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

Abstract

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.

Resveratrol inhibits proliferation and migration through SIRT1 mediated post-translational modification of PI3K/AKT signaling in hepatocellular carcinoma cells

“…SIRT1 has been also implicated as a negative regulator for the PI3K/AKT pathway by deacetylating the tumor suppressor PTEN ( 31 ) and by down-regulation of both AKT and phosphorylation levels to inhibit the PI3K/AKT pathway in glioblastoma cell ( 32 ). The regulation of PI3K/AKT pathway by SIRT1 may provide a potential mechanism in tumorigenesis, and SIRT1 inhibitor EX527 was used to evaluate the underlying mechanism.…”

Anti-Cancerous Potential of Polyphenol-Loaded Polymeric Nanotherapeutics

“…The results revealed an improvement in the pharmacokinetic and therapeutic properties of the encapsulated curcumin, compared with its control [ 27 ]. In addition, polyvinyl pyrrolidone–PEG conjugates were used to develop polymersomes loaded with Cotinus coggygria flavonoids for the treatment of glioblastoma [ 28 ]. Moreover, curcumin delivery systems were prepared by using protein-type polymers, such as gelatin, casein, and keratin [ 29 , 30 , 31 , 32 , 33 ].…”

Modern drug delivery strategies applied to natural active compounds

“…The results suggested that PEGylated liposomal honokiol improved the solubility and increased the concentration in plasma of the active compound. The technological solution before described, based on the modification and/or derivatization of liposome architecture, has been used by many researchers to maximize the anticancer effect and/or to obtain a targeted release of drug loaded in liposomes [41][42][43][44][45][46][47][48].…”