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Drug and apoptosis resistance in cancer stem cells: a puzzle with many pieces

Cancer Drug resistance 2022年第4期5卷 850-872页

作者： ahmad r.safa Department of Pharmacology and Toxicology Indiana University School of MedicineIndianapolisIN 46202USA

resistance to anticancer agents and apoptosis results in cancer relapse and is associated with cancer *** data have provided convincing evidence establishing that human cancers emerge from cancer stemcells (CSCs), which display self-renewal and are resistant to anticancer drugs, radiation, and apoptosis, andexpress enhanced epithelial to mesenchymal progression. CSCs represent a heterogeneous tumor cell populationand lack specific cellular targets, which makes it a great challenge to target and eradicate them. Similarly, theirclose relationship with the tumor microenvironment creates greater complexity in developing novel treatmentstrategies targeting CSCs. Several mechanisms participate in the drug and apoptosis resistance phenotype in CSCsin various cancers. These include enhanced expression of ATP-binding cassette membrane transporters, activationof various cytoprotective and survival signaling pathways, dysregulation of stemness signaling pathways, aberrantDNA repair mechanisms, increased quiescence, autophagy, increased immune evasion, deficiency ofmitochondrial-mediated apoptosis, upregulation of anti-apoptotic proteins including c-FLIP [cellular FLICE (FADDlikeIL-1β-converting enzyme)-inhibitory protein], Bcl-2 family members, inhibitors of apoptosis proteins, andPI3K/AKT signaling. Studying such mechanisms not only provides mechanistic insights into these cells that areunresponsive to drugs, but may lead to the development of targeted and effective therapeutics to eradicate *** studies have identified promising strategies to target CSCs. These emerging strategies may help targetCSC-associated drug resistance and metastasis in clinical settings. This article will review the CSCs drug and apoptosis resistance mechanisms and how to target CSCs.

关键词： Cancer stem cells(CSCs) apoptosis drug resistance death receptor pathways anti-apoptotic proteins Bcl-2 family c-FLIP

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Emerging targets for glioblastoma stem cell therapy

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The Journal of Biomedical research 2016年第1期30卷 19-31页

作者： ahmad r.safa Mohammad reza Saadatzadeh Aaron A.Cohen-Gadol Karen E.Pollok Khadijeh Bijangi-Vishehsaraei Indiana University Simon Cancer Center IU School of Medicine and Goodman Campbell Brain and Spine Department of Pharmacology and Toxicology IU School of Medicine and Goodman Campbell Brain and Spine Department of Neurosurgery IU School of Medicine and Goodman Campbell Brain and Spine Herman B.Wells Center for Pediatric research Indiana University School of MedicineIndianapolisIN 46202USA.

Glioblastoma multiforme（GBM）,designated as World Health Organization（WHO）grade IV astrocytoma,is a lethal and therapy-resistant brain cancer comprised of several tumor cell subpopulations,including GBM stem cells（GSCs）which are believed to contribute to tumor recurrence following initial response to *** evidence demonstrates that GBM tumors are initiated from *** development and use of novel therapies including small molecule inhibitors of specific proteins in signaling pathways that regulate sternness,proliferation and migration of GSCs,immunotherapy,and non-coding microrNAs may provide better means of treating *** and characterization of GSC-specific signaling pathways would be necessary to identify specific therapeutic targets which may lead to the development of more efficient therapies selectively targeting *** signaling pathways including mTOr,AKT,maternal embryonic leucine zipper kinase（MELK）,NOTCH1 and Wnt/β-catenin as well as expression of cancer stem cell markers CD133,CD44,Oct4,Sox2,Nanog,and ALDHlA1 maintain GSC ***,the data published in the Cancer Genome Atlas（TCGA）specifically demonstrated the activated PI3K/AKT/mTOr pathway in GBM *** such pathways may help to understand GSC biology and lead to the development of potential therapeutic interventions to render them more sensitive to chemotherapy and radiation ***,recent demonstration of dedifferentiation of GBM cell lines into CSC-like cells prove that any successful therapeutic agent or combination of drugs for GBM therapy must eliminate not only GSCs,but the differentiated GBM cells and the entire bulk of tumor cells.

关键词： glioblastoma multiforme stem cells dedifferentiation CD133 CD44 ALDHlAl SOX2

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Glioblastoma stem cells(GSCs)epigenetic plasticity and interconversion between differentiated non-GSCs and GSCs

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Genes & Diseases 2015年第2期2卷 152-163页

作者： ahmad r.safa Mohammad reza Saadatzadeh Aaron A.Cohen-Gadol Karen E.Pollok Khadijeh Bijangi-Vishehsaraei Indiana University Simon Cancer Center Indiana University School of MedicineIndianapolisIN 46202USA Department of Pharmacology and Toxicology Indiana University School of MedicineIndianapolisIN 46202USA Department of Neurosurgery IU School of Medicine and Goodman Campbell Brain and SpineIndiana University School of MedicineIndianapolisIN 46202USA Herman B.Wells Center for Pediatric research Indiana University School of MedicineIndianapolisIN 46202USA Otolaryngology-Head and Neck Surgery Indiana University School of MedicineIndianapolisIN 46202USA

