Citation: Rhman, M.A.; Devnarain, N.; Khan, R.; Owira, P.M.O. Synergism Potentiates Oxidative Antiproliferative Effects of Naringenin and Quercetin in MCF-7 Breast Cancer Cells. Nutrients 2022, 14, 3437. https://doi.org/10.3390/ nu14163437 Academic Editor: Francesca Oppedisano Received: 21 July 2022 Accepted: 18 August 2022 Published: 21 August 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). nutrients Article Synergism Potentiates Oxidative Antiproliferative Effects of Naringenin and Quercetin in MCF-7 Breast Cancer Cells Mahasin Abdel Rhman, Nikita Devnarain , Rene Khan and Peter M. O. Owira * Molecular and Clinical Pharmacology Research Laboratory, Department of Pharmacology, Discipline of Pharmaceutical Sciences, University of Kwazulu-Natal, P.O. Box X5401, Durban 4000, South Africa * Correspondence: owirap@ukzn.ac.za; Tel.: +27-31-260-7720; Fax: +27-31-260-7907 Abstract: Breast cancer (BC) is the most frequently diagnosed type of cancer as of 2020. Quercetin (Que) and Naringenin (Nar) are predominantly found in citrus fruits and vegetables and have shown promising antiproliferative effects in multiple studies. It is also known that the bioactive effects of these flavonoids are more pronounced in whole fruit than in isolation. This study investigates the potential synergistic effects of Que and Nar (CoQN) in MCF-7 BC cells. MCF-7 cells were treated with a range of concentrations of Que, Nar or CoQN to determine cell viability. The IC 50 of CoQN was then used to investigate caspase 3/7 activity, Bcl-2 gene expression, lipid peroxidation and mitochondrial membrane potential to evaluate oxidative stress and apoptosis. CoQN treatment produced significant cytotoxicity, reduced Bcl-2 gene expression and increased caspase 3/7 activity compared to either Nar or Que. Furthermore, CoQN significantly increased lipid peroxidation and reduced mitochondrial membrane potential (MMP) compared to either Nar or Que. Therefore, CoQN treatment has potential pharmacological application in BC chemotherapy by inducing oxidative stress and apoptosis in MCF-7 BC cells. The results of this study support the increased consumption of whole fruits and vegetables to reduce cell proliferation in cancer. Keywords: quercetin; naringenin; breast cancer; oxidative stress; apoptosis 1. Introduction By 2020, breast cancer (BC) was the most frequently diagnosed type of cancer and the fifth leading cause of cancer-related deaths globally in women [1]. Despite technological advancements in the diagnosis and treatment, BC continues to burden the healthcare systems due to increased prevalence associated with socioeconomic disadvantages and continued exposure to risk factors [2]. BC mainly originates in the lobules or ducts of the breast and can be non-invasive or invasive, spreading to the lymph nodes and metastasizing to other parts of the body [3]. Its treatment requires a multidisciplinary approach involving surgery, radiation, chemotherapy, endocrine therapy andhuman epidermal growth factor receptor 2 (HER2)-targeted therapy depending on staging and molecular subtype [4]. Despite advancements in therapeutic approaches to BC, drug side effects due to narrow therapeutic indices and radiation burden reduce compliance. Therefore, novel therapeutic agents targeting BC cells with less cytotoxicity are required. Polyphenolic flavonoids are plant-derived bioactive chemical substances [5] with anticancer, antioxidant, anti-inflammatory, antidiabetic and cardioprotective properties [6]. Flavonoids have been shown to exert their chemotherapeutic effects in various cancers by multiple pathways, including increased oxidative stress and apoptosis leading to reduced cell proliferation, invasion and migration [7]. Quercetin (Que) and Naringenin (Nar) are significant flavonoids found in many plant sources, including onions, broccoli, berries and citrus fruits [8,9]. Nar is the aglycone form of the flavanone glycoside, naringin [9]. The pharmacological effects of Que or Nar have previously been investigated in vitro in Nutrients 2022, 14, 3437. https://doi.org/10.3390/nu14163437 https://www.mdpi.com/journal/nutrients