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Overexpression of the MDM2 oncogene and mutations in the p53 tumor suppressor commonly occur in hepatocellular carcinoma (HCC) and are associated with increased mortality due to this disease. Inhibiting MDM2 has been demonstrated to be a valid approach for the treatment of HCC. However, most of the MDM2 inhibitors evaluated to date have been designed to block the MDM2 and p53 binding, and have limited efficacy against tumors with mutant or deficient p53. In the present study, we developed a novel MDM2 inhibitor (termed SP141) that has direct effects on MDM2 and exerts anti-HCC activity independent of the p53 status of the cancer cells. We demonstrate that SP141 inhibits cell growth and prevents cell migration and invasion, independent of p53. Mechanistically, SP141 directly binds the MDM2 protein and promotes MDM2 degradation. The inhibition of MDM2 by SP141 also increases the sensitivity of HCC cells to sorafenib. In addition, in orthotopic and patient-derived xenograft models, SP141 inhibits MDM2 expression and suppresses tumor growth and metastasis, without any host toxicity. Furthermore, the inhibition of MDM2 by SP141 is essential for its anti-HCC activities. These results provide support for the further development of SP141 as a lead candidate for the treatment of HCC. Keywords: CRISPR/Cas9, Hepatocellular carcinoma, MDM2, p53-independent, Patient-derived xenograft

There is a desperate need for novel and efficacious chemotherapeutic strategies for human brain cancers. There are abundant molecular alterations along the p53 and MDM2 pathways in human glioma, which play critical roles in drug resistance. The present study was designed to evaluate the in vitro and in vivo antitumor activity of a novel brain-penetrating small molecule MDM2 degrader, termed SP-141. In a panel of nine human glioblastoma and medulloblastoma cell lines, SP-141, as a single agent, potently killed the brain tumor-derived cell lines with IC50 values ranging from 35.8 to 688.8 nM. Treatment with SP-141 resulted in diminished MDM2 and increased p53 and p21cip1 levels, G2/M cell cycle arrest, and marked apoptosis. In intracranial xenograft models of U87MG glioblastoma (wt p53) and DAOY medulloblastoma (mutant p53) expressing luciferase, treatment with SP-141 caused a significant 4- to 9-fold decrease in tumor growth in the absence of discernible toxicity. Further, combination treatment with a low dose of SP-141 (IC20) and temozolomide, a standard anti-glioma drug, led to synergistic cell killing (1.3- to 31-fold) in glioma cell lines, suggesting a novel means for overcoming temozolomide resistance. Considering that SP-141 can be taken up by the brain without the need for any special delivery, our results suggest that SP-141 should be further explored for the treatment of tumors of the central nervous system, regardless of the p53 status of the tumor.

The tumor suppressor p53 is believed to be the mostly studied molecule in modern biomedical research. Although p53 interacts with hundreds of molecules to exert its biological functions, there are only a few modulators regulating its expression and function, with murine double minute 2 (MDM2) playing a key role in this regard. MDM2 also contributes to malignant transformation and cancer development through p53-dependent and -independent mechanisms. There is an increasing interest in developing MDM2 inhibitors for cancer prevention and therapy. We recently demonstrated that the nuclear factor of activated T cells 1 (NFAT1) activates MDM2 expression. NFAT1 regulates several cellular functions in cancer cells, such as cell proliferation, migration, invasion, angiogenesis, and drug resistance. Both NFAT isoforms and MDM2 are activated and overexpressed in several cancer subtypes. In addition, a positive correlation exists between NFAT1 and MDM2 in tumor tissues. Our recent clinical study has demonstrated that high expression levels of NFAT1 and MDM2 are independent predictors of a poor prognosis in patients with hepatocellular carcinoma. Thus, inhibition of the NFAT1-MDM2 pathway appears to be a novel potential therapeutic strategy for cancer. In this review, we summarize the potential oncogenic roles of MDM2 and NFAT1 in cancer cells and discuss the efforts of discovery and the development of several newly identified MDM2 and NFAT1 inhibitors, focusing on their potent in vitro and in vivo anticancer activities. This review also highlights strategies and future directions, including the need to focus on the development of more specific and effective NFAT1-MDM2 dual inhibitors for cancer therapy.

