Lipophilic but not hydrophilic statins selectively induce cell death in gynaecological cancers expressing high levels of HMGCoA reductase

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dc.contributor.authorKato, S.
dc.contributor.authorSmalley, S.
dc.contributor.authorSadarangani, A.
dc.contributor.authorChen Lin, K.
dc.contributor.authorOliva, B.
dc.contributor.authorBranes, J.
dc.contributor.authorCarvajal, J.
dc.contributor.authorGejman, R.
dc.contributor.authorOwen, G. I.
dc.contributor.authorCuello, M.
dc.date.accessioned2024-01-10T13:50:00Z
dc.date.available2024-01-10T13:50:00Z
dc.date.issued2010
dc.description.abstractRecent reports have suggested that statins induce cell death in certain epithelial cancers and that patients taking statins to reduce cholesterol levels possess lower cancer incidence. However, little is known about the mechanisms of action of different statins or the effects of these statins in gynaecological malignancies. The apoptotic potential of two lipophilic statins (lovastatin and simvastatin) and one hydrophilic statin (pravastatin) was assessed in cancer cell lines (ovarian, endometrial and cervical) and primary cultured cancerous and normal tissues. Cell viability was studied by MTS assays and apoptosis was confirmed by Western blotting of PARP and flow cytometry. The expressions of key apoptotic cascade proteins were analysed. Our results demonstrate that both lovastatin and simvastatin, but not pravastatin, selectively induced cell death in dose- and time-dependent manner in ovarian, endometrial and cervical cancers. Little or no toxicity was observed with any statin on normal cells. Lipophilic statins induced activation of caspase-8 and -9; BID cleavage, cytochrome C release and PARP cleavage. Statin-sensitive cancers expressed high levels of HMG-CoA reductase compared with resistant cultures. The effect of lipophilic statins was dependent on inhibition of enzymatic activity of HMG-CoA reductase since mevalonate pre-incubation almost completely abrogated the apoptotic effect. Moreover, the apoptotic effect involved the inhibition of synthesis of geranylgeranyl pyrophosphate rather than farnesyl pyrophosphate. In conclusion, lipophilic but not hydrophilic statins induce cell death through activation of extrinsic and intrinsic apoptotic cascades in cancerous cells from the human female genital tract, which express high levels of HMG-CoA reductase. These results promote further investigation in the use of lipophilic statins as anticancer agents in gynaecological malignancies.
dc.description.funderFONDECYT
dc.fechaingreso.objetodigital2024-05-09
dc.format.extent14 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1111/j.1582-4934.2009.00771.x
dc.identifier.eissn1582-4934
dc.identifier.pubmedidMEDLINE:19432822
dc.identifier.urihttps://doi.org/10.1111/j.1582-4934.2009.00771.x
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/79497
dc.identifier.wosidWOS:000278802200020
dc.information.autorucMedicina;Branes J;S/I;76860
dc.information.autorucMedicina;Carvajal J;S/I;3345
dc.information.autorucCiencias Biológicas;Chen-Lin K;S/I;154631
dc.information.autorucMedicina;Cuello M;S/I;80064
dc.information.autorucMedicina;Gejman R;S/I;900
dc.information.autorucMedicina;Kato S;S/I;82640
dc.information.autorucCiencias Biológicas;Oliva B;S/I;1008557
dc.information.autorucCiencias Biológicas;Owen GI;S/I;1000459
dc.information.autorucCiencias Biológicas;Sadarangani A;S/I;18788
dc.information.autorucMedicina;Smalley S;S/I;143948
dc.issue.numero5
dc.language.isoen
dc.nota.accesocontenido completo
dc.pagina.final1193
dc.pagina.inicio1180
dc.publisherWILEY
dc.revistaJOURNAL OF CELLULAR AND MOLECULAR MEDICINE
dc.rightsacceso abierto
dc.subjectstatins
dc.subjectgynaecological cancers
dc.subjectapoptosis
dc.subjecttherapy
dc.subjectOVARIAN-CANCER
dc.subjectENDOTHELIAL FUNCTION
dc.subjectMEDIATES APOPTOSIS
dc.subjectCOLON-CANCER
dc.subjectINHIBITORS
dc.subjectCARCINOMA
dc.subjectRISK
dc.subjectTHERAPY
dc.subjectLOVASTATIN
dc.subjectGROWTH
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleLipophilic but not hydrophilic statins selectively induce cell death in gynaecological cancers expressing high levels of HMGCoA reductase
dc.typeartículo
dc.volumen14
sipa.codpersvinculados76860
sipa.codpersvinculados3345
sipa.codpersvinculados154631
sipa.codpersvinculados80064
sipa.codpersvinculados900
sipa.codpersvinculados82640
sipa.codpersvinculados1008557
sipa.codpersvinculados1000459
sipa.codpersvinculados18788
sipa.codpersvinculados143948
sipa.indexWOS
sipa.indexScopus
sipa.trazabilidadCarga SIPA;09-01-2024
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