In human retinoblastoma Y79 cells okadaic acid-parthenolide co-treatment induces synergistic apoptotic effects, with PTEN as a key player

• Published in: Cancer biology & therapy Vol. 14; no. 10; pp. 922 - 931
• Main Authors: Di Fiore, Riccardo, Drago-Ferrante, Rosa, D'Anneo, Antonella, Augello, Giuseppa, Carlisi, Daniela, De Blasio, Anna, Giuliano, Michela, Tesoriere, Giovanni, Vento, Renza
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.10.2013; Landes Bioscience
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Cell Shape - drug effects; Cell Survival - drug effects; Drug Screening Assays, Antitumor; Drug Synergism; Gene Expression; Glutathione - metabolism; Humans; natural drugs; okadaic acid; Okadaic Acid - pharmacology; Oxidative Stress; parthenolide; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-mdm2 - metabolism; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; PTEN/Akt/Mdm2/p53 pathway; Reactive Oxygen Species - metabolism; Research Paper; Retinoblastoma; Sesquiterpenes - pharmacology; synergistic apoptotic effects; Tumor Suppressor Protein p53 - metabolism; Y79 cells; PTEN/Akt/Mdm2/p53 pathway; Y79 cells; natural drugs; parthenolide; retinoblastoma; synergistic apoptotic effects; okadaic acid; oxidative stress
• DOI: 10.4161/cbt.25944
• ISSN: 1538-4047

Retinoblastoma is the most common intraocular malignancy of childhood. In developing countries, treatment is limited, long-term survival rates are low and current chemotherapy causes significant morbidity to pediatric patients and significantly limits dosing. Therefore there is an urgent need to identify new therapeutic strategies to improve the clinical outcome of patients with retinoblastoma. Here, we investigated the effects of two natural compounds okadaic acid (OKA) and parthenolide (PN) on human retinoblastoma Y79 cells. For the first time we showed that OKA/PN combination at subtoxic doses induces potent synergistic apoptotic effects accompanied by lowering in p-Akt levels, increasing in the stabilized forms of p53 and potent decrease in pS166-Mdm2. We also showed the key involvement of PTEN which, after OKA/PN treatment, potently increased before p53, thus suggesting that p53 activation was under PTEN action. Moreover, after PTEN-knockdown p-Akt/ pS166Mdm2 increased over basal levels and p53 significantly lowered, while OKA/PN treatment failed both to lower p-Akt and pS166-Mdm2 and to increase p53 below/over their basal levels respectively. OKA/PN treatment potently increased ROS levels whereas decreased those of GSH. Reducing cellular GSH by l-butathionine-[S,R]-sulfoximine treatment significantly anticipated the cytotoxic effect exerted by OKA/PN. Furthermore, the effects of OKA/PN treatment on both GSH content and cell viability were less pronounced in PTEN silenced cells than in control cells. The results provide strong suggestion for combining a treatment approach that targets the PTEN/Akt/Mdm2/p53 pathway.