Regulated Necrotic Cell Death in Alternative Tumor Therapeutic Strategies

Abstract

The treatment of tumors requires the induction of cell death. Radiotherapy, chemotherapy, and immunotherapy are administered to kill cancer cells; however, some cancer cells are resistant to these therapies. Therefore, effective treatments require various strategies for the induction of cell death. Regulated cell death (RCD) is systematically controlled by intracellular signaling proteins. Apoptosis and autophagy are types of RCD that are morphologically different from necrosis, while necroptosis, pyroptosis, and ferroptosis are morphologically similar to necrosis. Unlike necrosis, regulated necrotic cell death (RNCD) is caused by disruption of the plasma membrane under the control of specific proteins and induces tissue inflammation. Various types of RNCD, such as necroptosis, pyroptosis, and ferroptosis, have been used as therapeutic strategies against various tumor types. In this review, the mechanisms of necroptosis, pyroptosis, and ferroptosis are described in detail, and a potential effective treatment strategy to increase the anticancer effects on apoptosis- or autophagy-resistant tumor types through the induction of RNCD is suggested.

Keywords: apoptosis; autophagy; ferroptosis; necroptosis; necrosis; pyroptosis; therapy-resistant tumors.

Figure 1

Classification of cell death types. Cell death types can be classified according to whether they are regulated by a specific signal pathway. Except for necrosis, most types of cell death are included in the RCD category. The type of RCD can also be classified according to membrane disruption. Apoptotic- and autophagic-cell death does not induce additional inflammatory responses, because their cellular components are sequestered within the membrane structures, such as apoptotic bodies and autophagosomes, respectively, during cell death processes. However, since RNCDs, including ferroptosis, pyroptosis, and necroptosis, are death types accompanied by membrane disruption, RNCDs can induce inflammatory responses in the tissues.

Figure 2

Types of RNCD. Necroptosis can be induced by the signals of TNF receptors, FAS receptors, TRAIL receptors, toll-like receptors, and interferon receptors. In the absence of caspase-8 activity, the phosphorylation of RIPK1 and RIPK3 induces phosphorylation and the subsequent activation of inactive MLKL. Activated MLKL is translocated into the plasma membrane and forms the pores approximately 4 nm in diameter. Pyroptosis is caused by gasdermin-mediated pore formation. The activation of the inflammasome complex induces the enzymatic activity of caspase-1, and caspase-1 cleaves gasdermin D. The N-terminal region of cleaved gasdermin D is translocated into the plasma membrane and forms the pores approximately 10–15 nm in diameter. In addition to caspase-1, gasdermin proteins can be cleaved by caspase-4, caspase-5, and caspase-11. Moreover, gasdermin E can be cleaved by granzyme B, which is released by cytotoxic CD8 T cells and natural killer (NK) cells. Ferroptosis is caused by membrane disruption induced by an iron-mediated lipid peroxidation process known as the Fenton reaction. Transferrin receptor transfers Fe³⁺ bound to extracellular transferrin into the intracellular endosomal regions. Fe³⁺ is reduced to Fe²⁺ by STEAP3, a ferrireductase, and generated Fe²⁺ is released into the cytoplasm by SLC11A2 (also known as divalent metal transporter 1, DMT1). The release of Fe²⁺ into the cytosol causes lipid peroxidation in the plasma membrane. As a result of RNCD induction, DAMPs, such as HMGB1 and ATP, can be released into the extracellular regions to induce inflammatory responses in the tissues.

Figure 3

Inducers of RNCD. RNCD inducers can be used to induce cell death of tumor cells that are resistant to apoptotic or autophagic cell death. RNCD inducers can cause membrane disruption of the tumor cells and subsequent inflammatory responses in the tumor tissues. The appropriate administration of the inducers according to tumor types may be effective tumor therapies. Aldehyde dehydrogenase (ALDH1A) inhibitor; 5-fluorouracil (5-FU); 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine (DAPE); 3-bromopyruvate (3-BrPA); buthionine sulfoximine (BSO); dihydroxyphenyl-imino-2-imidazolidine (DPI2); (1S,3R)-methyl 2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1-[4-(methoxycarbonyl)phenyl]-1H-pyrido[3¨C-b]indole-3-carboxylate (RSL3); α-[(2-chloroacetyl)(3-chloro-4-methoxyphenyl)amino]-N-(2-phenylethyl)-2-thiopheneacetamide (ML162); [4-[bis(4-chlorophenyl)methyl]-1-piperazinyl](5-methyl-4-nitro-3-isoxazolyl)methanone (ML210); N2,N7-dicyclohexyl-9-(hydroxyimino)-9H-fluorene-2,7-disulfonamide (FIN56); 2,7-bis(1-piperidinylsulfonyl)-9H-fluoren-9-one, oxime (CIL56).