Mechanisms of ferroptotic and non-ferroptotic organ toxicity of chemotherapy: protective and therapeutic effects of ginger, 6-gingerol and zingerone in preclinical studies

Abstract

Chemotherapy (CT) is one of the flagship options for the treatment of cancers worldwide. It involves the use of cytotoxic anticancer agents to kill or inhibit the proliferation of cancer cells. However, despite its clinical efficacy, CT triggers side effect toxicities in several organs, which may impact cancer patient's quality of life and treatment outcomes. While the side effect toxicity is consistent with non-ferroptotic mechanisms involving oxidative stress, inflammation, mitochondrial impairment and other aberrant signalling leading to apoptosis and necroptosis, recent studies show that ferroptosis, a non-apoptotic, iron-dependent cell death pathway, is also involved in the pathophysiology of CT organ toxicity. CT provokes organ ferroptosis via system Xc^-/GPX-4/GSH/SLC7A11 axis depletion, ferritinophagy, iron overload, lipid peroxidation and upregulation of ferritin-related proteins. Cisplatin (CP) and doxorubicin (DOX) are common CT drugs indicated to induce ferroptosis in vitro and in vivo. Studies have explored natural preventive and therapeutic strategies using ginger rhizome and its major bioactive compounds, 6-gingerol (6G) and zingerone (ZG), to combat mechanisms of CT side effect toxicity. Ginger extract, 6G and ZG mitigate non-ferroptotic oxidative inflammation, apoptosis and mitochondrial dysfunction mechanisms of CT side effect toxicity, but their effects on CT-induced ferroptosis remain unclear. Systematic investigations are, therefore, needed to unfold the roles of ginger, 6G and ZG on ferroptosis involved in CT side effect toxicity, as they are potential natural agents for the prevention of CT toxicity. This review reveals the ferroptotic and non-ferroptotic toxicity mechanisms of CT and the protective mechanisms of ginger, 6G and ZG against CT-induced, ferroptotic and non-ferroptotic organ toxicities.

Keywords: Zingiber officinale; Anticancer drugs; Chemotherapy; Ferroptosis; Ginger rhizome.

Fig. 1

Ginger rhizome, the molecular structures of its most bioactive compounds and common examples of CT drugs from the different classes of cytotoxic anticancer drugs

Fig. 2

Mechanisms underlying chemotherapeutic drug-induced organ toxicity. Cytotoxic anticancer drugs generate ROS and/or oxidative stress. Oxidative stress triggers activation of NF-kB-mediated inflammation, mitochondrial impairment and intrinsic caspase-dependent apoptosis, leading to organ damage or toxicity

Fig. 3

A schematic description of chemotherapy (CT)-induced ferroptosis. CT induces iron accumulation through transferrin receptor-1 (TFR-1) in cells, which leads to cellular iron overload. The binding of nuclear receptor coactivator-4 (NCOA4) to ferritin induces degradation of ferritin, a process known as ferritinophagy. As a result, cellular iron increases, causing iron overload–dependent excessive ROS accumulation, lipid peroxidation and ferroptosis. The cysteine/glutamate transporter receptor (Xc⁻) system (SLC3A2 + SLC7A11) enhances GSH synthesis and GPX-4 activity to inhibit ROS levels and lipid peroxidation. The activities of acyl-CoA synthetase long-chain family member 4 (ACSL4) and arachidonate lipoxygenase (ALOX) contribute to lipid peroxidation, ROS generation and ferroptosis

Fig. 4

Schematic illustration of the ferroptotic and non-ferroptotic pathways triggered by cytotoxic chemotherapy drugs (CT drugs) in non-targeted, healthy cells. CT induces the entry of iron (II) via the transferrin and membrane protein transferrin receptor-1 (TFR-1). The increasing concentrations of iron (II) ions set up Fenton reactions and degradation of iron-storage protein ferritin by nuclear receptor coactivator-4 (NCOA4) through an autophagy-mediated process called ferritinophagy. These result in iron overload, increased ROS generation and formation of phospholipid-polyunsaturated fatty acid peroxides (PL-PUFA-OOH) by the action of acyl-CoA synthetase long-chain family member 4, ACSL4. Due to inhibition of the glutathione-glutathione peroxidase-4 (GSH-GPX-4) synthetic pathway by CT drugs, lipid peroxides are copiously generated, leading to cell death by ferroptosis. CT drugs initiate non-ferroptotic pathway through generation of ROS and activation of inflammatory processes. The build-up of oxidative stress triggers inhibition of antioxidant enzyme activities, mitochondrial dysfunction, ER stress, activation of MAPK-PI3K axis and NF-κB-mediated inflammatory cascades. These ROS-mediated alterations result in apoptosis and inflammation

Fig. 5

Chemical structures of 6-gingerol and zingerone