MDM2-NFAT1 dual inhibitor, MA242: Effective against hepatocellular carcinoma, independent of p53

Wang, Wei; Qin, Jiang‐Jiang; Hu, Bo; Li, Xin; Nijampatnam, Bhavitavya; Velu, Sadanandan E.; Fan, Jia; Yang, Xin‐Rong; Zhang, Ruiwen

doi:10.1016/j.canlet.2019.114429

Cited by 38 publications

(46 citation statements)

References 36 publications

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“…Other types of MDM2 inhibitors, especially those that directly inhibit MDM2 itself, for example, SP141, JapA, and MA242, should be evaluated for their therapeutic efficacy and safety, as they may provide stronger activity by blocking both the p53‐dependent and p53‐independent functions of MDM2. Further evaluation and development of MDM2 inhibitors for cancer therapy are underway . These studies will provide proof‐of‐principle results to support the therapeutic value of this targeting strategy in drug discovery and may greatly contribute to the development of new therapeutics to treat noncancer diseases.…”

Section: General Discussion and Future Research Directionsmentioning

confidence: 90%

Targeting MDM2 for novel molecular therapy: Beyond oncology

Wang

Qin

Rajaei

et al. 2019

Medicinal Research Reviews

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The murine double minute 2 (MDM2) oncogene exerts major oncogenic activities in human cancers; it is not only the bestdocumented negative regulator of the p53 tumor suppressor, but also exerts p53-independent activities. There is an increasing interest in developing MDM2-based targeted therapies. Several classes of MDM2 inhibitors have been evaluated in preclinical models, with a few entering clinical trials, mainly for cancer therapy. However, noncarcinogenic roles for MDM2 have also been identified, demonstrating that MDM2 is involved in many chronic diseases and conditions such as inflammation and autoimmune diseases,

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Section: General Discussion and Future Research Directionsmentioning

confidence: 90%

Targeting MDM2 for novel molecular therapy: Beyond oncology

Wang

Qin

Rajaei

et al. 2019

Medicinal Research Reviews

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“…However, they are mainly used for advanced HCC and drug resistance is a main reason to cause chemotherapy failure in HCC. Therefore, there is an urgent need to develop safe and effective agents to treat patients with HCC [ 28 , 50 ].…”

Section: Introductionmentioning

confidence: 99%

Polyphenolic Proanthocyanidin-B2 suppresses proliferation of liver cancer cells and hepatocellular carcinogenesis through directly binding and inhibiting AKT activity

et al. 2020

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The well-documented anticarcinogenic properties of natural polyphenolic proanthocyanidins (OPC) have been primarily attributed to their antioxidant and anti-inflammatory potency. Emerging evidence suggests that OPC may target canonical oncogenic pathways, including PI3K/AKT; however, the underlying mechanism and therapeutic potential remain elusive. Here we identify that proanthocyanidin B2 (OPC–B2) directly binds and inhibits AKT activity and downstream signalling, thereby suppressing tumour cell proliferation and metabolism in vitro and in a xenograft and diethyl-nitrosamine (DEN)-induced hepatocellular carcinoma (HCC) mouse models. We further find that OPC-B2 binds to the catalytic and regulatory PH domains to lock the protein in a closed conformation, similar to the well-studied AKT allosteric inhibitor MK-2206. Molecular docking and dynamic simulation suggest that Lys297 and Arg86 are critical sites of OPC-B2 binding; mutation of Lys297 or Arg86 to alanine completely abolishes the antitumor effects of OPC-B2 but not MK-2206. Together, our study reveals that OPC-B2 is a novel allosteric AKT inhibitor with potent anti-tumour efficacy beyond its antioxidant and anti-inflammatory properties.

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“…Hence, some antineoplastic drugs/targets have been constructed/considered to antagonize MDM2, independent of p53. MDM2 and nuclear factor of activated T-cell 1 (NFAT1) dual inhibitor induces MDM2 autoubiquitination and degradation, and represses NFAT1-mediated MDM2 transcription, which can inhibit the growth and metastasis of HCC cells in vitro and in vivo 152 . SP141 and MA242 (MDM2 inhibitors) are the potential drugs for treating HCC, because their effectiveness had been confirmed in breast cancer models and pancreatic tumor mice 153,154 .…”

Section: Anti-hcc By Restoring P53 Function and Normalizing Mdm2-p53 mentioning

confidence: 99%

The role of MDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation

et al. 2020

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Liver cancer is the second most frequent cause of cancer-related death globally. The main histological subtype is hepatocellular carcinoma (HCC), which is derived from hepatocytes. According to the epidemiologic studies, the most important risk factors of HCC are chronic viral infections (HBV, HCV, and HIV) and metabolic disease (metabolic syndrome). Interestingly, these carcinogenic factors that contributed to HCC are associated with MDM2-p53 axis dysfunction, which presented with inactivation of p53 and overactivation of MDM2 (a transcriptional target and negative regulator of p53). Mechanically, the homeostasis of MDM2-p53 feedback loop plays an important role in controlling the initiation and progression of HCC, which has been found to be dysregulated in HCC tissues. To maintain long-term survival in hepatocytes, hepatitis viruses have lots of ways to destroy the defense strategies of hepatocytes by inducing TP53 mutation and silencing, promoting MDM2 overexpression, accelerating p53 degradation, and stabilizing MDM2. As a result, genetic instability, chronic ER stress, oxidative stress, energy metabolism switch, and abnormalities in antitumor genes can be induced, all of which might promote hepatocytes' transformation into hepatoma cells. In addition, abnormal proliferative hepatocytes and precancerous cells cannot be killed, because of hepatitis viruses-mediated exhaustion of Kupffer cells and hepatic stellate cells (HSCs) and CD4 + T cells by disrupting their MDM2-p53 axis. Moreover, inefficiency of hepatic immune response can be further aggravated when hepatitis viruses co-infected with HIV. Unlike with chronic viral infections, MDM2-p53 axis might play a dual role in glucolipid metabolism of hepatocytes, which presented with enhancing glucolipid catabolism, but promoting hepatocyte injury at the early and late stages of glucolipid metabolism disorder. Oxidative stress, fatty degeneration, and abnormal cell growth can be detected in hepatocytes that were suffering from glucolipid metabolism disorder, and all of which could contribute to HCC initiation. In this review, we focus on the current studies of the MDM2-p53 axis in HCC, and specifically discuss the impact of MDM2-p53 axis dysfunction by viral infection and metabolic disease in the transformation of normal hepatocytes into hepatoma cells. We also discuss the therapeutic avenues and potential targets that are being developed to normalize the MDM2-p53 axis in HCC.

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MDM2-NFAT1 dual inhibitor, MA242: Effective against hepatocellular carcinoma, independent of p53

Cited by 38 publications

References 36 publications

Targeting MDM2 for novel molecular therapy: Beyond oncology

Targeting MDM2 for novel molecular therapy: Beyond oncology

Polyphenolic Proanthocyanidin-B2 suppresses proliferation of liver cancer cells and hepatocellular carcinogenesis through directly binding and inhibiting AKT activity

The role of MDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation

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