The Role of Necroptosis in ROS-Mediated Cancer Therapies and Its Promising Applications

Hsu, Sheng‐Kai; Chang, Wen Tsan; Lin, I‐Ling; Chen, Yih-Fung; Padalwar, Nitin Balkrushna; Cheng, Kai‐Chun; Teng, Yen-Ni; Wang, Chihuei; Chiu, Chien‐Chih

doi:10.3390/cancers12082185

Cited by 69 publications

(50 citation statements)

References 155 publications

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“…Necroptosis, termed type III programmed cell death, is initiated in a manner similar to the extrinsic apoptotic pathway: the ligand-receptor interaction between TNFR or FasR and their respective ligands 155 . However, necroptosis is caspase-independent and involves receptor-interacting protein kinase 3 (RIP3) to form DISC IIb, distinct from DISC IIa in apoptosis 156 . Accumulating evidences suggest that necroptosis plays a vital role in cancer biology and influences the prognosis of patients who receive antineoplastic chemotherapy or radiotherapy 157 .…”

Section: Ros a Double-edged Sword In Cancer Progressionmentioning

confidence: 99%

The double-edged roles of ROS in cancer prevention and therapy

et al. 2021

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Reactive oxygen species (ROS) serve as cell signaling molecules generated in oxidative metabolism and are associated with a number of human diseases. The reprogramming of redox metabolism induces abnormal accumulation of ROS in cancer cells. It has been widely accepted that ROS play opposite roles in tumor growth, metastasis and apoptosis according to their different distributions, concentrations and durations in specific subcellular structures. These double-edged roles in cancer progression include the ROS-dependent malignant transformation and the oxidative stress-induced cell death. In this review, we summarize the notable literatures on ROS generation and scavenging, and discuss the related signal transduction networks and corresponding anticancer therapies. There is no doubt that an improved understanding of the sophisticated mechanism of redox biology is imperative to conquer cancer.

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Section: Ros a Double-edged Sword In Cancer Progressionmentioning

confidence: 99%

The double-edged roles of ROS in cancer prevention and therapy

et al. 2021

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“…Pimozide promoted the apoptosis of HTLV-1-infected T cells and increased ROS generation. In several studies, ROS generation has been associated with apoptosis and necroptosis induction [10,11]. NAC, a ROS scavenger, suppressed pimozide-induced apoptosis, indicating that the anti-ATL effect of pimozide was linked to ROS generation.…”

Section: Discussionmentioning

confidence: 98%

“…ROS accumulation could partially contribute to cell apoptosis and necroptosis [10,11]. We evaluated the effect of pimozide on the ROS levels in MT-2 and HUT-102 cells.…”

Section: Pimozide Induced Ros Accumulationmentioning

confidence: 99%

The antipsychotic drug pimozide is a novel chemotherapeutic agent for adult T cell leukemia

Ishikawa¹,

Mori²

2021

Preprint

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Patients with adult T cell leukemia (ATL), caused by the human T cell leukemia virus type 1 (HTLV-1), exhibit poor prognosis owing to drug resistance. Pimozide, a dopamine D2 receptor subfamily antagonist and antipsychotic drug, has been shown to exhibit anticancer activity. Herein, we investigated whether pimozide exerts anti-ATL effects and explored the mechanisms underlying these effects. While pimozide inhibited cell growth and survival in HTLV-1-infected T cells, it exerted limited effects on uninfected T cells. The dopamine D2 receptor subfamily mRNA expression levels in HTLV-1-infected T cells were high. Pimozide induced G1 cell cycle arrest concomitant with the upregulation of p21/p27/p53 and the suppression of cyclin D2/E, CDK2/4/6 and c-Myc expression and pRb phosphorylation. Pimozide also induced apoptosis via the activation of caspases and upregulation of pro-apoptotic proteins and downregulation of anti-apoptotic proteins. Additionally, it promoted ROS generation and increased the expression of the ER stress marker ATF4 and the DNA damage-inducible protein GADD45a and the phosphorylation of the DNA damage marker H2AX. Furthermore, pimozide-induced cytotoxicity was partially inhibited by a ROS scavenger and pan-caspase and necroptosis inhibitors, indicating the involvement of caspase-dependent and -independent lethal pathways. The activities of the NF-κB, Akt, STAT3/5 and AP-1 signaling pathways were inhibited via the dephosphorylation of IκBα, IKKα/β, Akt and STAT3/5, in addition to reduced JunB and JunD expression in HTLV-1-infected T cells in response to pimozide treatment. Pimozide also exhibited potent anti-ATL activity in the xenograft mouse model. These findings demonstrated the efficacy of pimozide as a potential therapeutic agent for ATL.

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“…Further studies are required to better understand the microenvironment and cellular factors responsible for the different expression profiles of these molecules found in tumor specimens. Cancer cells often acquire the ability to evade cell death induced by chemotherapeutic agents, and induction of necroptosis could represent an efficient way to overcome cell-death resistance [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Low P66shc with High SerpinB3 Levels Favors Necroptosis and Better Survival in Hepatocellular Carcinoma

Fasolato

Ruvoletto

Nardo

et al. 2021

Biology

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Cell proliferation and escape from apoptosis are important pathological features of hepatocellular carcinoma (HCC), one of the tumors with the highest mortality rate worldwide. The aim of the study was to evaluate the expression of the pro-apoptotic p66shc and the anti-apoptotic SerpinB3 in HCCs in relation to clinical outcome, cell fate and tumor growth. p66shc and SerpinB3 were evaluated in 67 HCC specimens and the results were correlated with overall survival. Proliferation and cell death markers were analyzed in hepatoma cells overexpressing SerpinB3, under different stress conditions. p66shc−/− mice and xenograft models were also used to assess the effects of p66shc and SerpinB3 on tumor growth. In patients with HCC, the best survival was observed in the subgroup with p66shc levels below median values and SerpinB3 levels above median values. Mice p66shc−/− showed high levels of SerpinB3, while in HepG2 cells overexpressing SerpinB3, p66shc expression was trivial. HepG2 overexpressing SerpinB3 cells were more prone to die after oxidizing treatments, such as diamide or high concentration H2O2. These cells injected in nude mice developed tumors five times smaller than those from control HepG2 cells. Tumors originating from HepG2 overexpressing SerpinB3 cells showed decreased activated Caspase-8, with concomitant increase of RIP3K and decreased levels of cleaved RIP3K, typical features of necroptosis. In conclusion, in patients affected by HCC, the pattern characterized by p66shc downregulation and elevated SerpinB3 levels was associated with markedly better survival. This pattern favored necroptosis in experimental high-stress conditions.

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The Role of Necroptosis in ROS-Mediated Cancer Therapies and Its Promising Applications

Cited by 69 publications

References 155 publications

The double-edged roles of ROS in cancer prevention and therapy

The double-edged roles of ROS in cancer prevention and therapy

The antipsychotic drug pimozide is a novel chemotherapeutic agent for adult T cell leukemia

Low P66shc with High SerpinB3 Levels Favors Necroptosis and Better Survival in Hepatocellular Carcinoma

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