Selective targeting p53WT lung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA

Lü, Wei; Cheng, Feixiong; Yan, Wanfeng; Li, X; Yao, Xing; Song, Wenqiang; Liu, M; Shen, Xiaoxia; Jiang, Hualiang; J, Chen; Li, J; Huang, Jin

doi:10.1038/onc.2017.41

Cited by 22 publications

(13 citation statements)

References 44 publications

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“…gain-of-function of p53 is a potential anticancer treatment for numerous types of cancer. In the present study, A549 and NCI-H460 cell lines were used, which are derived from NSCLCs that express detectable p53 mRNA at expression levels comparable to normal lung tissue and exhibit no gross structural DNA abnormalities (25). Accordingly, the present findings demonstrated that bergapten increased the expression levels of p53 and downstream p21 Cip1 and p27 Kip1 , suggesting that bergapten may exert its anticancer activity by inducing activation of the p53 cascade.…”

Section: Discussionmentioning

confidence: 53%

Bergapten induces G1 arrest of non‑small cell lung cancer cells, associated with the p53‑mediated cascade

Chiang

Lin

et al. 2019

Mol Med Report

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The pr incipal subtype of lung cancer, non-small cell lung cancer (NSCLC) is a life-threatening malignancy that causes high mortality rates. Bergapten (5-methoxypsoralen) has been identified to possess anticancer activity against a number of carcinomas. In the present study, the effects of bergapten on NSCLC cells were investigated. The cell viability was determined by MTT assay. Cell cycle distribution was analyzed using flow cytometry. Protein expression and kinase cascade were demonstrated using western blot analysis. The results demonstrated that treatment with bergapten (50 µM for 48 h) inhibited the viability of A549 and NCI-H460 NSCLC cells to 79.1±2.8% and 74.5±3.1%, respectively, compared with the controls. It was identified that bergapten induced G1 phase accumulation in A549 and NCI-H460 cells between ~58 and 75% (P<0.01). In addition, bergapten significantly increased the sub-G1 phase ratio to ~9% (P<0.05) in the two cell types. Further investigation demonstrated that bergapten upregulated the expression of cellular tumor antigen p53 (p53) and its downstream proteins cyclin-dependent kinase inhibitor 1 and cyclin-dependent kinase inhibitor 1B, whereas, it downregulated the expression of cyclin D1 and CDK4. Overall, these results suggested that bergapten may inhibit cell viability and trigger G1 arrest and apoptosis in A549 and NCI-H460 cells, which may be attributed to the activation of p53-mediated cascades. Therefore, bergapten may be beneficial for NSCLC treatment.

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Section: Discussionmentioning

confidence: 53%

Bergapten induces G1 arrest of non‑small cell lung cancer cells, associated with the p53‑mediated cascade

Chiang

Lin

et al. 2019

Mol Med Report

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“…Transformed HEK-293T cells are defective in terms of p53 protein activation [ 29 ] that has been described to be the central component in the complex network of apoptosis signaling pathways [ 30 ]. The fact that ZAMP induces caspase-3/7 activation in A549 cells having a functional p53 protein [ 31 ] as well as p53-deficient Huh7 cells [ 32 ] do not sustain a major role for p53-dependent signaling pathway in apoptosis mediated by ZAMP. The megakaryocyte-potentiating factor is part of the tumor-associated antigen (TAA) mesothelin.…”

Section: Discussionmentioning

confidence: 99%

Zika M Oligopeptide ZAMP Confers Cell Death-Promoting Capability to a Soluble Tumor-Associated Antigen through Caspase-3/7 Activation

