Dataset Information

Curcumin and Solid Lipid Curcumin Particles Induce Autophagy, but Inhibit Mitophagy and the PI3K-Akt/mTOR Pathway in Cultured Glioblastoma Cells.

ABSTRACT: Autophagy and the (PI3K-Akt/mTOR) signaling pathway play significant roles in glioblastoma multiforme (GBM) cell death and survival. Curcumin (Cur) has been reported to prevent several cancers, including GBM. However, the poor solubility and limited bioavailability of natural Cur limits its application in preventing GBM growth. Previously, we have shown the greater apoptotic and anti-carcinogenic effects of solid lipid Cur particles (SLCP) than natural Cur in cultured GBM cells. Here, we compared the autophagic responses on cultured U-87MG, GL261, F98, C6-glioma, and N2a cells after treatment with Cur or SLCP (25 µM for 24 h). Different autophagy, mitophagy, and chaperone-mediated autophagy (CMA) markers, along with the PI3K-AKkt/mTOR signaling pathway, and the number of autophagy vacuoles were investigated after treatment with Cur and or SLCP. We observed increased levels of autophagy and decreased levels of mitophagy markers, along with inhibition of the PI3K-Akt/mTOR pathway after treatments with Cur or SLCP. Cell survival markers were downregulated, and cell death markers were upregulated after these treatments. We found greater effects in the case of SCLP-treated cells in comparison to Cur. Given that fewer effects were observed on C-6 glioma and N2a cells. Our results suggest that SLCP could be a safe and effective means of therapeutically modulating autophagy in GBM cells.

SUBMITTER: Maiti P

PROVIDER: S-EPMC6359162 | biostudies-other | 2019 Jan

REPOSITORIES: biostudies-other

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Curcumin and Solid Lipid Curcumin Particles Induce Autophagy, but Inhibit Mitophagy and the PI3K-Akt/mTOR Pathway in Cultured Glioblastoma Cells.

Maiti Panchanan P Scott Jason J Sengupta Dipanwita D Al-Gharaibeh Abeer A Dunbar Gary L GL

International journal of molecular sciences 20190118 2

Autophagy and the (PI3K-Akt/mTOR) signaling pathway play significant roles in glioblastoma multiforme (GBM) cell death and survival. Curcumin (Cur) has been reported to prevent several cancers, including GBM. However, the poor solubility and limited bioavailability of natural Cur limits its application in preventing GBM growth. Previously, we have shown the greater apoptotic and anti-carcinogenic effects of solid lipid Cur particles (SLCP) than natural Cur in cultured GBM cells. Here, we compare ...[more]

PMID: 30669284

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Project description:The treatment of glioblastoma is challenging for the clinician, due to its chemotherapeutic resistance. Recent findings suggest that targeting glioblastoma using anti-cancer natural polyphenols is a promising strategy. In this context, curcumin and berberine have been shown to have potent anti-cancer and anti-inflammatory effects against several malignancies. Due to the poor solubility and limited bioavailability, these compounds have limited efficacy for treating cancer. However, use of a formulation of curcumin with higher bioavailability or combining it with berberine as a co-treatment may be proving to be more efficacious against cancer. Recently, we demonstrated that solid lipid curcumin particles (SLCPs) provided more bioavailability and anti-cancer effects in cultured glioblastoma cells than did natural curcumin. Interestingly, a combination of curcumin and berberine has proven to be more effective in inhibiting growth and proliferation of cancer in the liver, breast, lung, bone and blood. However, the effect of combining these drugs for treating glioblastoma, especially with respect to its effect on activating the PI3K/Akt/mTOR pathways has not been studied. Therefore, we decided to assess the co-treatment effects of these drugs on two different glioblastoma cell lines (U-87MG and U-251MG) and neuroblastoma cell lines (SH-SY5Y) derived from human tissue. In this study, we compared single and combination (1:5) treatment of SLCP (20 μM) and berberine (100 μM) on measures of cell viability, cell death markers, levels of c-Myc and p53, along with biomarkers of the PI3K/Akt/mTOR pathways after 24-48 h of incubation. We found that co-treatment of SLCP and berberine produced more glioblastoma cell death, more DNA fragmentation, and significantly decreased ATP levels and reduced mitochondrial membrane potential than did single treatments in both glioblastoma cells lines. In addition, we observed that co-treatment inhibited the PI3K/Akt/mTOR pathway more efficiently than their single treatments. Our study suggests that combination treatments of SLCP and berberine may be a promising strategy to reduce or prevent glioblastoma growth in comparison to individual treatments using either compound.

