The MDM2-p53 pathway revisited

The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA repair, cell cycle, apoptosis, angiogenesis, and senescence. It acts as an important defense mechanism against cancer onset and progression, and is negatively regulated by interaction with the oncoprotein MDM2. In human cancers, the TP53 gene is frequently mutated or deleted, or the wild-type p53 function is inhibited by high levels of MDM2, leading to downregulation of tumor suppressive p53 pathways. Thus, the inhibition of MDM2-p53 interaction presents an appealing therapeutic strategy for the treatment of cancer. However, recent studies have revealed the MDM2-p53 interaction to be more complex involving multiple levels of regulation by numerous cellular proteins and epigenetic mechanisms, making it imperative to reexamine this intricate interplay from a holistic viewpoint. This review aims to highlight the multifaceted network of molecules regulating the MDM2-p53 axis to better understand the pathway and exploit it for anticancer therapy.

Identification of lineariifolianoid A as a novel dual NFAT1 and MDM2 inhibitor for human cancer therapy

There is an increasing interest in development of novel anticancer agents that target oncogenes. We have recently discovered that nuclear factor of activated T cells 1 （NFAT1） is a novel regulator of the Mouse Double Minute 2 （MDM2） oncogene and the NFAT1-MDM2 pathway has been implicated in human cancer development and pro- gression, justifying that targeting the NFAT1-MDM2 pathway could be a novel strategy for discovery and develop- ment of novel cancer therapeutics. The present study was designed to examine the anticancer activity and underlying mechanisms of action of lineariifolianoid A （LinA）, a novel natural product inhibitor of the NFAT 1-MDM2 pathway. The cytotoxicity of LinA was first tested in various human cancer cell lines in comparison with normal cell lines. The results showed that the breast cancer cells were highly sensitive to LinA treatment. We next demonstrated the effects of LinA on cell proliferation, colony formation, cell cycle progression, and apoptosis in breast cancer MCF7 and MDA-MB-231 cells, in dose-dependent and p53-independent manners. LinA also inhibited the migration and invasion of these cancer cells. Our mechanistic studies further indicated that its anticancer activities were attributed to its inhibitory effects on the NFAT 1-MDM2 pathway and modulatory effects on the expression of key proteins involved in cell cycle progression, apoptosis, and DNA damage. In summary, LinA is a novel NFAT 1-MDM2 inhib- itor and may be developed as a preventive and therapeutic agent against human cancer.

Pathogenesis of RON receptor tyrosine kinase in cancer cells: activation mechanism, functional crosstalk, and signaling addiction

The RON receptor tyrosine kinase, a member of the MET proto-oncogene family, is a pathogenic factor im- plicated in tumor malignancy. Specifically, aberrations in RON signaling result in increased cancer cell growth, survival, invasion, angiogenesis, and drug resistance. Biochemical events such as ligand binding, receptor over- expression, generation of structure-defected variants, and point mutations in the kinase domain contribute to RON signaling activation. Recently, functional crosstalk between RON and signaling proteins such as MET and EFGR has emerged as an additional mechanism for RON activation, which is critical for tumorigenic develop- ment. The RON signaling crosstalk acts either as a regulatory feedback loop that strengthens or enhances tumor- igenic phenotype of cancer cells or serves as a signaling compensatory pathway providing a growth/survival ad- vantage for cancer cells to escape targeted therapy. Moreover, viral oncoproteins derived from Friend leukemia or Epstein-Barr viruses interact with RON to drive viral oncogenesis. In cancer cells, RON signaling is integrated into cellular signaling network essential for cancer cell growth and survival. These activities provide the mo- lecular basis of targeting RON for cancer treatment. In this review, we will discuss recent data that uncover the mechanisms of RON activation in cancer cells, review evidence of RON signaling crosstalk relevant to cancer malignancy, and emphasize the significance of the RON signaling addiction by cancer cells for tumor therapy. Understanding aberrant RON signaling will not only provide insight into the mechanisms of tumor pathogenesis, but also lead to the development of novel strategies for molecularly targeted cancer treatment.

