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 o...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.展开更多
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 Doubl...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.展开更多
Mitochondria as a signaling platform play crucial roles in deciding cell fate.Many classic anticancer agents are known to trigger cell death through induction of mitochondrial damage.Mitophagy,one selective autophagy,...Mitochondria as a signaling platform play crucial roles in deciding cell fate.Many classic anticancer agents are known to trigger cell death through induction of mitochondrial damage.Mitophagy,one selective autophagy,is the key mitochondrial quality control that effectively removes damaged mitochondria.However,the precise roles of mitophagy in tumorigenesis and anticancer agent treatment remain largely unclear.Here,we examined the functional implication of mitophagy in the anticancer properties of magnolol,a natural product isolated from herbal Magnolia officinalis.First,we found that magnolol induces mitochondrial depolarization,causes excessive mitochondrial fragmentation,and increases mitochondrial reactive oxygen species(mtROS).Second,magnolol induces PTEN-induced putative kinase protein 1(PINK1)-Parkin-mediated mitophagy through regulating two positive feedforward amplification loops.Third,magnolol triggers cancer cell death and inhibits neuroblastoma tumor growth via the intrinsic apoptosis pathway.Moreover,magnolol prolongs the survival time of tumor-bearing mice.Finally,inhibition of mitophagy by PINK1/Parkin knockdown or using inhibitors targeting different autophagy/mitophagy stages significantly promotes magnolol-induced cell death and enhances magnolol's anticancer efficacy,both in vitro and in vivo.Altogether,our study demonstrates that magnolol can induce autophagy/mitophagy and apoptosis,whereas blockage of autophagy/mitophagy remarkably enhances the anticancer efficacy of magnolol,suggesting that targeting mitophagy may be a promising strategy to overcome chemoresistance and improve anticancer therapy.展开更多
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 dem...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.展开更多
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...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.展开更多
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 manuscrip...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.展开更多
基金supported by National Institutes of Health(NIH)/National Cancer Institute(NCI)grants(R01 CA186662 and R01 CA214019 to RZ).The content is solely the responsibility of the authors,and does not necessarily represent the official views of the National Institutes of Health.supported by American Cancer Society(ACS)grant RSG-15-009-01-CDDsupported by funds for the Robert L.Boblitt Endowed Professor in Drug Discovery and research funds from the College of Pharmacy and the University of Houston+3 种基金supported by grants from the National Nature Science Foundation(81630086,81427805,81672763,31401611,and 81502122)the Key Research Program(ZDRW-ZS-2017-1)the Strategic Priority Research Program(XDA12020319)of the Chinese Academy of Sciencesthe Science and Technology Commission of Shanghai Municipality(16391903700 and 14391901800).
文摘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.
基金supported by the National Institutes of Health(NIH) grant R01 CA186662(to R.Z.) and CA102514(to R.A.)supported by American Cancer Society(ACS) grant RSG-15-009-01-CDD (to W.W.)
文摘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.
基金supported by research grants from Innovation and Technology Fund(PRP/036/20FX,China)Health and Medical Research Fund(MHRF-16170251,China)of Hong Kong to Hu-Biao Chen+1 种基金Singapore Ministry of Education(MOE)Tier 2(MOE2018-T2-1-060,Singapore)to Han-Ming ShenNational Natural Science Foundation of China(82074123 to Hu-Biao Chen,31501116 to Yingying Lu,82071441 to Liming Wang)。
文摘Mitochondria as a signaling platform play crucial roles in deciding cell fate.Many classic anticancer agents are known to trigger cell death through induction of mitochondrial damage.Mitophagy,one selective autophagy,is the key mitochondrial quality control that effectively removes damaged mitochondria.However,the precise roles of mitophagy in tumorigenesis and anticancer agent treatment remain largely unclear.Here,we examined the functional implication of mitophagy in the anticancer properties of magnolol,a natural product isolated from herbal Magnolia officinalis.First,we found that magnolol induces mitochondrial depolarization,causes excessive mitochondrial fragmentation,and increases mitochondrial reactive oxygen species(mtROS).Second,magnolol induces PTEN-induced putative kinase protein 1(PINK1)-Parkin-mediated mitophagy through regulating two positive feedforward amplification loops.Third,magnolol triggers cancer cell death and inhibits neuroblastoma tumor growth via the intrinsic apoptosis pathway.Moreover,magnolol prolongs the survival time of tumor-bearing mice.Finally,inhibition of mitophagy by PINK1/Parkin knockdown or using inhibitors targeting different autophagy/mitophagy stages significantly promotes magnolol-induced cell death and enhances magnolol's anticancer efficacy,both in vitro and in vivo.Altogether,our study demonstrates that magnolol can induce autophagy/mitophagy and apoptosis,whereas blockage of autophagy/mitophagy remarkably enhances the anticancer efficacy of magnolol,suggesting that targeting mitophagy may be a promising strategy to overcome chemoresistance and improve anticancer therapy.
基金W.W. and R.Z. were partially supported by National Institutesof Health (NIH)/National Cancer Institute grants(R01 CA186662 and R01CA214019)W.W. and R.Z. were alsosupported by American Cancer Society (ACS) grant RSG-15-009-01-CDD. R.Z. was also supported by funds for Robert L.Boblitt Endowed Professor in Drug Discovery and researchfunds from College of Pharmacy and University of Houston.J.C., J.F., and X-R. Y. were supported by grants from theNational Natural Science Foundation of China (No.81272389, 81472674, 81502486). The content of this reportis solely the responsibility of the authors, and does notnecessarily represent the official views of the National Institutesof Health or other funding agencies.
文摘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.
基金supported by the National Institutes of Health(NIH)grants R01 CA112029,R01 CA121211,and R01 CA186662(to R.Z.)and 1UL1RR025777(to S.V.)
文摘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.
文摘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.
