FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1483242826> ?p ?o ?g. }

• W1483242826 abstract "Background: Platinum-based drugs are since decades used as first-line treatment for many solid tumors. Patients with ovarian cancer often respond well to platinum compounds but a majority of patients rapidly develop resistance and die of chemotherapy refractory disease. The mechanisms underlying resistance are multifactorial, but two of the main causes are mutations in the tumor suppressor p53 and elevated intracellular glutathione (GSH) levels. Mutations in p53 occur in about 60% of ovarian tumors. APR-246 (PRIMA-1MET) is the first clinical-stage compound that reactivates mutant p53. APR-246 is a prodrug that accumulates in cancer cells and is converted to the active form MQ, a Michael acceptor that binds to mutant p53, refolds it to wild type conformation and triggers apoptosis (Lambert et al. Cancer Cell 15, 2009). APR-246 has been tested in a Phase I/IIa clinical trial with promising results (Lehmann et al. J Clin Oncol 30, 2012), and a Phase Ib/II study with platinum-based combination therapy in recurrent p53 mutant ovarian cancer is underway. Methods: Cell viability was assessed with WST-1, MTT or FMCA assay. p53 gene status was determined by Sanger sequencing and single strand conformation analysis, and p53 protein expression by Western blotting. Intracellular GSH levels were assessed with GSH kit (Cayman). Results: We have previously shown outstanding synergistic anticancer effects with APR-246 in combination with platinum compounds in p53 mutant solid cancer cell lines, including cisplatin resistant ovarian cancer cells. Synergistic effects were also observed ex vivo as well as in vivo in mice carrying human tumor xenografts. Here we show that APR-246 not only reactivates mutant p53 but also decreases intracellular GSH levels in a dose-dependent manner, presumably via adduct formation between MQ and GSH. APR-246 resensitized cisplatin resistant p53 mutant ovarian A2780-CP20 carcinoma cells to cisplatin, as shown by a decrease in the IC50 value from 52 to 2.9 µM, similar to the IC50 in parental A2780 cells. APR-246 also restored the sensitivity of resistant A2780ADR cells to doxorubicin. A2780-CP20 and A2780ADR were developed from the parental A2780 line with wild type p53 by chronic exposure to the respective drug. Moreover, APR-246 resensitized the p53 mutant OVCAR-3 cell line, established from a drug resistant patient, to cisplatin. Conclusions: Our results show that APR-246 not only reactivates mutant p53 but also decreases intracellular glutathione levels. We propose that this unique dual mechanism of action accounts for the resensitization and strong synergistic effects with APR-246 and platinum drugs. Our results provide strong rationale for the planned clinical study in ovarian cancer and suggest that combination treatment with APR-246 and DNA damaging drugs could have broad applicability in the treatment of drug resistant p53 mutant human tumors. Citation Format: Nina Mohell, Jessica Alfredsson, Asa Fransson, Vladimir Bykov, Mikael von Euler, Klas Wiman, Ulf Bjorklund. APR-246, a clinical-stage mutant p53-reactivating compound, resensitizes ovarian cancer cells to platinum compounds and doxorubicin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1801. doi:10.1158/1538-7445.AM2014-1801" @default.
• W1483242826 created "2016-06-24" @default.
• W1483242826 creator A5004434386 @default.
• W1483242826 creator A5018170018 @default.
• W1483242826 creator A5039876048 @default.
• W1483242826 creator A5042746726 @default.
• W1483242826 creator A5058197739 @default.
• W1483242826 creator A5078991694 @default.
• W1483242826 creator A5087783342 @default.
• W1483242826 date "2014-09-30" @default.
• W1483242826 modified "2023-10-01" @default.
• W1483242826 title "Abstract 1801: APR-246, a clinical-stage mutant p53-reactivating compound, resensitizes ovarian cancer cells to platinum compounds and doxorubicin" @default.
• W1483242826 doi "https://doi.org/10.1158/1538-7445.am2014-1801" @default.
• W1483242826 hasPublicationYear "2014" @default.
• W1483242826 type Work @default.
• W1483242826 sameAs 1483242826 @default.
• W1483242826 citedByCount "0" @default.
• W1483242826 crossrefType "proceedings-article" @default.
