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Role of prostate cancer stem-like cells in the development of antiandrogen resistance

Cancer Drug Resistance 2022年第2期5卷 459-471页

作者： Prem Prakash Kushwaha Shiv Verma Shashank Kumar sanjay gupta Department of Urology Case Western Reserve UniversityClevelandOH 44106USA. The Urology Institute University Hospitals Cleveland Medical CenterClevelandOH 44106USA. Molecular Signaling and Drug Discovery Laboratory Department of BiochemistryCentral University of PunjabBathinda 151401India. Department of Pathology Case Western Reserve UniversityClevelandOH 44106USA. Department of Pharmacology Case Western Reserve UniversityClevelandOH 44106USA. Department of Nutrition Case Western Reserve UniversityClevelandOH 44106USA. Divison of General Medical Sciences Case Comprehensive Cancer CenterClevelandOH 44106USA.

Androgen deprivation therapy(ADT)is the standard of care treatment for advance stage prostate cancer.Treatment with ADT develops resistance in multiple ways leading to the development of castration-resistant prostate cancer(CRPC).Present research establishes that prostate cancer stem-like cells(CSCs)play a central role in the development of treatment resistance followed by disease progression.Prostate CSCs are capable of self-renewal,differentiation,and regenerating tumor heterogeneity.The stemness properties in prostate CSCs arise due to various factors such as androgen receptor mutation and variants,epigenetic and genetic modifications leading to alteration in the tumor microenvironment,changes in ATP-binding cassette(ABC)transporters,and adaptations in molecular signaling pathways.ADT reprograms prostate tumor cellular machinery leading to the expression of various stem cell markers such as Aldehyde Dehydrogenase 1 Family Member A1(ALDH1A1),Prominin 1(PROM1/CD133),Indian blood group(CD44),SRY-Box Transcription Factor 2(Sox2),POU Class 5 Homeobox 1(POU5F1/Oct4),Nanog and ABC transporters.These markers indicate enhanced self-renewal and stemness stimulating CRPC evolution,metastatic colonization,and resistance to antiandrogens.In this review,we discuss the role of ADT in prostate CSCs differentiation and acquisition of CRPC,their isolation,identification and characterization,as well as the factors and pathways contributing to CSCs expansion and therapeutic opportunities.

关键词： Prostate cancer second-generation antiandrogens cancer stem cells castration resistance prostate cancer androgen deprivation therapy

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Real-world clinical effectiveness of sorafenib among patients with unresectable hepatocellular carcinoma at two centers in the United States

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World Journal of Gastrointestinal Oncology 2023年第10期15卷 1796-1806页

作者： Daneng Li Stephen B Gruber Shrividya Iyer sanjay gupta Mohamedtaki Tejani Department of Medical Oncology and Therapeutics Research City of Hope Comprehensive Cancer CenterDuarteCA 91010United States Center for Precision Medicine City of Hope Comprehensive Cancer CenterDuarteCA 91010United States Department of Oncology Worldwide Real-World EvidenceEisai Inc.NutleyNJ 07110United States Department of Oncology and Hematology Advent Health Cancer InstituteOrlandoFL 32804United States

BACKGROUND In the United States,sorafenib monotherapy was approved in 2007 for first-line(1L)treatment of patients with unresectable hepatocellular carcinoma(uHCC).As other therapies have been approved in recent years for hepatocellular carcinoma treatment in later lines,it is essential to assess clinical effectiveness of older therapies in actual clinical practice to inform healthcare practitioners’decisions for better patient care.AIM To assess patient characteristics/clinical effectiveness of 1L sorafenib in uHCC patients treated in United States academic and community practice settings.METHODS A retrospective observational study was conducted among adult patients(≥18 years)in the United States initiating sorafenib monotherapy as 1L systemic therapy for uHCC with Eastern Cooperative Oncology Group status of 0 or 1 between January 2016 and December 2019 at City of Hope and Advent Health.Data were extracted by trained abstractionists from individual patients’electronic health records and captured in electronic case report forms.Institutional Review Board approvals were obtained prior to study initiation.Data were captured from the time of sorafenib initiation until death or the end of follow-up.All data were de-identified prior to analyses.Clinical outcomes assessed included provider-reported best response,progression-free survival(PFS),and overall survival(OS).PFS and OS were estimated using Kaplan-Meier methods.RESULTS Among 134 uHCC patients treated with 1L sorafenib,majority were male(75%),and most were Caucasian(62%)or Asian(19%).Median patient age was 64 years.The most common etiologies of liver disease were hepatitis C(54%),alcohol-related liver disease(16%),and hepatitis B(11%).Most patients were reported to have Barcelona Clinic Liver Cancer stage B(19%)or stage C(70%)disease.Of 134 patients,110(82%)were reported to have discontinued treatment or died during follow-up.Primary reasons for sorafenib discontinuation were reported as progression(35%)and toxicity(30%).Best overall response was reported for 1