Project description:Glioblastoma is a high-grade glioma with poor prognosis even after surgery and standard therapy. Here, we asked whether carnosine (β-alanyl-L-histidine), a naturally occurring dipeptide, exert its anti-neoplastic effect on glioblastoma cells via PI3K/Akt/mTOR signaling. Therefore, glioblastoma cells from the lines U87 and T98G were exposed to carnosine, to the mTOR inhibitor rapamycin and to the PI3K inhibitor Ly-294,002. Pyruvate dehydrogenase kinase (PDK4) expression, known to be a target of PI3K/Akt/mTOR, and which is also affected by carnosine, was analyzed by RT-qPCR, and reporter gene assays with the human PDK4 promoter were performed. Cell viability was assessed by cell-based assays and mTOR and Akt phosphorylation by Western blotting. Rapamycin and Ly-294,002 increased PDK4 mRNA expression in both cell lines but significance was only reached in U87. Carnosine significantly increased expression in both lines. A significant combinatorial effect of carnosine was only detected in U87 when the dipeptide was combined with Ly-294,002. Reporter gene assays revealed no specific effect of carnosine on the human PDK4 promoter, whereas both inhibitors increased reporter gene expression. Rapamycin reduced phosphorylation of mTOR, and Ly-294,002 that of Akt. A significant reduction of Akt phosphorylation was observed in the presence of carnosine in U87 but not in T98G, and carnosine had no effect on mTOR phosphorylation. Cell viability as determined by ATP in cell lysates was reduced only in the presence of carnosine. We conclude that carnosine's anti-neoplastic effect is independent from PI3K/Akt/mTOR signaling. As the dipeptide reduced viability in tumor cells that do not respond to PI3K or mTOR inhibitors, it appears to be worth to further investigate the mechanisms by which carnosine exerts its anti-tumor effect and to consider it for therapy, especially as it is a naturally occurring compound that has already been used for the treatment of other diseases without indication of side-effects.

Project description:Background:Doxorubicin (DOX) is one of the most effective anti-neoplastic drugs although its clinical use is limited by the severe cardiotoxicity. Apoptosis and defective autophagy are believed to contribute to DOX-induced cardiotoxicity. Here we explored the effect of curcumin (Cur) on DOX-induced cardiac injury and the mechanism involved with a focus on oxidative stress, autophagy and pyroptosis. Methods:Kunming mice were challenged with DOX (3 mg·kg-1, i.p. every other day) with cohorts of mice receiving Cur at 50, 100, 200 and 400 mg·kg-1 via gavage daily. Serum levels of cardiac enzymes, such as aspartate amino transferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), and heart homogenate oxidative stress markers, such as superoxide dismutase (SOD) and malondialdehyde (MDA) were determined. Echocardiographic and cardiac contraction were examined. Apoptosis, pyroptosis, autophagy and Akt/mTOR-signalling proteins were detected using western blot or electron microscopy. Cardiac contractile properties were assessed including peak shortening, maximal velocity of shortening/relengthening (± dL/dt), time-to-PS, and time-to-90% relengthening (TR90). Superoxide levels were evaluated using DHE staining. GFP-LC3 was conducted to measure autophagosomes. Results:Our study showed that Cur protected against cardiotoxicity manifested by a significant decrease in serum myocardial enzymes and improvement of anti-oxidative capacity. Cur inhibited autophagy and offered overt benefit for cardiomyocyte survive against DOX-induced toxicity. Cur attenuated DOX-induced cardiomyocyte pyroptosis as evidenced by NLR family pyrin domain containing 3 (NLRP3), Caspase-1, and interleukin-18 levels. DOX impaired cardiac function (reduced fractional shortening, ejection fraction, increased plasma cTnI level and TR90, decreased PS and ± dL/dt), the effects of which were overtly reconciled by 100 mg·kg-1 but not 50 mg·kg-1 Cur. H9c2 cells exposure to DOX displayed increased intracellular reactive oxygen species (ROS) and autophagy, the effects of which were nullified by Cur. Autophagy activator rapamycin cancelled off Cur-induced protective effects. Conclusions:Our finding suggested that Cur rescued against DOX-induced cardiac injury probably through regulation of autophagy and pyroptosis in a mTOR-dependent manner.

Dataset Information

Curcumin and Solid Lipid Curcumin Particles Induce Autophagy, but Inhibit Mitophagy and the PI3K-Akt/mTOR Pathway in Cultured Glioblastoma Cells.

Publications

Curcumin and Solid Lipid Curcumin Particles Induce Autophagy, but Inhibit Mitophagy and the PI3K-Akt/mTOR Pathway in Cultured Glioblastoma Cells.

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