000145391 001__ 145391
000145391 005__ 20241024135331.0
000145391 0247_ $$2doi$$a10.1186/s12967-024-05739-x
000145391 0248_ $$2sideral$$a140296
000145391 037__ $$aART-2024-140296
000145391 041__ $$aeng
000145391 100__ $$aSoler-Agesta, R.$$uUniversidad de Zaragoza
000145391 245__ $$aCancer cell-selective induction of mitochondrial stress and immunogenic cell death by PT-112 in human prostate cell lines
000145391 260__ $$c2024
000145391 5060_ $$aAccess copy available to the general public$$fUnrestricted
000145391 5203_ $$aPT-112 is a novel immunogenic cell death (ICD)-inducing small molecule currently under Phase 2 clinical development, including in metastatic castration-resistant prostate cancer (mCRPC), an immunologically cold and heterogeneous disease state in need of novel therapeutic approaches. PT-112 has been shown to cause ribosome biogenesis inhibition and organelle stress followed by ICD in cancer cells, culminating in anticancer immunity. In addition, clinical evidence of PT-112-driven immune effects has been observed in patient immunoprofiling. Given the unmet need for immune-based therapies in prostate cancer, along with a Phase I study (NCT#02266745) showing PT-112 activity in mCRPC patients, we investigated PT-112 effects in a panel of human prostate cancer cell lines. PT-112 demonstrated cancer cell selectivity, inhibiting cell growth and leading to cell death in prostate cancer cells without affecting the non-tumorigenic epithelial prostate cell line RWPE-1 at the concentrations tested. PT-112 also caused caspase-3 activation, as well as stress features in mitochondria including ROS generation, compromised membrane integrity, altered respiration, and morphological changes. Moreover, PT-112 induced damage-associated molecular pattern (DAMP) release, the first demonstration of ICD in human cancer cell lines, in addition to autophagy initiation across the panel. Taken together, PT-112 caused selective stress, growth inhibition and death in human prostate cancer cell lines. Our data provide additional insight into mitochondrial stress and ICD in response to PT-112. PT-112 anticancer immunogenicity could have clinical applications and is currently under investigation in a Phase 2 mCRPC study.
000145391 536__ $$9info:eu-repo/grantAgreement/ES/MICINN/PID2019-105128RB-I00
000145391 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/
000145391 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000145391 700__ $$0(orcid)0000-0002-6600-1618$$aMoreno-Loshuertos, R.$$uUniversidad de Zaragoza
000145391 700__ $$aYim, C. Y.
000145391 700__ $$aCongenie, M. T.
000145391 700__ $$aAmes, T. D.
000145391 700__ $$aJohnson, H. L.
000145391 700__ $$aStossi, F.
000145391 700__ $$aMancini, M. G.
000145391 700__ $$aMancini, M. A.
000145391 700__ $$aRipollés-Yuba, C.$$uUniversidad de Zaragoza
000145391 700__ $$aMarco-Brualla, J.
000145391 700__ $$0(orcid)0000-0002-9951-1075$$aJunquera, C.$$uUniversidad de Zaragoza
000145391 700__ $$aMartínez-De-Mena, R.
000145391 700__ $$aEnríquez, J. A.
000145391 700__ $$aPrice, M. R.
000145391 700__ $$aJimeno, J.
000145391 700__ $$0(orcid)0000-0002-5175-8394$$aAnel, A.$$uUniversidad de Zaragoza
000145391 7102_ $$11003$$2443$$aUniversidad de Zaragoza$$bDpto. Anatom.Histolog.Humanas$$cArea Histología
000145391 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000145391 773__ $$g22, 1 (2024), 927 [17 pp.]$$pJ. transl. med.$$tJournal of translational medicine$$x1479-5876
000145391 8564_ $$s9875681$$uhttps://zaguan.unizar.es/record/145391/files/texto_completo.pdf$$yVersión publicada
000145391 8564_ $$s2117346$$uhttps://zaguan.unizar.es/record/145391/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000145391 909CO $$ooai:zaguan.unizar.es:145391$$particulos$$pdriver
000145391 951__ $$a2024-10-24-12:11:56
000145391 980__ $$aARTICLE