关键词： Retrospective observational study Sorafenib Hepatocellular carcinoma Clinical effectiveness

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Triple tube drainage for “difficult” gastroduodenal perforations:A prospective study

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World Journal of Gastrointestinal Surgery 2017年第1期9卷 19-24页

作者： Nitin Agarwal Nishant Kumar Malviya Nikhil gupta Iqbal Singh sanjay gupta Department of Surgery and Renal Transplant Postgraduate Institute of Medical Education and Research (PG-IMER) and Dr. Ram Manohar Lohia Hospital Depart-ment of Surgery University College of Medical Sciences and Guru Tegh Bahadur Hospital Department of Surgery Post Graduate Institute of Medical Education and Research (PGIMER) and Dr RML Hospital

AIM To prospectively study the outcome of difficult gastroduodenal perforations(GDPs) treated by triple tube drainage(TTD) in order to standardize the procedure.METHODS Patients presenting to a single surgical unit of a tertiary hospital with difficult GDPs(large, unfavourable local and systemic factors) were treated with TTD(gastrostomy, duodenostomy and feeding jejunostomy). Postoperative parameters were observed like time to return of bowel sounds, time to start enteral feeds, time to start oral feeds, daily output of all drains, time to clamping/removal of all drains, time for skin to heal, complications, hospital stay, and, mortality. Descriptive statistics were used. RESULTS Between December 2013 and April 2015, 20 patients undergoing TTD for GDP were included, with mean age of 44.6 ± 19.8 years and male:female ratio of 17:3. Mean pre-operative APACHE Ⅱ scores were 10.85 ± 3.55; most GDPs were prepyloric(9/20; 45%) or proximal duodenal(8/20; 40%) and mean size was 1.83 ± 0.59 cm(largest 2.5 cm). Median times of resumption of enteral feeding, removal of gastrostomy, removal of duodenostomy,removal of feeding jejunostomy and oral feeding were 4 d(4-5 IQR), 13(12-16.5 IQR), 16(16.25-22.25 IQR), 18(16.5-24 IQR) and 12 d(10.75-18.5 IQR) respectively. Median hospital stay was 22 d(19-26 IQR) while mortality was 4/20(20%). CONCLUSION TTD for difficult GDP is feasible, easy in the emergency, and patients recover in two-three weeks. It obviates the need for technically demanding and riskier procedures.

关键词：消化剂溃疡穿孔腹膜炎 APACHE 使试管排水增加两倍十二指肠造口术

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Hepatocellular carcinoma: Understanding molecular mechanisms for defining potential clinical modalities

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World Journal of Hepatology 2021年第11期13卷 1568-1583页

作者： Abhiram Natu Anjali Singh sanjay gupta Epigenetics and Chromatin Biology Group Gupta LaboratoryCancer Research InstituteAdvanced Centre for TreatmentResearch and Education in CancerTata Memorial CentreKhargharNavi Mumbai 410210MaharashtraIndia Homi Bhabha National Institute Training School ComplexAnushakti NagarMumbai 400085MaharashtraIndia

