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Potential role of nimbolide in chemoprevention and therapy of prostate cancer

中国药理学与毒理学杂志 2015年第S1期29卷 78-79页

作者： Jing-wen ZHANG MuthuK.SHANMUGAM Amudha DEIVASIGAMANI Alan Prem KUMAR KamMan HUI gautam.sethi Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore Singapore 117597 Division of Cellular and Molecular Research Humphrey Oei Institute of Cancer Research National Singapore 1169610 Cancer Centre Cancer Science Institute of Singapore Centre for Translational Medicine Singapore 117599

OBJECTIVE Prostate cancer is one of the most commonly diagnosed cancers *** therapies for metastatic prostate cancer are only marginally effective,and hence novel treatment modalities are urgently *** evidence suggests that chronic inflammation plays a pivotal role in the development and progression of prostate *** agents that can suppress these inflammatory mediators could form the basis of novel therapy for prostate cancer *** our study,we focused on analyzing the potential anticancer effects of nimbolide,a terpenoid lactone derived from Azadirachta indica(Neem tree)against prostate *** Molecular biology techniques such as western blot analysis,DNA binding,luciferase assays,and immunohistochemistry were used for both in vitro and in vivo *** Data from the in vitrostudies indicated that nimbolide could inhibit cell proliferation,induce apoptosis and suppress cellular invasion and ***,nimbolide also abrogated the activation of pro-inflammatory STAT 3 transcription factor,and this effect was found to be mediated via an increased production of reactive oxygen species(ROS),whereas depletion of ROS attenuated pSTAT 3 inhibitory effects of the *** in vivo efficacy of nimbolide was also noted in transgenic adenocarcinoma of mouse prostate(TRAMP)model,in which this triterpenoid significantly suppressed the tumor progression and growth without exhibiting any substantial adverse *** Overall our findings indicate that nimbolide exhibits significant anticancer effects in prostate cancer,and these effects may be mediated at least in part through the modulation of STAT 3 signaling pathway.

关键词： prostate cancer nimbolide STAT3 ROS

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Targeting oncogenic transcription factors for cancer therapy

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中国药理学与毒理学杂志 2018年第4期32卷 250-250页

作者： gautam.sethi Department of Pharmacology National University of Singapore 117600 Singapore

Signal transducers and activators of transcription(STATs) comprise an important class of transcription factors that have been implicated in a wide variety of essential cellular functions related to proliferation,survival,and *** various STAT members,STAT3 is frequently overexpressed in tumor cells as well as tissue samples,and regulates the expression of numerous oncogenic genes controlling the growth and metastasis of tumor cells.I will briefly discuss the importance of STAT3 as a potential target for prostate cancer therapy and also provide novel insights into various classes of existing pharmacological inhibitors of this transcription factor that can be potentially developed as anti-cancer drugs.

关键词：信号转导肿瘤治疗方法临床分析

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Garcinol suppresses the growth of human hepatocellular carcinoma by inducing abrogation of STAT3 phosphorylation,acetylation and dimerization

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中国药理学与毒理学杂志 2015年第S1期29卷 82-83页

作者： Muthu K SHANMUGAM Snehajyoti CHATTERJEE Peramaiyan RAJENDRAN Feng LI Parijat SENAPATI Kwong Fai WONG Alan Prem KUMAR John MLUK Kam Man HUI gautam.sethi Tapas K KUNDU Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore Singapore 117957 Jawaharlal Nehru Centre for Advanced Scientific Research Molecular Biology and Genetics Unit Transcription and Disease Laboratory Jakkur P.O. Bangalore 560064 India Cancer Science Institute of Singapore National University of Singapore Singapore 117456 School of Biomedical Sciences Faculty of Health Sciences Curtin University Western Australia Division of Cellular and Molecular Research Humphrey Oei Institute of Cancer Research National Cancer Centre Singapore 169610 Institute of Molecular and Cell Biology Singapore 138673

