Recent advances in stem cell biology have resulted in identifying new agents to differentiate stem cell-derived-neural cells. Different stem cell types have been shown to differentiate into neural cells. It has been shown that P19 line of embryonal carcinoma cells develops into neurons and astroglia after exposure to some hormones such as dehydroepiandrosterone (DHEA). Steroid 5Î±-reductase is a key enzyme in the conversion of several Î�4-3 keto steroids, such as testosterone into their respective 5Î±-reductase derivatives. Finasteride is a 5Î±-reductase inhibitor that inhibits conversion of testosterone to the more potent androgen dihydrotestosterone (DHT). Reduction in DHT and sustaining testosterone levels has an important impact on differentiation and proliferation of embryonal carcinoma cells to neural cells. We hypothesize that finasteride, a 5Î±-reductase inhibitor, will be differentiate embryonal carcinoma cell to the neural cell and increase their proliferation due to the elevation levels of testosterone, a neuroprotective neurosteroid. Â© 2010

Sharif, S.

Shoae-Hassani, A.

Verdi, J.

kashan university of medical sciences

A 5-reductase inhibitor, finasteride, increases differentiation and proliferation of embryonal carcinoma cell-derived-neural cells

Recent advances in stem cell biology have resulted in identifying new agents to differentiate stem cell-derived-neural cells. Different stem cell types have been shown to differentiate into neural cells. It has been shown that P19 line of embryonal carcinoma cells develops into neurons and astroglia after exposure to some hormones such as dehydroepiandrosterone (DHEA). Steroid 5Î±-reductase is a key enzyme in the conversion of several4-3 keto steroids, such as testosterone into their respective 5Î±-reductase derivatives. Finasteride is a 5Î±-reductase inhibitor that inhibits conversion of testosterone to the more potent androgen dihydrotestosterone (DHT). Reduction in DHT and sustaining testosterone levels has an important impact on differentiation and proliferation of embryonal carcinoma cells to neural cells. We hypothesize that finasteride, a 5Î±-reductase inhibitor, will be differentiate embryonal carcinoma cell to the neural cell and increase their proliferation due to the elevation levels of testosterone, a neuroprotective neurosteroid