Liver cancer is the sixth most commonly occurring cancer and costs millions of lives per year.The diagnosis of hepatocellular carcinoma(HCC)has relied on scanning techniques and serum-based markers such asα-fetoprotein.These measures have limitations due to their detection limits and asymptomatic conditions during the early stages,resulting in late-stage cancer diagnosis where targeted chemotherapy or systemic treatment with sorafenib is offered.However,the aid of conventional therapy for patients in the advanced stage of HCC has limited outcomes.Thus,it is essential to seek a new treatment strategy and improve the diagnostic techniques to manage the disease.Researchers have used the omics profile of HCC patients for sub-classification of tissues into different groups,which has helped us with prognosis.Despite these efforts,a promising target for treatment has not been identified.The hurdle in this situation is genetic and epigenetic variations in the tumor,leading to disparities in response to treatment.Understanding reversible epigenetic changes along with clinical traits help to define new markers for patient categorization and design personalized therapy.Many clinical trials of inhibitors of epigenetic modifiers(also known as epi-drugs)are in progress.Epi-drugs like azacytidine or belinostat are already approved for other cancer treatments.Furthermore,epigenetic changes have also been observed in drug-resistant HCC tumors.In such cases,combinatorial treatment of epi-drugs with systemic therapy or trans-arterial chemoembolization might re-sensitize resistant cells.

关键词： Hepatocellular carcinoma Diagnosis Treatment Epigenetics Epi-drugs Drug resistance

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Emerging targets in cancer drug resistance

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Cancer Drug Resistance 2019年第2期2卷 161-177页

作者： Shashank Kumar Prem Prakash Kushwaha sanjay gupta School of Basic and Applied Sciences Department of Biochemistry and Microbial SciencesCentral University of PunjabBathinda 151001India Department of Urology Case Western Reserve UniversityClevelandOhio 44106USA The Urology Institute University Hospitals Cleveland Medical CenterClevelandOhio 44106USA Department of Nutrition Case Western Reserve UniversityClevelandOhio 44106USA Divison of General Medical Sciences Case Comprehensive Cancer CenterClevelandOhio 44106USA Department of Urology Louis Stokes Cleveland Veterans Affairs Medical CenterClevelandOhio 44106USA.

Drug resistance is a complex phenomenon that frequently develops as a failure to chemotherapy during cancer treatment.Malignant cells increasingly generate resistance to various chemotherapeutic drugs through distinct mechanisms and pathways.Understanding the molecular mechanisms involved in drug resistance remains an important area of research for identification of precise targets and drug discovery to improve therapeutic outcomes.This review highlights the role of some recent emerging targets and pathways which play critical role in driving drug resistance.

关键词： Drug resistance transforming growth factor-β Keap1-Nrf2 PI3K-Akt FOXO transcription factors focal adhesion kinases annexins MIEN1 gene splicing sphingolipids microRNA

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Genome-Wide Comparative in silico Analysis of Calcium Transporters of Rice and Sorghum

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Genomics, Proteomics & Bioinformatics 2011年第4期9卷 138-150页

作者： Anshita Goel Gohar Taj Dinesh Pandey sanjay gupta Anil Kumar Department of Molecular Biology and Genetic Engineering College of Basic Sciences and Humanities G.B. Pant University of Agriculture and Technology Department of Biotechnology Uttrakhand Technical University Department of Biotechnology SBS Biomedical P.G. Institute of Biomedical Science and Research

The mechanism of calcium uptake, translocation and accumulation in Poaceae has not yet been fully understood. To address this issue, we conducted genome-wide comparative in silico analysis of the calcium （Ca2＋） transporter gene family of two crop species, rice and sorghum. Gene annotation, identification of upstream cis-acting ele- ments, phylogenetic tree construction and syntenic mapping of the gene family were performed using several bio- informatics tools. A total of 31 Ca2＋ transporters, distributed on 9 out of 12 chromosomes, were predicted from rice genome, while 28 Ca2＋ transporters predicted from sorghum are distributed on all the chromosomes except chromosome 10 （Chr 10）. Interestingly, most of the genes on Chr 1 and Chr 3 show an inverse syntenic relation- ship between rice and sorghum. Multiple sequence alignment and motif analysis of these transporter proteins re- vealed high conservation between the two species. Phylogenetic tree could very well identify the subclasses of channels, ATPases and exchangers among the gene family. The in silico c/s-regulatory element analysis suggested diverse functions associated with light, stress and hormone responsiveness as well as endosperm- and meris- tem-specific gene expression. Further experiments are warranted to validate the in silico analysis of the predicted transporter gene family and elucidate the functions of Ca2＋ transporters in various biological processes.

