Molecular Pathways of Rosmarinic Acid Anticancer Activity in Triple-Negative Breast Cancer Cells: A Literature Review

Abstract

Breast cancer is the most frequent type of cancer in women. Oncogenic transcription factors promote the overproduction of cellular adhesion molecules and inflammatory cytokines during cancer development. Cancer cells exhibit significant upregulation of antiapoptotic proteins, resulting in increased cell survival, tumor growth, and metastasis. Research on the cell cycle-mediated apoptosis pathway for drug discovery and therapy has shown promising results. In fact, dietary phytoconstituents have been extensively researched for anticancer activity, providing indirect protection by activating endogenous defense systems. The role of polyphenols in key cancer signaling pathways could shed light on the underlying mechanisms of action. For instance, Rosmarinic Acid, a polyphenol constituent of many culinary herbs, has shown potent chemoprotective properties. In this review, we present recent progress in the investigation of natural products as potent anticancer agents, with a focus on the effect of Rosmarinic Acid on triple-negative BC cell lines resistant to hormone therapy. We highlight a variety of integrated chemical biology approaches aimed at utilizing relevant mechanisms of action that could lead to significant clinical advances in BC treatment.

Keywords: antioxidants; breast cancer; natural products; polyphenols; rosmarinic acid.

Figure 1

Chemical structure of Rosmarinic Acid. * Ιndicates the presence of a stereogenic center.

Figure 2

Proposed biosynthetic pathway of Rosmarinic Acid. Enzymes are shown with in orange and blue letters. Enzyme substrates are shown in black letters. The chemical structure derived from L-Phenylalanine is shown in blue and the chemical structure derived from L-Tyrosine is shown in brown-red. Green color shows the hydroxyl groups that come from the action of enzyme CYP450.

Figure 3

The mechanisms of action of Rosmarinic Acid on MDA-MB-231 and MDA-MB-468 TNBC cell lines. Rosmarinic Acid is cytotoxic and antiproliferative in two TNBC cell lines, MDA-MB-231 and MDA-MB-468, which suggests that it might be used as a therapeutic. Following apoptosis, Rosmarinic Acid regulates the cell cycle, halting the G0/G1 phase in MDA-MB-231 cells and the S-phase in MDA-MB-468 cells. Rosmarinic Acid increases the expression of TNF, GADD45A, and BNIP3 genes in MDA-MB-468 cells but not in MDA-MB-231 cells. Rosmarinic Acid causes the repression of three genes, one of which is BIRC5 (Survivin), which is responsible for decreased chemotherapy and radiation efficacy. Survivin control by Rosmarinic Acid might offer a novel target for cancer treatment.