OBJECTIVE Hepatocellular carcinoma(HCC)is the fifth most common malignancy worldwide and the third cause of global cancer *** of signal transducer and activator of transcription 3(STAT3)is commonly observed in tumor cells and is a critical mediator of on cogenic signaling in HCC and controls the expression of several genes involved in proliferation,survival,metastasis and *** drug-targeted therapies,besides being expensive,are associated with serious side effects and ***,novel agents that can suppress STAT3 activation have potential for both prevention and treatment of *** the present report,we investigated whether the potent HAT/KAT inhibitor,garcinol,(apolyisoprenylatedbenzophenone),could suppress STAT3 activation in HCC cells and in nude mice *** The effect of garcinol on HCC cell lines wasdetermined by MTT assay,immunoblotting,DNA binding assays,immuno-fluorescenceand immune-histochemical *** effect of garcinolon the inhibition of tumor growth in vivo was also investigated using HCCxenograft tumor modelin athymic nu/nu *** We found that garcinol could inhibit constitutive STAT3 activation in a dose-and time-dependent manner both by inhibiting STAT3 phosphorylation and acetylation in HCC *** investigated for molecular mechanism(s),we found that garcinol interferes with the dimer formation of STAT3 thereby inhibits its nuclear *** modeling showed that garcinol could bind to the SH2 domain of STAT3 and suppresses its dimerization in *** understand the cellular mechanism(s)of inhibition of STAT3 function by garcinol,we observed that upon inhibition of STAT3 dimerization bygarcinol,STAT3 DNA binding ability gets *** inhibition of STAT3 activation by garcinol led to the suppression of various gene products involved in proliferation,survival,and ***,when administered i.p.,garcinol inhibited the growth of human HCC xenograft tumors in

关键词： STAT3 HCC garcinol acetylation dimerization nude m

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RNF6 promotes myeloma cell proliferation and survival by inducing glucocorticoid receptor polyubiquitination

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中国药理学与毒理学杂志 2019年第10期 886-887页

作者： REN Ying XU Xin MAO Chen-Yu HAN Kun-Kun XU Yu-Jia CAO Bi-Yin ZHANG Zu-Bin sethi gautam TANG Xiao-Wen MAO Xin-Liang Department of Pharmacology College of Pharmaceutical Sciences Soochow University School of Medicine South University of Science and Technology Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore Key Laboratory of Protein Modification and Degradation School of Basic Medical Sciences Affiliated Cancer Hospital & Institute of Guangzhou Medical University Department of Hematology the First Affiliated Hospital of Soochow University

OBJECTIVE To elucidate the action and specific mechanisms of RNF6 in MM. METHODS Co-immunoprecipitation was used for the interaction between RNF6 and glucocorticoid receptor(GR). Immunoblotting was employed for protein expression. Luciferase assay was used for GR transcriptional activity and lentiviral infection was applied for RNF6 function in MM *** The expression levels of RNF6 in multiple myeloma(MM) were significantly elevated compared to the bone marrow cells of healthy donors. Overexpression of RNF6 in LP1 and PRMI-8266 MM cell lines promoted cell proliferation, whereas knockdown of RNF6 led to apoptosis of MM cells. Furthermore, we revealed that RNF6, as a ubiquitin ligase, interacted with glucocorticoid receptor(GR) and induced its K63-linked polyubiquitination. Different from current knowledge, RNF6 increased GR stability at both endogenous and exogenous *** an action greatly promoted GR transcriptional activity,which was confirmed by luciferase assays and by the increased expression levels of pro-survival genes including Bcl-x L and Mcl-1, two typical downstream genes of the GR pathway. Consistent with these findings, ectopic expression of RNF6 in MM cells conferred resistance to dexamethasone, a typical anti-myeloma agent. CONCLUSION RNF6 promotes MM cel proliferation and survival by inducing atypical polyubiquitination to GR, and RNF6 could be a promising therapeutic target for the treatment of MM.

关键词： GR RNF6 ubiquitin proteasome pathway multiple myeloma dexamethasone

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Targeting the PI3K/Akt signaling pathway in gastric carcinoma: A reality for personalized medicine?