关键词： in silico comparison calcium transporter rice sorghum genomic annotation synteny

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Dietary phytochemicals and their role in cancer chemoprevention

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Journal of Cancer Metastasis and Treatment 2021年第1期7卷 709-712页

作者： Shashank Kumar sanjay gupta Molecular Signaling and Drug Discovery Laboratory Department of BiochemistrySchool of Basic and Applied SciencesCentral University of PunjabBathinda 151401India Department of Urology Case Western Reserve UniversityClevelandOH 44106USA Department of Urology The Urology InstituteUniversity Hospitals Cleveland Medical CenterClevelandOH 44106USA Department of Nutrition Case Western Reserve UniversityClevelandOH 44106USA Divison of General Medical Sciences Case Comprehensive Cancer CenterClevelandOH 44106USA Department of Urology Louis Stokes Cleveland Veterans Affairs Medical CenterClevelandOH 44106USA.

Epidemiological studies suggest a close association between diet and cancer initiation,which provides evidence that the dietary components may be effectively developed as chemopreventive agents[1].These pieces of evidence are further supported by several case-control and cohort studies,which overwhelmingly support a converse association between the intake of phytochemicals and cancer risk[2,3].A number of clinical studies have been conducted demonstrating that dietary phytochemicals have the ability to inhibit tumorigenesis[4].Components presenting in fruit and vegetables termed“bioactive”phytochemicals belong to several classes of micronutrients,including flavonoids,polyphenols,and dietary fiber.These components have the ability to reduce the cancer risk alone or by interactions between them.

关键词： prevention cancer dietary

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Resistance to second generation antiandrogens in prostate cancer: pathways and mechanisms

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Cancer Drug Resistance 2020年第4期3卷 742-761页

作者： Shiv Verma Kumari Sunita Prajapati Prem Prakash Kushwaha Mohd Shuaib Atul Kumar Singh Shashank Kumar sanjay gupta Department of Urology Case Western Reserve UniversityClevelandOH 44106USA The Urology Institute University Hospitals Cleveland Medical CenterClevelandOH 44106USA School of Basic and Applied Sciences Department of Biochemistry and Microbial SciencesCentral University of PunjabBathinda 151001India Department of Nutrition Case Western Reserve UniversityClevelandOH 44106USA Divison of General Medical Sciences Case Comprehensive Cancer CenterClevelandOH 44106USA Department of Urology Louis Stokes Cleveland Veterans Affairs Medical CenterClevelandOH 44106USA

Androgen deprivation therapy targeting the androgens/androgen receptor(AR)signaling continues to be the mainstay treatment of advanced-stage prostate cancer.The use of second-generation antiandrogens,such as abiraterone acetate and enzalutamide,has improved the survival of prostate cancer patients;however,a majority of these patients progress to castration-resistant prostate cancer(CRPC).The mechanisms of resistance to antiandrogen treatments are complex,including specific mutations,alternative splicing,and amplification of oncogenic proteins resulting in dysregulation of various signaling pathways.In this review,we focus on the major mechanisms of acquired resistance to second generation antiandrogens,including AR-dependent and AR-independent resistance mechanisms as well as other resistance mechanisms leading to CRPC emergence.Evolving knowledge of resistance mechanisms to AR targeted treatments will lead to additional research on designing more effective therapies for advanced-stage prostate cancer.

关键词： Prostate cancer second-generation antiandrogens androgen receptor castration resistance prostate cancer

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A Simple Method to Produce Sub-Nucleosome Complexes of High Purity In Vitro

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Advances in Bioscience and Biotechnology 2016年第3期7卷 133-141页

作者： Saikat Bhattacharya sanjay gupta Epigenetics and Chromatin Biology Group Gupta Lab Cancer Research Institute Advanced Centre for Treatment Research and Education in Cancer (ACTREC) Tata Memorial Centre Kharghar Navi Mumbai India