Cancer stem cells(CSCs)or cancer initiating cells(CICs)maintain self-renewal and multilineage differentiation properties of various tumors,as well as the cellular heterogeneity consisting of several subpopulations within *** display the malignant phenotype,self-renewal ability,altered genomic stability,specific epigenetic signature,and most of the time can be phenotyped by cell surface markers(e.g.,CD133,CD24,and CD44).Numerous studies support the concept that non-stem cancer cells(non-CSCs)are sensitive to cancer therapy while CSCs are relatively resistant to *** glioblastoma stem cells(GSCs),there is clonal heterogeneity at the genetic level with distinct tumorigenic potential,and defined GSC marker expression resulting from clonal evolution which is likely to influence disease progression and response to *** level of complexity in glioblastoma multiforme(GBM)tumors is the dynamic equilibrium between GSCs and differentiated non-GSCs,and the potential for non-GSCs to revert(dedifferentiate)to GSCs due to epigenetic alteration which confers phenotypic plasticity to the tumor cell ***,exposure of the differentiated GBM cells to therapeutic doses of temozolomide(TMZ)or ionizing radiation(Ir)increases the GSC pool both in vitro and in *** review describes various subtypes of GBM,discusses the evolution of CSC models and epigenetic plasticity,as well as interconversion between GSCs and differentiated non-GSCs,and offers strategies to potentially eliminate GSCs.

关键词： Cancer stem cells Epigenetic GBM plasticity Glioblastoma Stemness Dedifferentiation GBM stem cells

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Epithelial-mesenchymal transition:a hallmark in pancreatic cancer stem cell migration,metastasis formation,and drug resistance

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Journal of Cancer Metastasis and Treatment 2020年第1期6卷 425-439页

作者： ahmad r.safa Department of Pharmacology and Toxicology Indiana University School of MedicineIndianapolisIN46202USA

Metastasis,tumor progression,and chemoresistance are the major causes of death in patients with pancreatic ductal adenocarcinoma(PDAC).Tumor dissemination is associated with the activation of an epithelial-tomesenchymal transition(EMT)process,a program by which epithelial cells lose their cell polarity and cell-tocell adhesion,and acquire migratory and invasive abilities to become mesenchymal stem cells(MSC).These MSCs are multipotent stromal cells capable of differentiating into various cell types and trigger the phenotypic transition from an epithelial to a mesenchymal ***,EMT promotes migration and survival during cancer metastasis and confers stemness features to particular subsets of ***,a major problem limiting our ability to treat PDAC is the existence of rare populations of pancreatic cancer stem cells(PCSCs)or cancer-initiating cells in pancreatic *** may represent sub-populations of tumor cells resistant to therapy which are most crucial for driving invasive tumor *** cells are capable of regenerating the cellular heterogeneity associated with the primary tumor when xenografted into ***,the presence of PCSCs has prognostic relevance and influences the therapeutic response of *** express markers of cancer stem cells(CSCs)including CD24,CD133,CD44,and epithelial specific antigen as well as the drug transporter ABCG2 grow as spheroids in a defined growth medium.A major difficulty in studying tumor cell dissemination and metastasis has been the identification of markers that distinguish metastatic cancer cells from cells that are normally circulating in the bloodstream or at sites where these cells *** highlights a linkage between CSC and *** this review,The current understanding of the PCSCs,signaling pathways regulating these cells,PDAC heterogeneity,EMT mechanism,and links between EMT and metastasis in PCSCs are *** information may provide potential therapeutic s

关键词： Pancreatic cancer cancer stem cells epithelial-mesenchymal transition metastasis drug resistance

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A complex signature network that controls the upregulation of PrMT5 in colorectal cancer

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Genes & Diseases 2022年第2期9卷 285-287页

作者： Han Wei Antja-Voy Hartley Aishat Motolani Guanglong Jiang ahmad safa Lakshmi Prabhu Yunlong Liu Tao Lu Department of Pharmacology and Toxicology Indiana University School of Medicine635 Barnhill DriveIndianapolisIN 46202USA Department of Medical&Molecular Genetics Indiana University School of Medicine975 W.Walnut StreetIndianapolisIN 46202USA Department of Biochemistry and Molecular Biology Indiana University School of Medicine635 Barnhill DriveIndianapolisIN 46202USA Current address:Beckman Coulter Life Sciences 5350 Lake-view Pkwy S DrIndianapolisIN 46268USA Current address:Dana-Farber Cancer Institute Harvard Med-ical School450 Brookline Ave.BostonMA 02215USA Current address:Gilead Sciences Inc.333 Lakeside Drive Foster CityCA 94404USA

Protein arginine methyltransferase 5(PrMT5)deregulation has emerged as an important prognostic indicator in human *** aberrant methylation-mediated epige-netic modification of signaling molecules,PrMT5 over-expression contributes to dysregulation of a variety of cellular processes related to cancer progression.1 However,the mechanisms governing PrMT5 expression levels in cancer remain largely *** this study,we examined factors that regulate PrMT5 expression at multiple levels.