• W1483242826 hasAuthorship W1483242826A5004434386 @default.
• W1483242826 hasAuthorship W1483242826A5018170018 @default.
• W1483242826 hasAuthorship W1483242826A5039876048 @default.
• W1483242826 hasAuthorship W1483242826A5042746726 @default.
• W1483242826 hasAuthorship W1483242826A5058197739 @default.
• W1483242826 hasAuthorship W1483242826A5078991694 @default.
• W1483242826 hasAuthorship W1483242826A5087783342 @default.
• W1483242826 hasConcept C104317684 @default.
• W1483242826 hasConcept C121608353 @default.
• W1483242826 hasConcept C126322002 @default.
• W1483242826 hasConcept C143065580 @default.
• W1483242826 hasConcept C153911025 @default.
• W1483242826 hasConcept C185592680 @default.
• W1483242826 hasConcept C207001950 @default.
• W1483242826 hasConcept C2776694085 @default.
• W1483242826 hasConcept C2778239845 @default.
• W1483242826 hasConcept C2780427987 @default.
• W1483242826 hasConcept C2781303535 @default.
• W1483242826 hasConcept C502942594 @default.
• W1483242826 hasConcept C54355233 @default.
• W1483242826 hasConcept C55493867 @default.
• W1483242826 hasConcept C71924100 @default.
• W1483242826 hasConcept C86803240 @default.
• W1483242826 hasConcept C96232424 @default.
• W1483242826 hasConceptScore W1483242826C104317684 @default.
• W1483242826 hasConceptScore W1483242826C121608353 @default.
• W1483242826 hasConceptScore W1483242826C126322002 @default.
• W1483242826 hasConceptScore W1483242826C143065580 @default.
• W1483242826 hasConceptScore W1483242826C153911025 @default.
• W1483242826 hasConceptScore W1483242826C185592680 @default.
• W1483242826 hasConceptScore W1483242826C207001950 @default.
• W1483242826 hasConceptScore W1483242826C2776694085 @default.
• W1483242826 hasConceptScore W1483242826C2778239845 @default.
• W1483242826 hasConceptScore W1483242826C2780427987 @default.
• W1483242826 hasConceptScore W1483242826C2781303535 @default.
• W1483242826 hasConceptScore W1483242826C502942594 @default.
• W1483242826 hasConceptScore W1483242826C54355233 @default.
• W1483242826 hasConceptScore W1483242826C55493867 @default.
• W1483242826 hasConceptScore W1483242826C71924100 @default.
• W1483242826 hasConceptScore W1483242826C86803240 @default.
• W1483242826 hasConceptScore W1483242826C96232424 @default.
• W1483242826 hasLocation W14832428261 @default.
• W1483242826 hasOpenAccess W1483242826 @default.
• W1483242826 hasPrimaryLocation W14832428261 @default.
• W1483242826 hasRelatedWork W1498141812 @default.
• W1483242826 hasRelatedWork W1975154333 @default.
• W1483242826 hasRelatedWork W1985746552 @default.
• W1483242826 hasRelatedWork W1995228865 @default.
• W1483242826 hasRelatedWork W2011175387 @default.
• W1483242826 hasRelatedWork W2012106833 @default.
• W1483242826 hasRelatedWork W2040640178 @default.
• W1483242826 hasRelatedWork W2057798647 @default.
• W1483242826 hasRelatedWork W2315307800 @default.
• W1483242826 hasRelatedWork W2315816673 @default.
• W1483242826 hasRelatedWork W2316202114 @default.
• W1483242826 hasRelatedWork W2400235072 @default.
• W1483242826 hasRelatedWork W2564547994 @default.
• W1483242826 hasRelatedWork W2565604292 @default.
• W1483242826 hasRelatedWork W2566746813 @default.
• W1483242826 hasRelatedWork W2622925394 @default.
• W1483242826 hasRelatedWork W2741141842 @default.
• W1483242826 hasRelatedWork W2741522525 @default.
• W1483242826 hasRelatedWork W2944548570 @default.
• W1483242826 hasRelatedWork W3036325719 @default.
• W1483242826 isParatext "false" @default.
• W1483242826 isRetracted "false" @default.
• W1483242826 magId "1483242826" @default.
• W1483242826 workType "article" @default.