A Paradoxical Chemoresistance and Tumor Suppressive Role of Antioxidant in Solid Cancer Cells: A Strange Case of Dr. Jekyll and Mr. Hyde

Abstract

Modulation of intracellular antioxidant concentration is a double-edged sword, with both sides exploited for potential therapeutic benefits. While antioxidants may hamper the efficacy of chemotherapy by scavenging reactive oxygen species and free radicals, it is also possible that antioxidants alleviate unwanted chemotherapy-induced toxicity, thus allowing for increased chemotherapy doses. Under normoxic environment, antioxidants neutralize toxic oxidants, such as reactive oxygen species (ROS), maintaining them within narrow boundaries level. This redox balance is achieved by various scavenging systems such as enzymatic system (e.g., superoxide dismutases, catalase, and peroxiredoxins), nonenzymatic systems (e.g., glutathione, cysteine, and thioredoxin), and metal-binding proteins (e.g., ferritin, metallothionein, and ceruloplasmin) that sequester prooxidant metals inhibiting their participation in redox reactions. On the other hand, therapeutic strategies that promote oxidative stress and eventually tumor cells apoptosis have been explored based on availability of chemotherapy agents that inhibit ROS-scavenging systems. These contradictory assertions suggest that antioxidant supplementation during chemotherapy treatment can have varied outcomes depending on the tumor cellular context. Therefore, understanding the antioxidant-driven molecular pathways might be crucial to design new therapeutic strategies to fight cancer progression.

TIGAR cooperated with glycolysis to inhibit the apoptosis of leukemia cells and associated with poor prognosis in patients with cytogenetically normal acute myeloid leukemia

“…Furthermore, high expression of TIGAR showed an anti-apoptotic effect on human leukemia cells, which may contribute to the poor OS and higher cumulative incidence of relapse in patients with CN-AML treated with chemotherapy. The relationship between TIGAR expression and prognosis in patients with solid cancers was also shown in multiple studies [11, 15, 28]. Similar with human acute leukemia cells, the increased expression of TIGAR was able to protect against metabolic stress, contributes to tumor growth, and be uncoupled from its normal dependence on p53 in several cancer cell types [4].…”

Mitochondrial ROS and cancer drug resistance: Implications for therapy

“…ROS has been aptly described as a heterogeneous group of diatomic oxygen from free and non-free radical species [1]. Enzyme-catalyzed reactions are major contributors of endogenous ROS, with mitochondrial metabolism being central to the process [15,16].…”

“…superoxide (O 2− ) to hydrogen peroxide (H 2 O 2 ). Hydrogen peroxide can in turn lead to different oxidizing derivatives, such as hydroxyl radicals [1]. Hence, a cooperative or positive feed-forward mechanism can be set in motion by the action of a single ROS, with resultant exaggerated effects.…”

“…Various redox systems at play within biological systems, and their essential but often conflicting functions in physiology and disease have been reported [1–4]. ROS is widely implicated in cancer initiation, progression and survival phenotypes [4,5].…”

Progress and Prospects of Reactive Oxygen Species in Metal Carcinogenesis

“…For example, at normal physiological concentrations, ROS can act as secondary messengers and activate some intercellular and intracellular signaling pathways (18). These pathways are involved in proliferation, apoptosis, autophagy, inflammation, and other biological processes (19). On the other hand, ROS are toxic to cells.…”