of NF-κB, the cell cycle, and angiogenesis.

Genipin, a constituent of Gardenia jasminoides Ellis, induces apoptosis and inhibits invasion in MDA-MB-231 breast cancer cells

“…Bioactive compounds and phytochemicals from plants have been shown to suppress early and late stages of carcinogenesis and can consequently inhibit proliferation of malignant cancer cells (23)(24)(25). In the present study, we showed that genipin efficiently inhibited the growth of MDA-MB-231 human breast cancer cells.…”

Propolis and its Active Component, Caffeic Acid Phenethyl Ester (CAPE), Modulate breast Cancer Therapeutic Targets via an Epigenetically Mediated Mechanism of Action

“…We have previously described that CAPE, the major active component of propolis, induces a diversity of anti-tumor effects in ER+ and ER-breast cancer [25,26]. Here, we compared propolis with CAPE alone to determine whether CAPE's effects were intact in the natural product.…”

“…We previously demonstrated that CAPE inhibits growth of breast cancer cells and breast cancer stem cells, induces cell cycle arrest and apoptosis, and suppresses angiogenesis. Gene arrays showed that CAPE causes extensive changes in gene expression in both ER+ and ER-types of breast cancer cells including the inhibition of NF-κB [25,26].…”

“…CAPE has been shown to be cytotoxic to many types of cancer cells, including breast cancer cells, while having no such effects against normal cells [17][18][19][20][21][22][23][24][25][26]. We have previously demonstrated that CAPE: (i) inhibits the growth of MDA-MB-231 (MDA-231) triple-negative (ER-, PR-, Her2-) BC cells (TNBC), and MCF-7 (ER+/PR+) BC cells both in vivo and in vitro; (ii) inhibits growth of breast cancer stem cells; (iii) induces cell cycle arrest and apoptosis and (iv) suppresses angiogenesis [25,26]. These findings are reminiscent of the pleiotropic effects seen with drugs targeting the epigenetic apparatus such as the histone deacetylases inhibitors (HDACi) like vorinostat, aliphatic acids and depsipeptide in models of both epithelial and hematopoietic origin.…”

Regulation of Apoptosis, Invasion and Angiogenesis of Tumor Cells by Caffeic Acid Phenethyl Ester

“…CAPE is chemopreventive against intestinal, colon and skin cancer, and also has been shown to decreases the formation of preneoplastic hepatic lesions when is administrated in a rat model of liver carcinogenesis [19][20][21], but the mechanism of these properties is not completely understood. Recently, CAPE, in a concentration dependent fashion, was shown to inhibit MCF-7 (hormone receptor positive, HR+) and MDA-MB-231 (a model of triple negative BC (TNBC)) tumor growth, either in vitro or in vivo without much effect on normal mammary cells [22]. At the same time, CAPE was found to cause pronounced changes in bCSC characteristics manifested by inhibition of self renewal, progenitor formation, clonal growth in soft agar, and concurrent significant decrease in CD44 content, all signs of decreased malignancy potential [23].…”