Role of SIRT1-mediated mitochondrial and Akt pathways in glioblastoma cell death induced by Cotinus coggygria flavonoid nanoliposomes.
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.
Department of Pharmaceutics, Shanghai Eighth People's Hospital, Shanghai, People's Republic of China ; College of Pharmacy, Hubei University of Medicine, Shiyan, Hubei Province, People's Republic of China.
Gang
G
Wang
Department of Pharmaceutics, Shanghai Eighth People's Hospital, Shanghai, People's Republic of China ; College of Pharmacy, Hubei University of Medicine, Shiyan, Hubei Province, People's Republic of China.
Jun Jie
JJ
Wang
Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, People's Republic of China.
Tony S S
TS
To
Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, People's Republic of China.
Hua Fu
HF
Zhao
Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, People's Republic of China.
Jing
J
Wang
D027926:Anacardiaceae / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry*; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D008928:Mitochondria / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism*; D012995:Solubility; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; D005419:Flavonoids; D008081:Liposomes; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; C447939:SIRT1 protein, human; D056564:Sirtuin 1
Cotinus coggygria flavonoid nanoliposomes; PI3K/Akt pathway; SIRT1; cell death; mitochondrial