The murine double minute 2 (MDM2) oncogene exerts major oncogenic activities in human cancers; it is not only the best‐documented 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, dementia and neurodegenerative diseases, heart failure and cardiovascular diseases, nephropathy, diabetes, obesity, and sterility. MDM2 inhibitors have been shown to have promising therapeutic efficacy for treating inflammation and other nonmalignant diseases in preclinical evaluations. Therefore, targeting MDM2 may represent a promising approach for treating and preventing these nonmalignant diseases. In addition, a better understanding of how MDM2 works in nonmalignant diseases may provide new biomarkers for their diagnosis, prognostic prediction, and monitoring of therapeutic outcome. In this review article, we pay special attention to the recent findings related to the roles of MDM2 in the pathogenesis of several nonmalignant diseases, the therapeutic potential of its downregulation or inhibition, and its use as a biomarker. [ABSTRACT FROM AUTHOR]

Variation in DNA repair genes is one of the mechanisms that may lead to variation in DNA repair capacity. Ku, a heterodimeric DNA-binding complex, is directly involved in repair of DNA double-strand breaks. Ku consists of two subunits, Ku70 and Ku80, which are encoded by the XRCC6 and XRCC5 genes, respectively. In the present study, we investigated whether common genetic variant in variable number of tandem repeats (VNTR) XRCC5 and T-991C XRCC6 was associated with an altered risk of breast cancer. The present study included 407 females with breast cancer and 395 age frequency-matched controls which were randomly selected from the healthy female blood donors. The XRCC5 and XRCC6 polymorphisms were determined using PCR-based methods. For XRCC5 polymorphism, in comparison with the 1R/1R genotype, the 0R/0R genotype increased breast cancer risk (OR 9.55, 95 %CI 1.19-76.64, P = 0.034). The 1R/3R genotype compared with 1R/1R genotype decreased the risk of breast cancer (Fisher's exact test P = 0.015). There was no association between T-991C polymorphism of XRCC6 and breast cancer risk. Mean of age at diagnosis of breast cancer for 0, 1, 2, 3, and >4 repeat in XRCC5 were 39.2, 41.9, 44.3, 45.8, and 47.3 years, respectively. The Kaplan-Meier survival analysis revealed that the number of repeat was associated with age at diagnosis of breast cancer (log rank statistic = 13.90, df = 4, P = 0.008). The findings of the present study revealed that either breast cancer risk or age at diagnosis of breast cancer was associated with the VNTR polymorphism at promoter region of XRCC5. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroblastoma is a malignant tumor of the sympathetic nervous system that causes aggressive disease in children. The overall survival rate of high-risk patients is very low, therefore developing effective and safe therapies for neuroblastoma is an urgent unmet medical need. The mouse double minute 2 (MDM2) homolog gene is amplified and overexpressed in neuroblastoma and contributes to the poor response to treatment and poor prognosis in patients with high-risk neuroblastoma. Therefore, targeting MDM2 provides a promising approach to neuroblastoma therapy, especially for advanced disease. In the present study, we tested a unique MDM2 inhibitor, SP141, for its therapeutic efficacy and safety in neuroblastoma tumor models. We found that SP141 has significant anti- neuroblastoma activity in cell culture and inhibits tumor growth in animal models of human neuroblastoma, without any noticeable host toxicity. These results provide the basis for targeting MDM2 to treat high-risk neuroblastoma. Background: Neuroblastoma is an aggressive pediatric solid tumor with an overall survival rate of <50% for patients with high-risk disease. The majority (>98%) of pathologically-diagnosed neuroblastomas have wild-type p53 with intact functional activity. However, the mouse double minute 2 (MDM2) homolog, an E3 ubiquitin ligase, is overexpressed in neuroblastoma and leads to inhibition of p53. MDM2 also exerts p53-independent oncogenic functions. Thus, MDM2 seems to be an attractive target for the reactivation of p53 and attenuation of oncogenic activity in neuroblastoma. Methods: In this study, we evaluated the anticancer activities and underlying mechanisms of action of SP141, a first-in-class MDM2 inhibitor, in neuroblastoma cell lines with different p53 backgrounds. The findings were confirmed in mouse xenograft models of neuroblastoma. Results: We demonstrate that SP141 reduces neuroblastoma cell viability, induces apoptosis, arrests cells at the G2/M phase, and prevents cell migration, independent of p53. In addition, in neuroblastoma xenograft models, SP141 inhibited MDM2 expression and suppressed tumor growth without any host toxicity at the effective dose. Conclusions: MDM2 inhibition by SP141 results in the inhibition of neuroblastoma growth and metastasis, regardless of the p53 status of the cells and tumors. These findings provide proof-of-concept that SP141 represents a novel treatment option for both p53 wild-type and p53 null neuroblastoma. [ABSTRACT FROM AUTHOR]

