The Phytochemical Indicaxanthin Synergistically Enhances Cisplatin-Induced Apoptosis in HeLa Cells via Oxidative Stress-Dependent p53/p21waf1 Axis

Abstract

<jats:p>Combining phytochemicals with chemotherapics is an emerging strategy to treat cancer to overcome drug toxicity and resistance with natural compounds. We assessed the effects of indicaxanthin (Ind), a pigment obtained from Opuntia ficus-indica (L. Mill) fruit, combined with cisplatin (CDDP) against cervical cancer cells (HeLa). Measured cell viability via Trypan blue assay; cell morphology via fluorescence microscopy; apoptosis, cell cycle, mitochondrial membrane potential (MMP) and cell redox balance via flow-cytometry; expression levels of apoptosis-related proteins via western blot. Cell viability assays and Chou-Talalay plot demonstrated that the combination of CDDP and Ind had synergistic cytotoxic effects. Combined treatment had significant effects (p &lt; 0.05) on phosphatidylserine externalization, cell morphological changes, cell cycle arrest, fall in MMP, ROS production and GSH decay compared with the individual treatment groups. Bax, cytochrome c, p53 and p21waf1 were over-expressed, while Bcl-2 was downregulated. Pre-treatment with N-acetyl-l-cysteine abolished the observed synergistic effects. We also demonstrated potentiation of CDDP anticancer activity by nutritionally relevant concentrations of Ind. Oxidative stress-dependent mitochondrial cell death is the basis of the chemosensitizing effect of Ind combined with CDDP against HeLa cancer cells. ROS act as upstream signaling molecules to initiate apoptosis via p53/p21waf1 axis. Ind can be a phytochemical of interest in combo-therapy.</jats:p>

Structural Effects on the Antioxidant Properties of Amino Acid Betaxanthins

“…The fact that all experiments have been performed using compounds prepared, purified, and studied in the same way increase the confidence for comparing the results obtained. Our results on Pro-Bx (indicaxanthin) agree with reports showing that, despite being a well-known antioxidant and anti-inflammatory agent in vivo [ 73 , 74 , 75 ], Pro-Bx does not have an exceptional antioxidant capacity [ 55 , 72 ], and is lower than that of vulgaxanthin I (Gln-Bx) [ 72 ], which is abundant in Golden beetroots [ 76 ]. These results have been rationalized by considering that the presence of a positively charged iminium group in indicaxanthin decreases its antioxidant capacity [ 53 , 72 ], but this interpretation implies that other more negatively charged betaxanthins may have even better antioxidant properties and/or that the iminium portion of Pro-Bx is important for its biological properties.…”

Antiproliferative effects of bioaccessible fractions of honeys from Sicilian black honeybee (Apis mellifera ssp. sicula) on human colorectal carcinoma cells

“…In many systems, the depolarisation of MMP reflects mitochondrial dysfunction with the loss of mitochondrial inner membrane potential, which is responsible for the release of some pro‐apoptotic factors from the organelle and considered an early apoptotic event (Allegra et al ., 2020).…”

“…Loss of mitochondrial integrity could be related to excessive production of ROS causing irreversible cell damage and induction to apoptosis (Allegra et al ., 2020). As shown in Fig.…”

Cholesterol-Lowering Phytochemicals: Targeting the Mevalonate Pathway for Anticancer Interventions

“…Several phytochemicals have been shown to modulate p53, thus, inducing anticancer signalling pathways, including p53-dependent apoptosis. There are several anticancer mechanisms that are p53-dependent, and phytochemicals also target p53-dependent reduction of cholesterol to reduce cancer risk ( Heo et al, 2018 ; Fang et al, 2019 ; Allegra et al, 2020 ). There are several ways that p53 suppresses tumorigenesis, which include the metabolic pathways and one of these includes the regulation of the mevalonate pathway ( Freed-Pastor et al, 2012 ).…”