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World Journal of Gastroenterology 2015年第43期21卷 12261-12273页

作者： Shikha Satendra Singh Wei Ney Yap Frank Arfuso Shreya Kar Chao Wang Wanpei Cai Arunasalam M Dharmarajan gautam.sethi Alan Prem Kumar Cancer Science Institute of Singapore National University of Singapore Department of Pharmacology Yong Loo Lin School of MedicineNational University of Singapore Davos Life Science Pte Ltd School of Biomedical Sciences Curtin Health Innovation Research InstituteCurtin University National University Cancer Institute Department of Biological Sciences University of North Texas

Frequent activation of phosphatidylinositol-3 kinases(PI3K)/Akt/m TOR signaling pathway in gastric cancer(GC) is gaining immense popularity with identification of mutations and/or amplifications of PIK3 CA gene or loss of function of PTEN,a tumor suppressor protein,to name a few; both playing a crucial role in regulating this pathway. These aberrations result in dysregulation of this pathway eventually leading to gastric oncogenesis,hence,there is a need for targeted therapy for more effective anticancer treatment. Several inhibitors are currently in either preclinical or clinical stages for treatment of solid tumors like GC. With so many inhibitors under development,further studies on predictive biomarkers are needed to measure the specificity of any therapeutic intervention. Herein,we review the common dysregulation of PI3K/Akt/m TOR pathway in GC and the various types of single or dual pathway inhibitors under development that might have a superior role in GC treatment. We also summarize the recent developments in identification of predictive biomarkers and propose use of predictive biomarkers to facilitate more personalized cancer therapy with effective PI3K/Akt/m TOR pathway inhibition.

关键词： Epidemiology Gastric cancer PI3K/Akt/ m TOR pathwa

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Garcinol sensitizes human head and neck carcinoma to cisplatin in a xenograft mouse model despite downregulation of proliferative biomarkers

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中国药理学与毒理学杂志 2015年第S1期29卷 80-80页

作者： Feng Li Muthu K. Shanmugam Kodappully Sivaraman Siveen Fan Wang Tina H. Ong Ser Yue Loo Mahadeva M.M. Swamy Somnath Mandal Alan Prem Kumar Boon Cher Goh Tapas Kundu Kwang Seok Ahn Ling Zhi Wang Kam Man Hui gautam.sethi Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore Singapore 117957 Cancer Science Institute of Singapore Centre for Translational Medicine Singapore 117957 Division of Cellular and Molecular Research Humphrey Oei Institute of Cancer Research National Cancer Centre Singapore 169610 Genome Institute of Singapore Agency for Science Technology and Research (A*STAR) Singapore Jawaharlal Nehru Centre for Advanced Scientific Research Molecular Biology and Genetics Unit Transcription and Disease Laboratory Bangalore 560064 India School of Biomedical Sciences Faculty of Health Sciences Curtin University Western Australia 6009 Australia Department of Biological Sciences University of North Texas Denton Texas 76203 Department of Haematology-Oncology National University Health System Singapore 117957 College of Korean Medicine Kyung Hee University Seoul 130-701 Republic of Korea

OBJECTIVE Platinum compounds such as cisplatin and carboplatin are frequently used as the first-line chemotherapy for the treatment of the head and neck squamous cell carcinoma(HNSCC).In the present study,we investigated whether garcinol,apolyisoprenylated benzophenone can chemosensitize HNSCC to *** The effect of garcinol and cisplatin on HNSCC was assessed by MTT,Western blotting,real time PCR,FACS,immunohistochemistry,DNA binding assay and xenograft mouse *** We found that garcinol inhibited the viability of a panel of diverse HNSCC cell lines,enhanced the apoptotic effect of cisplatin,suppressed constitutive as well as cisplatin-induced NF-κB activation,and downregulated the expression of various oncogenic gene products(cyclin D1,Bcl-2,survivin and VEGF).In vivo study showed that administration of garcinol alone(0.5 mg·kg-1,ip five times/week)significantly suppressed the growth of the tumor,and this effect was further increased by *** the markers of proliferation index(Ki-67)and microvessel density(CD31)were downregulated in tumor tissues by the combination of cisplatin and *** pharmacokinetic results of garcinol indicated that good systemic exposure was achievable after ip administration of garcinol at 0.5and 2mg·kg-1 with mean peak concentration(cmax)of 1825.4 and 6635.7nmol·L-1 in the mouse serum,*** Overall,our results suggest that garcinol can indeed potentiate the effects of cisplatin by negative regulation of various inflammatory and proliferative biomarkers.

关键词： HNSCC chemoresistance NF-κB proliferation garcinol

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