Role of SIRT1-mediated mitochondrial and Akt pathways in glioblastoma cell death induced by Cotinus coggygria flavonoid nanoliposomes

• Published in: International journal of nanomedicine Vol. 10; no. default; pp. 5005 - 5023
• Main Authors: Wang, Gang, Wang, Jun Jie, To, Tony S S, Zhao, Hua Fu, Wang, Jing
• Format: Journal Article
• Language: English
• Published: New Zealand Taylor & Francis Ltd 01.01.2015; Dove Medical Press
• Subjects: Anacardiaceae - chemistry; Angina pectoris; Antineoplastic Agents - chemistry; Apoptosis; Apoptosis - drug effects; bcl-2-Associated X Protein - metabolism; Brain cancer; Brain Neoplasms - pathology; Breast cancer; Cardiovascular disease; Caspase 3 - metabolism; Caspase 9 - metabolism; Caspases - metabolism; Cell Death; Cell growth; Cell Line, Tumor - drug effects; Cell Proliferation; Cell Survival; Cotinus coggygria; Extracellular Signal-Regulated MAP Kinases - metabolism; Flavonoids; Flavonoids - chemistry; Glioblastoma - pathology; Humans; Kinases; Liposomes - chemistry; Medical prognosis; Metabolic disorders; Mitochondria - metabolism; Nanoparticles; Nanoparticles - chemistry; Original Research; Phosphatidylinositol 3-Kinases - metabolism; Proteins; Proto-Oncogene Proteins c-bcl-2 - metabolism; Quantum dots; Reactive Oxygen Species - metabolism; Senescence; Signal Transduction - drug effects; Sirtuin 1 - metabolism; Solubility; Stem cells; Tumorigenesis; Hong Kong China; China; Cotinus coggygria flavonoid nanoliposomes; PI3K/Akt pathway; mitochondrial; cell death; SIRT1
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S82282

Flavonoids, the major polyphenol components in Cotinus coggygria (CC), have been found to show an anticancer effect in our previous study; however, the exact mechanisms of inducing human glioblastoma (GBM) cell death remain to be resolved. In this study, a novel polyvinylpyrrolidone K-30/sodium dodecyl sulfate and polyethyleneglycol-coated liposome loaded with CC flavonoids (CCFs) was developed to enhance solubility and the antibrain tumor effect, and the molecular mechanism regarding how CCF nanoliposomes (CCF-NLs) induce apoptotic cell death in vitro was investigated. DBTRG-05MG GBM cell lines treated with CCF-NLs showed potential antiproliferative effects. Regarding the underlying mechanisms of inducing apoptosis in DBTRG-05MG GBM cells, CCF-NLs were shown to downregulate the expression of antiapoptotic B-cell lymphoma/leukemia 2 (Bcl-2), an apoptosis-related protein family member, but the expression of proapoptotic Bcl-2-associated X protein was enhanced compared with that in controls. CCF-NLs also inhibited the activity of caspase-3 and -9, which is the initiator caspase of the extrinsic and intrinsic apoptotic pathways. Blockade of caspase activation consistently induced apoptosis and inhibited growth in CCF-NL-treated DBTRG-05MG cells. This study further investigated the role of the Akt pathway in the apoptotic cell death by CCF-NLs, showing that CCF-NLs deactivated Akt. Specifically, CCF-NLs downregulated the expression of p-Akt and SIRT1 as well as the level of phosphorylated p53. Together, these results indicated SIRT1/p53-mediated cell death was induced by CCF-NLs, but not by extracellular signal-regulated kinase, in DBTRG-05MG cells. Overall, this study suggested caspase-dependent activation of both the intrinsic and extrinsic signaling pathways, probably through blockade of the SIRT1/p53-mediated mitochondrial and Akt pathways to exert the proapoptotic effect of CCF-NLs in DBTRG-05MG GBM cells.