Possible Mechanisms of the Prevention of Doxorubicin Toxicity by Cichoric Acid—Antioxidant Nutrient

Abstract

Skin is the largest organ in the human body, and which protects organism against unfavorable external factors e.g., chemicals, environment pollutants, allergens, microorganisms, and it plays a crucial role in maintaining general homeostasis. It is also an important target of oxidative stress due to the activity of oxygen reactive species (ROS), which are constantly generated in the fibroblasts in response to exogenous or endogenous prooxidant agents. An example of such compound with proved prooxidant activity is Doxorubicin (DOX), which is an effective anticancer agent belongs in anthracycline antibiotic group. Increasingly frequent implementation of various strategies to reduce undesirable DOX side effects was observed. Very promising results come from the combination of DOX with dietary antioxidants from the polyphenol group of compounds, such as cichoric acid (CA) in order to lower oxidative stress level. The aim of this work was to evaluate the influence of CA combined with DOX on the oxidative stress parameters in fibroblasts, which constitute the main cells in human skin. We also wanted to examine anti-apoptotic activity of CA in fibroblasts treated with selected concentrations of DOX. Results obtained from the combination of DOX with CA revealed that CA exhibits cytoprotective activity against DOX-induced damage by lowering oxidative stress level and by inhibiting apoptosis. The present finding may indicate that CA may serve as antioxidative and anti-apoptotic agent, active against DOX-induced damage.

Biological Activity of New Cichoric Acid–Metal Complexes in Bacterial Strains, Yeast-Like Fungi, and Human Cell Cultures In Vitro

“…In normal healthy fibroblasts CA-metal complexes exhibited a significant toxicity level as compared to control untreated cells and as compared to free CA. Similarly, as we have shown in our previous work, CA has positive influence on normal healthy cells, stimulating their proliferation and decreasing oxidative stress level, even in the presence of strong prooxidants [22].…”

“…Our research group has shown in recent years that CA exhibits cytoprotective activity against Doxorubicin induced oxidative stress in human skin fibroblasts [22]. Furthermore we have shown that polyphenol-metal complexes exhibit better biological and antioxidative properties than free polyphenols [23].…”

The nucleolus, an ally, and an enemy of cancer cells

“…Oxaliplatin-induced neuropathic side effects could be mitigated by pre-treatment with AC591, a herbal medicine composed of certain neuroprotective herbs (Cheng et al 2017; Noh et al 2018). However, the combined treatment of Dox with a plant-originating antioxidant polyphenolic compound, cichoric acid, revealed that the latter reduced oxidative stress and apoptosis in human normal fibroblasts, so it can counteract Dox-induced cytotoxicity (Hajra et al 2018; Jabłońska-Trypuć et al 2018). Moreover, plant-derived small molecules such as indole-3-carbinol (Hajra et al 2018), d -methionine (Lin et al 2018a), or vivartana (Gnanasekaran et al 2017) were reported to protect certain tissue types against specific chemotherapy side effects.…”

Mitochondrial Dysfunction Associated with Doxorubicin

“…Through extrinsic (receptor-mediated) or intrinsic (mitochondrial) pathways. Both pathways have a role in the trigger of apoptosis as upstream (initiator) caspase, e.g., caspase-8 and -9, and downstream (effector) caspase, e.g., caspase-3, -6 and -7 [76]. When MMP is depolarized and opened, mitochondrial apoptotic factors are released such as cytochrome-c and AIF to the cytosol [73].…”

“…Caspase-3 can be activated from both pathways [73]. The human fibroblast cell was used in one of the previous studies and reported that DOX at 3 μM concentration causes apoptosis through caspase-3, -7, and -9 by ROS [76]. DOX has been said to stimulate apoptosis via caspase-3-dependent pathways.…”