Abstract
Over the past decades, promising therapies targeting different signaling pathways have emerged. Among these pathways, apoptosis has been well investigated and targeted to design diverse chemotherapies. However, some patients are chemoresistant to these therapies due to compromised apoptotic cell death. Hence, exploring alternative treatments aimed at different mechanisms of cell death seems to be a potential strategy for bypassing impaired apoptotic cell death. Emerging evidence has shown that necroptosis, a caspase-independent form of cell death with features between apoptosis and necrosis, can overcome the predicament of drug resistance. Furthermore, previous studies have also indicated that there is a close correlation between necroptosis and reactive oxygen species (ROS); both necroptosis and ROS play significant roles both under human physiological conditions such as the regulation of inflammation and in cancer biology. Several small molecules used in experiments and clinical practice eliminate cancer cells via the modulation of ROS and necroptosis. The molecular mechanisms of these promising therapies are discussed in detail in this review.
Highlights
In recent decades, the biological characteristics of apoptosis have been well established; this has resulted in an increase in apoptosis-associated drugs [1,2]
It is evident that the downregulation of RIP1, RIP3 and mixed lineage kinase domain-like (MLKL) is associated with the inhibition of cancer cell growth and increased sensitivity to RT in breast cancer; in addition, necrosulfonamide (NSA), an inhibitor of necroptosis, leads to significant tumor growth suppression [74]
Wang et al showed that in the human colon cancer cell line HT-29, cobalt chloride can induce a significant increase in RIPK1, RIPK3 and MLKL in the presence of aberrant caspases, initiating necroptosis; it may serve as a potential treatment for cancer cells that are resistant to apoptosis [96]
Summary
The biological characteristics of apoptosis have been well established; this has resulted in an increase in apoptosis-associated drugs [1,2]. O2 within the matrix is reduced to hydrogen peroxide (H2 O2 ) by superoxide dismutase protein 2 (SOD2) [23]; O2 within the intermembrane space needs to be translocated to the cytosol and converted into H2 O2 by superoxide dismutase protein 1 (SOD1) This process initiates cell signaling events [24,25]. Intermembrane ROS translocate to the cytosol and cellular trigger events; ROS can stabilize HIFα under hypoxic conditions, and this stabilization subsequently induces VEGF expression to promote endothelial cell proliferation and angiogenesis. ROS can initiate the ERK signaling pathway, promoting cell proliferation and survival and anchorage-independent growth. They can lead to genomic instability and induce cancer progression
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