Bypassing drug resistance by triggering necroptosis: recent advances in mechanisms and its therapeutic exploitation in leukemia

Abstract

Resistance to regulated cell death is one of the hallmarks of human cancers; it maintains cell survival and significantly limits the effectiveness of conventional drug therapy. Leukemia represents a class of hematologic malignancies that is characterized by dysregulation of cell death pathways and treatment-related resistance. As the majority of chemotherapeutic and targeted drugs kill leukemia cells by triggering apoptosis, the observed resistance indicates the need for novel therapeutic strategies to reactivate nonapoptotic cell death programs in refractory leukemia. Necroptosis is a regulated form of necrosis that is precisely modulated by intracellular signaling pathways and thus provides potential molecular targets for rational therapeutic intervention. Indeed, accumulating evidence indicates that many current antitumor agents can activate necroptotic pathways and thereby induce leukemia cell death. Elucidation of the complete regulatory mechanism of necroptosis is expected to accelerate the development of novel therapeutic strategies for overcoming apoptosis resistance in leukemia. Here, we review the latest research advances in the regulatory mechanisms of necroptosis and summarize the progression of necroptosis-based therapeutic strategies in leukemia.

BAD sensitizes breast cancer cells to docetaxel with increased mitotic arrest and necroptosis

“…Therefore, apoptosis is not a major cell death pathway for docetaxel in these triple-negative breast carcinoma cells. Recently, necroptosis activation has been shown to overcome chemotherapy resistance 50 . Aldehyde dehydrogenase inhibitors kill ovarian cancer stem cells by activating necroptosis, in part, by the induction of mitochondrial uncoupling proteins and reduction in mitochondrial oxidative phosphorylation 51 .…”

Ophiopogonin B-inducing Pyroptosis Through Caspase-1/gsdmd Pathway Contributes to Alleviation of Paclitaxel Resistance in Lung Cancer Cells 

“…As tumor cells always show innate resistance to apoptosis, the development of new strategies to induce pyroptosis may provide more e cient cancer therapy options and improve patient survival (21,22). While, there is a lack of research on the relationship between pyroptosis and tumor resistance currently.…”

Necroptosis in Immuno-Oncology and Cancer Immunotherapy

“…For instance, cIAPs can elicit poly-ubiquitination of RIPK1, thereby abolishing any downstream pro-apoptotic signaling and instead facilitating cellular survival ( Figure 2). Via this route the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPKs) pathways are initiated [78,82,94,[97][98][99][100]. Alternatively, inhibition of cIAPs [e.g., via degradation through second mitochondria-derived activator of caspases (SMAC)] and/or RIPK1 de-ubiquitination via CYLD, can inhibit NF-κB stimulation, causing dissociation of RIPK1/TRADD from the death-receptors complex [101].…”