There is a desperate need for novel and efficacious chemotherapeutic strategies for human brain cancers. There are abundant molecular alterations along the p53 and MDM2 pathways in human glioma, which play critical roles in drug resistance. The present study was designed to evaluate the in vitro and in vivo antitumor activity of a novel brain-penetrating small molecule MDM2 degrader, termed SP-141. In a panel of nine human glioblastoma and medulloblastoma cell lines, SP-141, as a single agent, potently killed the brain tumor-derived cell lines with IC50 values ranging from 35.8 to 688.8 nM. Treatment with SP-141 resulted in diminished MDM2 and increased p53 and p21cip1 levels, G2/M cell cycle arrest, and marked apoptosis. In intracranial xenograft models of U87MG glioblastoma (wt p53) and DAOY medulloblastoma (mutant p53) expressing luciferase, treatment with SP-141 caused a significant 4- to 9-fold decrease in tumor growth in the absence of discernible toxicity. Further, combination treatment with a low dose of SP-141 (IC20) and temozolomide, a standard anti-glioma drug, led to synergistic cell killing (1.3- to 31-fold) in glioma cell lines, suggesting a novel means for overcoming temozolomide resistance. Considering that SP-141 can be taken up by the brain without the need for any special delivery, our results suggest that SP-141 should be further explored for the treatment of tumors of the central nervous system, regardless of the p53 status of the tumor. [ABSTRACT FROM AUTHOR]

The tumor suppressor p53 is believed to be the mostly studied molecule in modern biomedical research. Although p53 interacts with hundreds of molecules to exert its biological functions, there are only a few modulators regulating its expression and function, with murine double minute 2 (MDM2) playing a key role in this regard. MDM2 also contributes to malignant transformation and cancer development through p53-dependent and -independent mechanisms. There is an increasing interest in developing MDM2 inhibitors for cancer prevention and therapy. We recently demonstrated that the nuclear factor of activated T cells 1 (NFAT1) activates MDM2 expression. NFAT1 regulates several cellular functions in cancer cells, such as cell proliferation, migration, invasion, angiogenesis, and drug resistance. Both NFAT isoforms and MDM2 are activated and overexpressed in several cancer subtypes. In addition, a positive correlation exists between NFAT1 and MDM2 in tumor tissues. Our recent clinical study has demonstrated that high expression levels of NFAT1 and MDM2 are independent predictors of a poor prognosis in patients with hepatocellular carcinoma. Thus, inhibition of the NFAT1-MDM2 pathway appears to be a novel potential therapeutic strategy for cancer. In this review, we summarize the potential oncogenic roles of MDM2 and NFAT1 in cancer cells and discuss the efforts of discovery and the development of several newly identified MDM2 and NFAT1 inhibitors, focusing on their potent in vitro and in vivo anticancer activities. This review also highlights strategies and future directions, including the need to focus on the development of more specific and effective NFAT1-MDM2 dual inhibitors for cancer therapy. [ABSTRACT FROM AUTHOR]