eprints Iran University of Medical Sciences

Medical Hypotheses 76 (2011) 11–13Contents lists available at ScienceDirectMedical Hypothesesjournal homepage: www.elsevier .com/locate /mehyA 5a-reductase inhibitor, ﬁnasteride, increases differentiation and proliferationof embryonal carcinoma cell-derived-neural cellsAlireza Shoae-Hassani a, Shiva Sharif a,b, Javad Verdi a,c,d,⇑aResearch center for Science and Technology in Medicine, Tehran University of Medical Sciences, Tehran, IranbCellular and Molecular Research Center and Department of Tissue Engineering, Iran University of Medical School, Tehran, IrancPhysiology and Pharmacology Department, Kashan University of Medical Sciences, Kashan, IrandDepartment of Tissue Engineering, Faculty of Advance Technology, Tehran University of Medical Sciences, Tehran, Irana r t i c l e i n f oArticle history:Received 13 July 2010Accepted 12 August 20100306-9877/$ - see front matter  2010 Published bydoi:10.1016/j.mehy.2010.08.018⇑ Corresponding author at: Physiology and PharmUniversity of Medical Sciences, Kashan, Iran. Tel.: +98E-mail address: jverdi2@yahoo.com (J. Verdi).s u m m a r yRecent advances in stem cell biology have resulted in identifying new agents to differentiate stem cell-derived-neural cells. Different stem cell types have been shown to differentiate into neural cells. It hasbeen shown that P19 line of embryonal carcinoma cells develops into neurons and astroglia after expo-sure to some hormones such as dehydroepiandrosterone (DHEA). Steroid 5a-reductase is a key enzyme inthe conversion of several D4-3 keto steroids, such as testosterone into their respective 5a-reductasederivatives. Finasteride is a 5a-reductase inhibitor that inhibits conversion of testosterone to the morepotent androgen dihydrotestosterone (DHT). Reduction in DHT and sustaining testosterone levels hasan important impact on differentiation and proliferation of embryonal carcinoma cells to neural cells.We hypothesize that ﬁnasteride, a 5a-reductase inhibitor, will be differentiate embryonal carcinoma cellto the neural cell and increase their proliferation due to the elevation levels of testosterone, a neuropro-tective neurosteroid. 2010 Published by Elsevier Ltd.BackgroundCulture of embryonal carcinoma (EC) cells revealed the poten-tial application of these cells in developing assays of pharmacol-ogy, toxicology and cell therapy in a large spectrum of diseases.Protocols for controlled differentiation of EC cells ordinarily de-pend on the application of growth and/or differentiation factorsin a deﬁned temporal order.The aggregation of EC cells to embryoid bodies is used to inducedifferentiation. The embryoid bodies represent multicellular struc-tures which undergo spontaneous differentiation in derivatives ofgerm layers [1]. Initial differentiation of embryoid bodies occurswhen the outer cells of the aggregate differentiate into endo-derm-like cells that surround an undifferentiated core [1]. Embry-onal carcinoma cells are derived from teratocarcinomas. Malignantteratomas also contain populations of undifferentiated stem cellsthat can grow as undifferentiated cell lines [2,3]. Examples of suchcells that have been applicable are the human Tera-2 EC cells [4],mouse F9 EC cells [5] and P19 EC cells [6].Early works showed that P19 EC cells are very suitable for iso-lating clonal sub-lines. In addition, hormones like retinoic acid(RA) and neurosteroids induce differentiation of EC cells, in mono-Elsevier Ltd.acology Department, Kashan3615550021 25.layer culture, without an aggregation phase [7,8]. It was shownthat relatively high concentrations of RA induce the formation ofneuronal and glial cells [9], while 0.5–1% DMSO leads to the forma-tion of a wide variety of endodermal and mesodermal tissues [10].Dehydroepiandrosterone (DHEA) is a neurosteroid that has beenshown to be a potential signaling molecule in neuronal differenti-ation during development. DHEA can increase proliferation of hu-man neural stem cells. DHEA has recently been shown to beneuroprotective [11]. The adrenal cortex is the primary source ofcirculating concentrations of DHEA [12], which is secreted in re-sponse to adrenal corticotropin-releasing hormone [13]. DHEA actas the precursor to the approximately 50% of androgens in adultmen and positively regulate elevation of testosterone [14]. DHEAproduction and concentration declines signiﬁcantly and steadilyduring aging [15]. Testosterone is an important determinant ofbody composition in masculine. Its administration is associatedwith hypertrophy of muscle ﬁbers and signiﬁcant increases inmyo-nuclear, satellite and neural cell numbers [16]. Transdifferentiationinto neural stem cells and differentiating neurons was observed inhuman stem cells after exposure to certain combinations ofsteroids especially testosterone [17]. Testosterone enhances neuro-genesis via increased cell survival through an androgen dependentmechanism [18].Recently, ﬁnasteride was described as a potential clinicalcandidate for the treatment of androgen-dependent disorders.Finasteride is an inhibitor of 5a-reductase. Steroid 5a-reductase12 A. Shoae-Hassani et al. /Medical Hypotheses 76 (2011) 11–13is a NADPH-dependent enzyme which converts testosterone tothe more potent androgen, 5a-dihydrotestosterone (DHT), pro-gesterone to dihydroprogesterone and deoxycorticosterone todihydrodeoxycorticosterone, steroids modulating the action ofc-aminobutyric acid on GABA receptors [19]. In an extensiveinvestigation of the effects of androgens on the proliferation,differentiation, and function of stem cells, it was clear thatDHT inhibits the differentiation of stem cells. The