Combination of cyanidin‐3‐O‐glucoside and cisplatin induces oxidative stress and apoptosis in HeLa cells by reducing activity of endogenous antioxidants, increasing bax/bcl‐2 mRNA expression ratio, and downregulating Nrf2 expression

Abstract

Investigation on potentiation of existing drugs with natural compounds to enhance efficacy and reduce toxic effect of the drugs has been increasing in recent years. This paper reports cytotoxic effect (apoptosis‐related and oxidative stress‐related effect) of cyanidin‐3‐O‐glucoside (C3G), cisplatin (DDP), and their combination (C3G‐DDP) on cervical cancer HeLa cells. Concentration of intracellular reactive oxygen species (ROS) was determined by employing fluorescent marker 2′,7′‐dichlorodihydrofluorescein diacetate. On the other hand, malondialdehyde (MDA) and glutathione (GSH) concentration, and activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH‐Px) were quantitated by commercially available assay kits. C3G‐DDP significantly inhibited the activity of SOD, CAT, and GSH‐Px. Simultaneously, C3G‐DDP reduced GSH concentration while increased the concentration of ROS and MDA. Moreover, Western blot analysis suggested that C3G‐DDP significantly reduced the expression of nuclear factor erythroid 2‐related factor‐2 (Nrf2) and Nrf2 target proteins: heme oxygenase‐1 (HO‐1) and NAD(P)H quinone dehydrogenase 1 (NQO1). In contrast, C3G‐DDP increased the expression of Keap1. Furthermore, C3G‐DDP significantly upregulated and downregulated the mRNA expressions of bax and bcl‐2, respectively, thereby increasing bax/bcl‐2 mRNA expression ratio. Overall, our findings propose that potentiation of DDP with C3G improves cancer cell susceptibility, specifically cervical cancer cells, to DDP. Practical applications Cisplatin is recommended by most medical oncologists worldwide to treat cancer. Despite its neoplastic efficacy, it has undesirable side effects including nausea, vomiting, nephrotoxicity, and hepatotoxicity. Natural biologically active food ingredients are suggested to be used as antioxidants along with DDP therapy to prevent cisplatin‐induced toxicity. C3G‐DDP protected HeLa cells from oxidative stress by reducing NQO1 and HO‐1 levels and regulated the Nrf2 signaling pathway. In addition, C3G‐DDP protected HeLa cells from oxidative stress‐induced apoptosis by increasing bcl‐2 levels and decreasing bax levels. These results expanded our understanding of the role of C3G in a cervical cancer cell model, and provided a potential new treatment strategy for this cancer, as well as a theoretical basis for the development of new drugs in the future.

Low expression of MYCN promotes cisplatin resistance by suppressing cisplatin‑induced apoptosis in epithelial ovarian cancer

“…Balance of Bcl2 family members determines whether a cell undergoes apoptosis or survival (39). Cisplatin increases p53 levels and facilitates the apoptotic response in tumor cells (40); moreover, cisplatin activates Bax, decreases expression of Bcl2 and shifts the Bax/Bcl2 ratio in a pro-apoptotic direction in tumor cells (41). Furthermore, the emergence of p53 mutant cisplatin-resistant OC cells has been demonstrated following drug exposure (42) and patients with OC who have p53 mutations are more resistant to cisplatin-based therapy (43).…”

Nuclear factor erythroid 2‐related factor 2 in human papillomavirus‐related cancers

“…The natural compound cyanidin‐3‐ O ‐glucoside significantly increased Keap1 expression, reducing Nrf2 levels and its target proteins: HO‐1 and NQO1. The latter improves HeLa cells susceptibility to cisplatin treatment 105 . Also, Galanginan, the active principle of galangal, downregulates Nrf2, inducing ROS production and apoptosis in HeLa cells 106 .…”

“…The latter improves HeLa cells susceptibility to cisplatin treatment. 105 Also, Galanginan, the active principle of galangal, downregulates Nrf2, inducing ROS production and apoptosis in HeLa cells. 106 Wang et al 80 showed that the inhibition of ATF2 induces Nrf2 depletion and cancer cell sensitivity to BETis, which generates ferroptosis.…”

The Involvement of Natural Polyphenols in Molecular Mechanisms Inducing Apoptosis in Tumor Cells: A Promising Adjuvant in Cancer Therapy

“…In particular, this drug combination remarkably increased the expression of PTEN, cytosolic cytochrome c, bax, cleaved caspase-9 and -3 and AIF; moreover, p-AKT and bcl-2 protein expression levels were reduced [ 191 ]. The apoptosis- and oxidative-stress-related effects of cyanidin-3-O-glucoside, cisplatin and their combination were investigated on HeLa cervical cancer cells [ 192 ]. Results showed that cyanidin-3-O-glucoside and cisplatin increased oxidative stress by downregulating Nrf2 and consequently HO-1 and NQO1 expression.…”