Molecular targeting in cancer therapy and prevention

Recent progress made in many biological sciences such as genomics, genetics, and molecular biology has made molecular targeting possible. Although thousands of disease-causing molecules（genes and proteins alike） can theoretically be drug targets, there have been limited cases with successful drag targets that have been moved to clinical practice. Advances in experimental biomedical research have provided many sophisticated methods that can improve our ability to link human diseases with specific genes or proteins and to explore the underlying mechanisms. However, these approaches have not bee well validated for drag targeting. This presentation aims at providing a systemic review on the state-of-art information and technology in the field of drag targeting and its role in the process of drag discovery and drug development. After a brief discussion of the process of modem drag discovery and development, the roles of drag targeting in drug discovery, design, development, and delivery will be reviewed.

Novel natural product therapeutics targeting both inflammation and cancer

Inflammation is recently recognized as one of the hallmarks of human cancer. Chronic inflammatory response plays a critical role in cancer development, progression, metastasis, and resistance to chemotherapy. Conversely, the oncogenic aberrations also generate an inflammatory microenvironment, enabling the development and progression of cancer. The molecular mechanisms of action that are responsible for inflammatory cancer and cancer-associated inflammation are not fully understood due to the complex crosstalk between oncogenic and pro-inflammatory genes. However, molecular mediators that regulate both inflammation and cancer, such as NF-κB and STAT have been considered as promising targets for preventing and treating these diseases. Recent works have further demonstrated an important role of oncogenes(e.g., NFAT1, MDM2) and tumor suppressor genes(e.g., p53) in cancer-related inflammation. Natural products that target these molecular mediators have shown anticancer and anti-inflammatory activities in preclinical and clinical studies. Sesquiterpenoids(STs), a class of novel plant-derived secondary metabolites have attracted great interest in recent years because of their diversity in chemical structures and pharmacological activities. At present, we and other investigators have found that dimeric sesquiterpenoids(DSTs) may exert enhanced activity and binding affinity to molecular targets due to the increased number of alkylating centers and improved conformational flexibility and lipophilicity. Here, we focus our discussion on the activities and mechanisms of action of STs and DSTs in treating inflammation and cancer as well as their structure-activity relationships.

Natural products targeting the p53-MDM2 pathway and mutant p53: Recent advances and implications in cancer medicine

The p53 tumor suppressor plays a major role in controlling the initiation and development of cancer by regulating cell cycle arrest,apoptosis,senescence,and DNA repair.The MDM2 oncogene is a major negative regulator of p53 that inhibits the activity of p53 and reduces its protein stability.MDM2,p53,and the p53-MDM2 pathway represent welldocumented targets for preventing and/or treating cancer.Natural products,especially those from medicinal and food plants,are a rich source for the discovery and development of novel therapeutic and preventive agents against human cancers.Many natural product-derived MDM2 inhibitors have shown potent efficacy against various human cancers.In contrast to synthetic small-molecule MDM2 inhibitors,the majority of which have been designed to inhibit MDM2-p53 binding and activate p53,many natural product inhibitors directly decrease MDM2 expression and/or MDM2 stability,exerting their anticancer activity in both p53-dependent and p53-independent manners.More recently,several natural products have been reported to target mutant p53 in cancer.Therefore,identification of natural products targeting MDM2,mutant p53,and the p53-MDM2 pathway can provide a promising strategy for the development of novel cancer chemopreventive and chemotherapeutic agents.In this review,we focus our discussion on the recent advances in the discovery and development of anticancer natural products that target the p53-MDM2 pathway,emphasizing several emerging issues,such as the efficacy,mechanism of action,and specificity of these natural products.

Development and validation of an HPLC-MS/MS analytical method for quantitative analysis of TCBA-TPQ,a novel anticancer makaluvamine analog,and application in a pharmacokinetic study in rats

We have recently designed and synthesized several novel iminoquinone anticancer agents that have entered preclinical development for the treatment of human cancers.Herein we developed and validated a quantitative HPLC-MS/MS analytical method for one of the lead novel anticancer makaluvamine analog,TCBA-TPQ,and conducted a pharmacokinetic study in laboratory rats.Our results indicated that the HPLC-MS/MS method was precise,accurate,and specific.Using this method,we carried out in vitro and in vivo evaluations of the pharmacological properties of TCBA-TPQ and plasma pharmacokinetics in rats.Our results provide a basis for future preclinical and clinical development of this promising anticancer marine analog.