With the identification of increasing number of chromatin modifiers, histone variants, histone post-translational modifications and their cross-talk, it is essential to validate these findings and interactions in vitro for which pure histone complexes are required. Although, the production of such complexes has been described earlier but still it remains a challenge for a non-specialist lab. Here we describe a protocol to quickly obtain large quantities of highly pure histones using bacterial expression system for GST pull-down and reconstitution experiments. In addition, we describe methods to quickly reconstitute and purify H2A/H2B dimers, H3/H4 tetramers and histone octamers for in vitro experiments. We demonstrate that these sub-complexes are properly folded and are hence, true representatives of the actual substrates in vivo. We also show that histones have a propensity to be non-specifically cleaved by proteases. Our results suggest that TEV protease is the most suitable protease while working with histones. The methodology described here should allow researchers to purify histone complexes in three days enabling functional and structural analyses of histone variants, mutants and post-translational modifications.

关键词： Histone Nucleosome H2A/H2B Dimer Histidine-Tag Recombinant

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Histone deacetylase inhibitor pre-treatment enhances the efficacy of DNA-interacting chemotherapeutic drugs in gastric cancer

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World Journal of Gastroenterology 2020年第6期26卷 598-613页

作者： Ramchandra Vigay Amnekar Shafqat Ali Khan Mudasir Rashid Bharat Khade Rahul Thorat Poonam Gera Shailesh V Shrikhande Duane T Smoot Hassan Ashktorab sanjay gupta Epigenetics and Chromatin Biology Group Gupta LaboratoryCancer Research InstituteAdvanced Centre for Treatment Research and Education in CancerTata Memorial CentreKhargharNavi MumbaiMaharashtra 410210India Homi Bhabha National Institute Training School ComplexAnushakti NagarMumbaiMaharashtra 400085India Department of Developmental Biology School of MedicineWashington University in St.LouisSaint LouisMO 63130United States Animal House Facility Cancer Research InstituteAdvanced Centre for Treatment Research and Education in CancerTata Memorial CentreKhargharNavi MumbaiMaharashtra 410210India Biorepository Lab Advanced Centre for Treatment Research and Education in CancerTata Memorial CentreKhargharNavi MumbaiMaharashtra 410210India Gastrointestinal and Hepato-Pancreato-Biliary Service Department of Surgical OncologyTata Memorial HospitalParelMumbai 400012India Department of Medicine Meharry Medical CenterNashvilleTN 37208United States Department of Medicine and Cancer Center College of MedicineHoward UniversityWashington DCWA 20060United States

BACKGROUND The prognosis of gastric cancer continues to remain poor,and epigenetic drugs like histone deacetylase inhibitors(HDACi)have been envisaged as potential therapeutic agents.Nevertheless,clinical trials are facing issues with toxicity and efficacy against solid tumors,which may be partly due to the lack of patient stratification for effective treatments.To study the need of patient stratification before HDACi treatment,and the efficacy of pre-treatment of HDACi as a chemotherapeutic drug sensitizer.METHODS The expression activity of class 1 HDACs and histone acetylation was examined in human gastric cancer cells and tissues.The potential combinatorial regime of HDACi and chemotherapy drugs was defined on the basis of observed drug binding assays,chromatin remodeling and cell death.RESULTS In the present study,the data suggest that the differential increase in HDAC activity and the expression of class 1 HDACs are associated with hypoacetylation of histone proteins in tumors compared to normal adjacent mucosa tissue samples of gastric cancer.The data highlights for the first time that pretreatment of HDACi results in an increased amount of DNA-bound drugs associated with enhanced histone acetylation,chromatin relaxation and cell cycle arrest.Fraction-affected plots and combination index-based analysis show that pre-HDACi chemo drug combinatorial regimes,including valproic acid with cisplatin or oxaliplatin and trichostatin A with epirubicin,exhibit synergism with maximum cytotoxic potential due to higher cell death at low combined doses in gastric cancer cell lines.CONCLUSION Expression or activity of class 1 HDACs among gastric cancer patients present an effective approach for patient stratification.Furthermore,HDACi therapy in pretreatment regimes is more effective with chemotherapy drugs,and may aid in predicting individual patient prognosis.

关键词： Chemotherapy Combinatorial index Gastric cancer Histone acetylation Histone deacetylase inhibitor Patient stratification

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