关键词： cancer PrMT5 colorectal

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Human GM3 Synthase Attenuates Taxol-Triggered Apoptosis Associated with Downregulation of Caspase-3 in Ovarian Cancer Cells

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Journal of Cancer Therapy 2012年第5期3卷 504-510页

作者： Su Huang Khadijeh Bijangi-Vishehsaraei Mohammad reza Saadatzadeh ahmad r. safa Department of Medicine Division of Hematology/Oncology Indiana University School of Medicine Indianapolis USA. Department of Pharmacology and Toxicology Indiana University Simon Cancer Center Indianapolis USA

Background: Taxol (paclitaxel) inhibits proliferation and induces apoptosis in a variety of cancer cells, but it also upregulates cytoprotective proteins and/or pathways that compromise its therapeutic efficacy. Materials and Method: The roles of GM3 synthase (α2,3-sialyltransferase, ST3Gal V), in attenuating Taxol-induced apoptosis and triggering drug resistance were determined by cloning and overexpressing this enzyme in SKOV3 human ovarian cancer cell line, treating SKOV3 and the transfectants (SKOV3/GS) with Taxol and determining apoptosis, cell survival, clonogenic ability, and caspase-3 activation. results: In this report, we demonstrated that Taxol treatment resulted in apoptosis which was associated with caspase-3 activation. Taxol treatment upregulated the expression of human GM3 synthase, an enzyme that transfers a sialic acid to lactosylceramide. Moreover, we cloned the full-length GM3 synthase gene and showed for the first time that forced expression of GM3 synthase attenuated Taxol-induced apoptosis and increased resistance to Taxol in SKOV3 cells. Conclusions: GM3 synthase overexpression inhibited Taxol-triggered caspase-3 activation, revealing that upregulation of GM3 synthase prevents apoptosis and hence reduces the efficacy of Taxol therapy.

关键词： Ovarian Cancer Taxol GM3 Synthase Apoptosis Caspase-8 Drug resistance

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Inhibition of PrMT5 by market drugs as a novel cancer therapeutic avenue

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Genes & Diseases 2023年第1期10卷 267-283页

作者： Lakshmi Prabhu Matthew Martin Lan Chen Ozlem Demir Jiamin Jin Xiumei Huang Aishat Motolani Mengyao Sun Guanglong Jiang Harikrishna Nakshatri Melissa L.Fishel Steven Sun ahmad safa rommie E.Amaro Mark r.Kelley Yunlong Liu Zhong-Yin Zhang Tao Lu Department of Pharmacology and Toxicology Indiana University School of MedicineIndianapolisIN 46202USA Chemical Genomics Core Facility Indiana University School of MedicineIndiana University School of MedicineIndianapolisIN 46202USA Department of Biochemistry and Molecular Biology Indiana University School of MedicineIndiana University School of MedicineIndianapolisIN46202USA Department of Chemistry and Biochemistry University of CaliforniaSan DiegoCA 92093USA Department of radiation Oncology Indiana University School of MedicineIndianapolisIN 46202USA Department of Medical and Molecular Genetics Indiana University School of MedicineIndianapolisIN 46202USA Department of Medicine Indiana University School of MedicineIndianapolisIN 46202USA Department of Pediatrics Herman B Wells Center for Pediatric ResearchIndianapolisiN 46202USA Indiana University Simon Comprehensive Cancer Center Indiana University School of MedicineIndianapolisIN46202USA

Market drugs,suchas Foodand Drug Administration(FDA)or European Medicines Agency(EMA)-approved drugs for specific indications provide opportunities for repurposing for newer *** potentially saves resources invested in clinical trials that verify drug safety and tolerance in humans prior to alternative indication *** arginine methyltransferase 5(PrMT5)overexpression has been linked to promoting the tumor phenotype in several cancers,including pancreatic ductal adenocarcinoma(PDAC),colorectal cancer(CrC),and breast cancer(BC),making PrMT5 an important target for cancer ***,we showed that PrMT5-mediated methylation of the nuclear factor(NF)-kB,partially contributes to its constitutive activation observed in *** this study,we utilized an AlphaLiSA-based high-throughput screening method adapted in our lab,and identified one FDA-approved drug,Candesartan cilexetil(Can,used in hypertension treatment)and one EMA-approved drug,Cloperastine hydrochloride(Clo,used in cough treatment)that had significant PrMT5-inhibitory activity,and their anti-tumor properties were validated using cancer phenotypic assays in ***,PrMT5 selective inhibition of methyltransferase activity was confirmed by reduction of both NF-kB methylation and its subsequent activation upon drug *** in silico prediction,we identified critical residues on PrMT5 targeted by these drugs that may interfere with its enzymatic ***,Clo and Can treatment have exhibited marked reduction in tumor growth in ***,we provide basis for pursuing repurposing Clo and Can as anti-PrMT5 cancer *** study offers potential safe and fast repurposing of previously unknown PrMT5 inhibitors into clinical practice.

关键词： Cancer research NF-kB Pharmacology PrMT5 PrMT5 inhibitors

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