A novel inhibitor of MDM2 oncogene blocks metastasis of hepatocellular carcinoma and overcomes chemoresistance

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.

Discovery and development of synthetic tricyclic pyrroloquinone （TPQ） alkaloid analogs for human cancer therapy

Natural products and their derivatives repre- sent a rich source for the discovery and development of new cancer therapeutic drugs. Bioactive components derived from natural sources including marine compounds have been shown to be effective agents in the clinic or in preclinical settings. In the present review, we present a story of discovery, synthesis and evaluation of three synthetic tricyclic pyrroloquinone （TPQ） alkaloid analogs as cancer therapeutic agents. Chemical synthesis of these compounds （BA-TPQ, TBA-TPQ, and TCBA-TPQ） has been accomplished and the mechanisms of action （MOA） and structure-activity relationships （SAR） have been investigated. In the past, the complexity of chemical synthesis and the lack of well-defined MOA have dampened the enthusiasm for the development of some makaluvamines. Recent discovery of novel molecular targets for these alkaloids （unrelated to inhibition of Topoisomerase II） warrant further consideration as clinical candidates in the future. In addition to the establishment of novel synthetic approaches and demonstration of in vitro and in vivo anticancer activities, we have successfully demonstrated that these makaluvamines attack several key molecular targets, including the MDM2-p53 pathway, providing ample opportunities of modulating the compound structure based on SAR and the use of such compounds in combination therapy in the future.

High open-circuit voltage organic solar cells enabled by a difluorobenzoxadiazole-based conjugated polymer donor

A new polymer donor based on 3,3′-difluoro-2,2′-bithiophene(2F2T) and difluorobenzoxadiazole(ffBX), named 2F2T-ffBX, is designed and synthesized. The organic solar cell(OSC) based on 2F2T-ffBX donor and [6,6]-phenyl-C60-butyl acid methyl ester([60]PCBM) acceptor exhibits a high efficiency of 7.3% with a high open-circuit voltage(Voc) of 1.03 V. When blended with perylenediimide-based acceptor(PDI6), the corresponding OSC shows a higher Voc of 1.19 V with a low energy loss of 0.50 e V but a much lower efficiency of 2.0%. The detailed analyses including charge generation, transport, recombination properties, and morphology were performed to understand the performance of corresponding devices.

BCCIPβ modulates the ribosomal and extraribosomal function of S7 through a direct interaction

ribosomal 蛋白质(RP ) 的 Extraribosomal 功能在 tumorigenesis 和前进为他们的含意获得了许多注意。然而，为在 ribosomal 和 RP 的 extraribosomal 功能之间的转变的规定很少被报导。此处，我们识别了一个 ribosomal 蛋白质交往 S7 搭挡， BCCIP，它调制 S7 的功能的变换。通过 N 终端酸的领域， BCCIP 在 S7 与中央基本区域交往并且调整 S7 的 extraribosomal 分发。BCCIP 缺乏废除 ribosomal 累积，但是提高 S7 的没有核糖体的地点。这 translocation 进一步损害蛋白质合成和扳机 ribosomal 应力。因而， BCCIP 缺乏压制 ribosomal 功能并且开始 S7 的 extraribosomal 功能，导致房间增长的限制。而且，临床上相关的 S7 变化被发现阻抑和 BCCIP 的相互作用并且便于 S7 的功能的转变。在结论，作为一个 S7 调节的人， BCCIP 贡献 ribosomal 的规定， extraribosomal S7 工作并且在房间生长和肿瘤开发有含意。

Corrigendum to“A novel inhibitor of MDM2 oncogene blocks metastasis of hepatocellular carcinoma and overcomes chemoresistance”[Genes Dis 694(2019)419e430]

We regret that an error was made in“A novel inhibitor of MDM2 oncogene blocks metastasis of hepatocellular carcinoma and overcomes chemoresistance”(Genes Dis 2019 Dec;694:419e430).In Fig.1C of the original manuscript,the right panel(showing the migration ability of the MHCCLM3 cells)was erroneously duplicated with the left panel(showing the migration ability of the Huh7 cells)when the figures were assembled.We have now checked the original data and request to replace the right panel with the correct data for MHCCLM3 cells.The corrected Fig.