Combinatorial Effects of the Natural Products Arctigenin, Chlorogenic Acid, and Cinnamaldehyde Commit Oxidation Assassination on Breast Cancer Cells

Abstract

Major obstacles in current breast cancer treatment efficacy include the ability of breast cancer cells to develop resistance to chemotherapeutic drugs and the off-target cytotoxicity of these drugs on normal cells, leading to debilitating side effects. One major difference between cancer and normal cells is their metabolism, as cancer cells acquire glycolytic and mitochondrial metabolism alterations throughout tumorigenesis. In this study, we sought to exploit this metabolic difference by investigating alternative breast cancer treatment options based on the application of phytochemicals. Herein, we investigated three phytochemicals, namely cinnamaldehyde (CA), chlorogenic acid (CGA), and arctigenin (Arc), regarding their anti-breast-cancer properties. These phytochemicals were administered alone or in combination to MCF-7, MDA-MB-231, and HCC1419 breast cancer or normal MCF-10A and MCF-12F breast cells. Overall, our results indicated that the combination treatments showed stronger inhibitory effects on breast cancer cells versus single treatments. However, only treatments with CA (35 μM), CGA (250 μg/mL), and the combination of CA + CGA (35 μM + 250 μg/mL) showed no significant cytotoxic effects on normal mammary epithelial cells, suggesting that Arc was the driver of normal cell cytotoxicity in all other treatments. CA + CGA and, to a lesser extent, CGA alone effectively induced breast cancer cell death accompanied by decreases in mitochondrial membrane potential, increased mitochondrial superoxide, reduced mitochondrial and glycolytic ATP production, and led to significant changes in cellular and mitochondrial morphology. Altogether, the combination of CA + CGA was determined as the best anti-breast-cancer treatment strategy due to its strong anti-breast-cancer effects without strong adverse effects on normal mammary epithelial cells. This study provides evidence that targeting the mitochondria may be an effective anticancer treatment, and that using phytochemicals or combinations thereof offers new approaches in treating breast cancer that significantly reduce off-target effects on normal cells.

Phytochemical Composition and Biological Activities of Arctium minus (Hill) Bernh.: A Potential Candidate as Antioxidant, Enzyme Inhibitor, and Cytotoxic Agent

“…These data may explain the stronger cytotoxic effect of A. minus dichloromethane extracts compared with that of other extracts. In addition, other research discovered that the arctigenin compound significantly reduced cell proliferation when applied in combination with chlorogenic acid and cinnamaldehyde to MCF-7 and MDA-MB-231 cells [ 67 ]. These results also indicate that the compounds in the extracts can exhibit stronger biological activities by providing synergistic effects together.…”

Natural Compounds and Breast Cancer: Chemo-Preventive and Therapeutic Capabilities of Chlorogenic Acid and Cinnamaldehyde

“…While other methods have shown simultaneous promise and challenges, the use of plant-derived natural compounds has been proven to hold the much-sought-after Ehrlich’s “poison arrow”. This is because of their unmatched effectiveness in their cytotoxic effects against breast cancer cells and other types of neoplastic diseases, their bioavailability, and safety to normal cells as well as their capability to prevent cancer relapse [ 4 , 5 , 7 , 8 , 9 , 10 , 42 , 43 , 44 ].…”

In Vitro and In Silico Study on the Impact of Chlorogenic Acid in Colorectal Cancer Cells: Proliferation, Apoptosis, and Interaction with β-Catenin and LRP6

“…Previous studies using in vitro colon cancer models have shown that CGA decreases viability and modulates the proliferative and migratory capabilities of Caco-2 [ 6 ], HT-29, SW480, and SW620 [ 7 , 8 ] cells at EC50 758 uM and IC 50 8114 μg/mL, 686.6 μg/mL, and 828.6 μg/mL, respectively. Likewise, it has been shown that CGA diminishes the viability of cancer cells derived from liver [ 9 , 10 , 11 ], breast [ 12 , 13 ], lung [ 14 , 15 ], blood [ 16 , 17 ], bone [ 18 ], and kidney [ 19 ] tissues, suggesting the potential of CGA for the modulation of biological mechanisms involved in cancer cell survival.…”