Dataset Information

Combined treatments with AZD5363, AZD8542, curcumin or resveratrol induce death of human glioblastoma cells by suppressing the PI3K/AKT and SHH signaling pathways.

ABSTRACT: Glioblastoma (GBM) is a very aggressive tumor that presents vascularization, necrosis and is resistant to chemotherapy and radiotherapy. Current treatments are not effective eradicating GBM, thus, there is an urgent need to develop novel therapeutic strategies against GBM. AZD5363, AZD8542, curcumin and resveratrol, are widely studied for the treatment of cancer and in the present study we explored the effects of the administration of combined treatments with AZD5363, AZD8542, curcumin or resveratrol on human GBM cells. We found that the combined treatments with AZD5363+AZD8542+Curcumin and AZD8542+Curcumin+Resveratrol inhibit the PI3K/AKT and SHH survival pathways by decreasing the activity of AKT, the reduction of the expression of SMO, pP70S6k, pS6k, GLI1, p21 and p27, and the activation of caspase-3 as a marker of apoptosis. These results provide evidence that the combined treatments AZD5363+AZD8542+Curcumin and AZD8542+Curcumin+Resveratrol have the potential to be an interesting option against GBM.

SUBMITTER: Mejia-Rodriguez R

PROVIDER: S-EPMC9876780 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Combined treatments with AZD5363, AZD8542, curcumin or resveratrol induce death of human glioblastoma cells by suppressing the PI3K/AKT and SHH signaling pathways.

Mejía-Rodríguez Rosalinda R Romero-Trejo Daniel D González Rosa O RO Segovia José J

Biochemistry and biophysics reports 20230120

Glioblastoma (GBM) is a very aggressive tumor that presents vascularization, necrosis and is resistant to chemotherapy and radiotherapy. Current treatments are not effective eradicating GBM, thus, there is an urgent need to develop novel therapeutic strategies against GBM. AZD5363, AZD8542, curcumin and resveratrol, are widely studied for the treatment of cancer and in the present study we explored the effects of the administration of combined treatments with AZD5363, AZD8542, curcumin or resver ...[more]

PMID: 36714540

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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.

Dataset Information

Combined treatments with AZD5363, AZD8542, curcumin or resveratrol induce death of human glioblastoma cells by suppressing the PI3K/AKT and SHH signaling pathways.

Publications

Combined treatments with AZD5363, AZD8542, curcumin or resveratrol induce death of human glioblastoma cells by suppressing the PI3K/AKT and SHH signaling pathways.

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