ﬁnal effectis a reduced number of fully differentiated cells [20]. Like DHEA,ﬁnasteride increase testosterone levels and decrease otherandrogen levels [21].Understanding the consequence actions of DHEA, DHT and ﬁn-asteride inspired us to propose that ﬁnasteride, the 5a-reductaseinhibitor, will be differentiate embryonal carcinoma cell to theneural cell and increase proliferation of neural cells due to eleva-tion of testosterone, a neuroprotective neurosteroid.HypothesisTestosterone levels have an important impact on differentiationand proliferation of embryonal stem cells to neural cells. Thehypothesis we propose here is that ﬁnasteride, a 5a-reductaseinhibitor, that could change the balance between testosteroneand DHT will be differentiate embryonal carcinoma cell to neuralcell and increase proliferation of neural cells. The hypothesis isdue to elevation of testosterone and lessens in DHT levels. DHT, anon-aromatizable androgen, can decrease proliferation and differ-entiation of EC cells and its existence is contrarily to ﬁnasteriderole. This idea would be important and has implication for futureuse.Evaluation of hypothesisInvestigations of androgens effects on differentiation of stemcells revealed that DHT inhibits the differentiation of stem cells.Adipocytes differentiated from stem cells in the presence of DHTare smaller and accumulate fewer lipids [20]. Testosterone andDHT regulate the differentiation of pluripotent cells of mesenchy-mal origin; these androgens stimulate myogenic differentiationwhile inhibiting adipogenic differentiation [22]. Androgens regu-late body composition by stimulating the commitment of pluripo-tent cells that are resident within the skeletal muscle andelsewhere into the myogenic lineage [22].Finasteride blocks the actions of DHT that mainly has actions onthe prostate and hair loss. Therefore, testosterone replacement canbe safely prescribed alongside ﬁnasteride in patients with low tes-tosterone [23]. The presence of 100 nM/L ﬁnasteride during theischemic insult results in substantial protection. In some cases sur-viving rate of neurons is quantiﬁed by counting distinct function-ally active neurons before and after insult [19].DiscussionAndrogens inhibit bodies fat mass; thus, their deﬁciency is asso-ciated with higher fat mass [24], and testosterone supplementationlessens whole body and inter-muscular fat mass [25,26]. DePergolahas reported that testosterone inhibits differentiation of precursorcells, suppresses lipid uptake and lipoprotein lipase activity, andup-regulates the number of beta-adrenergic receptors [27].Pregnenolone, a steroid precursor of testosterone, had no signif-icant effect on the differentiation of stem cells, indicating thatthese effects are speciﬁc to androgenic steroids. Steroids affectneuronal operation through binding to cognate intracellular recep-tors which may act as transcription factors in regulation of geneexpression [28].Neuroactive steroids modulate ligand-gated ion channels vianon-genomic mechanisms. Classical steroid hormones such as tes-tosterone and progesterone are neuroactive steroids because theymay act as functional antagonists at the 5-hydroxytryptaminereceptor, a ligand-gated ion channel or distinct glutamate recep-tors. Although a binding’s site for steroids at GABAA receptors isstill a subject for further discussions, there is an evidence that ste-roids interact allosterically with ligand-gated ion channels at thereceptor membrane interface [28].Animal studies showed that testosterone is converted rapidlyinto GABAergic neuroactive steroids in vivo. It reduces locomotoractivity in a dose-dependent fashion in Wistar rats. Both the geno-mic and non-genomic effects of steroids in the brain may contrib-ute to pathophysiological disorders. Neuroactive steroids affectembryonal carcinoma cells and may represent a new treatmentstrategy for neurological disorders [29].This discussion suggests a promising strategy for promotingneurogenesis by ﬁnasteride in the aged brain and potentially forrestoration of neuronal populations in brains recovering from neu-rodegenerative disease or injury.ConclusionIn summary according to the theory mentioned above, wewould use the ﬁnasteride to induce development of neurons in cul-tures of P19 cells. Finasteride could provide a suitable inducer fordifferentiation of stem cell-derived-neural cells, including neuro-spheres and neurons.Role of funding sourceFunding for this study was provided by the Center of Sciencesand Technology Research in Medicine, Tehran University of Medi-cal Sciences.Conﬂicts of interest statementNone declared.AcknowledgementThis hypothesis is based on our present study in the Laboratoryof Tissue engineering and Stem cell of Sciences and Technology inMedical Research Centre in Tehran University of Medical Sciences,Tehran, Iran.References[1] Masters JR. HeLa cells 50 years on: the good, the bad and the ugly. Nat RevCancer 2002;2:315–9.[2] Martin GR, Evans MJ. Differentiation of clonal lines of teratocarcinoma cells:formation of embryoid bodies in vitro. Proc Natl Acad Sci USA 1975;72:1441–5.[3] Martin GR. Teratocarcinomas as a model system for the study ofembryogenesis and neoplasia. Cell 1975;5:229–43.[4] Andrews PW. 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A reductase inhibitor, finasteride, increases differentiation and proliferation of embryonal carcinoma cell-derived-neural cells

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A 5-reductase inhibitor, finasteride, increases differentiation and proliferation of embryonal carcinoma cell-derived-neural cells

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