Vanwalscappel

Haddad

Almokdad

et al. 2020

IJMS

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Mosquito-borne Zika virus (ZIKV) is an emerging flavivirus of medical concern associated with neurological disorders. ZIKV utilizes apoptosis as a mechanism of cell killing. The structural M protein may play a role in flavivirus-induced apoptosis. The death-promoting capability of M has been restricted to an oligopeptide representing the residues M-32/40. Here, we evaluated the apoptosis inducing ability of the residues M-31/41 of ZIKV. The ZIKV M oligopeptide was associated to a soluble form of GFP (sGFP) and the resulting sGFP-M31/41 construct was assessed in Huh7 cells. Expression of sGFP-M31/41 can trigger apoptosis in Huh7 cells through caspase-3/7 activation. The translocation of sGFP-M31/41 in the endoplasmic reticulum was a prerequisite for apoptosis induction. The residues M-33/35/38 may play a critical role in the death-promoting activity of sGFP-M31/41. The effect of ZIKV M oligopeptide defined as ZAMP (for Zika Apoptosis M Peptide) on expression of a tumor-associated antigen was assayed on megakaryocyte-potentiating factor (MPF). Expression of MPF-ZAMP construct resulted in caspase-associated apoptosis activation in A549 and Huh7 cells. ZIKV has been proposed as an oncolytic virus for cancer therapy. The ability of the Zika M oligopeptide to confer death-promoting capability to MPF opens up attractive perspectives for ZAMP as an innovative anticancer agent.

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“…The reduction in fibrosis may have limited tumor growth because hepatocellular carcinoma is regulated strongly by the extracellular milieu (Cox and Erler, 2014; Baglieri et al, 2019; Sircana et al, 2019). CRV431 may have restored levels or function of the tumor suppressor, p53, by blocking the binding of Cyp D to p53 or blocking p53 degradation through a Cyp A-mediated mechanism (Bigi et al, 2016; Lu et al, 2017). Cancer cells frequently express high levels of cyclophilins, which appears to support the elevated anabolic demands, cell proliferation, and hypoxia adaptations of the cells.…”

Section: Discussionmentioning

confidence: 99%

A Pan-Cyclophilin Inhibitor, CRV431, Decreases Fibrosis and Tumor Development in Chronic Liver Disease Models

Kuo

Bobardt

Chatterji

et al. 2019

J Pharmacol Exp Ther

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Previous studies show that cyclophilins contribute to many pathologic processes, and cyclophilin inhibitors demonstrate therapeutic activities in many experimental models. However, no drug with cyclophilin inhibition as the primary mode of action has advanced completely through clinical development to market. In this study, we present findings on the cyclophilin inhibitor, CRV431, that highlight its potential as a drug candidate for chronic liver diseases. CRV431 was found to potently inhibit all cyclophilin isoforms tested-A, B, D, and G. Inhibitory constant or IC 50 values ranged from 1 to 7 nM, which was up to 13 times more potent than the parent compound, cyclosporine A (CsA), from which CRV431 was derived. Other CRV431 advantages over CsA as a nontransplant drug candidate were significantly diminished immunosuppressive activity, less drug transporter inhibition, and reduced cytotoxicity potential. Oral dosing to mice and rats led to good blood exposures and a 5-to 15-fold accumulation of CRV431 in liver compared with blood concentrations across a wide range of CRV431 dosing levels. Most importantly, CRV431 decreased liver fibrosis in a 6-week carbon tetrachloride model and in a mouse model of nonalcoholic steatohepatitis (NASH). Additionally, CRV431 administration during a late, oncogenic stage of the NASH disease model resulted in a 50% reduction in the number and size of liver tumors. These findings are consistent with CRV431 targeting fibrosis and cancer through multiple, cyclophilin-mediated mechanisms and support the development of CRV431 as a safe and effective drug candidate for liver diseases. SIGNIFICANCE STATEMENT Cyclophilin inhibitors have demonstrated therapeutic activities in many disease models, but no drug candidates have yet advanced completely through development to market. In this study, CRV431 is shown to potently inhibit multiple cyclophilin isoforms, possess several optimized pharmacological properties, and decrease liver fibrosis and tumors in mouse models of chronic liver disease, which highlights its potential to be the first approved drug primarily targeting cyclophilin isomerases.

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Selective targeting p53WT lung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA

Cited by 22 publications

References 44 publications

Bergapten induces G1 arrest of non‑small cell lung cancer cells, associated with the p53‑mediated cascade

Bergapten induces G1 arrest of non‑small cell lung cancer cells, associated with the p53‑mediated cascade

Zika M Oligopeptide ZAMP Confers Cell Death-Promoting Capability to a Soluble Tumor-Associated Antigen through Caspase-3/7 Activation

A Pan-Cyclophilin Inhibitor, CRV431, Decreases Fibrosis and Tumor Development in Chronic Liver Disease Models

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