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The combination of the novel glycolysis inhibitor 3-BrOP and rapamycin is effective against neuroblastoma.

ABSTRACT: Children with high-risk and recurrent neuroblastoma have poor survival rates, and novel therapies are needed. Many cancer cells have been found to preferentially employ the glycolytic pathway for energy generation, even in the presence of oxygen. 3-BrOP is a novel inhibitor of glycolysis, and has demonstrated efficacy against a wide range of tumor types. To determine whether human neuroblastoma cells are susceptible to glycolysis inhibition, we evaluated the role of 3-BrOP in neuroblastoma model systems. Neuroblastoma tumor cell lines demonstrated high rates of lactate accumulation and low rates of oxygen consumption, suggesting a potential susceptibility to inhibitors of glycolysis. In all ten human tested neuroblastoma tumor cell lines, 3-BrOP induced cell death via apoptosis in a dose and time dependent manner. Furthermore, 3-BrOP-induced depletion of ATP levels correlated with decreased neuroblastoma cell viability. In a mouse neuroblastoma xenograft model, glycolysis inhibition with 3-BrOP demonstrated significantly reduced final tumor weight. In neuroblastoma tumor cells, treatment with 3-BrOP induced mTOR activation, and the combination of 3-BrOP and mTOR inhibition with rapamycin demonstrated synergistic efficacy. Based on these results, neuroblastoma tumor cells are sensitive to treatment with inhibitors of glycolysis, and the demonstrated synergy with rapamycin suggests that the combination of glycolysis and mTOR inhibitors represents a novel therapeutic approach for neuroblastoma that warrants further investigation.

SUBMITTER: Levy AG

PROVIDER: S-EPMC4831635 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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The combination of the novel glycolysis inhibitor 3-BrOP and rapamycin is effective against neuroblastoma.

Levy Alejandro G AG Zage Peter E PE Akers Lauren J LJ Ghisoli Maurizio L ML Chen Zhao Z Fang Wendy W Kannan Sankaranarayanan S Graham Timothy T Zeng Lizhi L Franklin Anna R AR Huang Peng P Zweidler-McKay Patrick A PA

Investigational new drugs 20101005 1

Children with high-risk and recurrent neuroblastoma have poor survival rates, and novel therapies are needed. Many cancer cells have been found to preferentially employ the glycolytic pathway for energy generation, even in the presence of oxygen. 3-BrOP is a novel inhibitor of glycolysis, and has demonstrated efficacy against a wide range of tumor types. To determine whether human neuroblastoma cells are susceptible to glycolysis inhibition, we evaluated the role of 3-BrOP in neuroblastoma model ...[more]

PMID: 20890785

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Project description:BackgroundNeuroblastoma (NB), the most common extracranial solid malignancy in children, carries a poor prognosis in high-risk disease, thus requiring novel therapeutic approaches. Survivin is overexpressed in NB, has pro-mitotic and anti-apoptotic functions, and impacts on oxidative phosphorylation (OXPHOS) and aerobic glycolysis. The subcellular localization and hence function of survivin is directed by the GTPase Ran.AimTo determine efficacy and modes of action of the survivin-Ran inhibitor LLP-3 as a potential novel therapy of NB.MethodsSurvivin and Ran mRNA expression in NB tumors was correlated to patient survival. Response to LLP-3 in NB cell lines was determined by assays for viability, proliferation, apoptosis, clonogenicity and anchorage-independent growth. Interaction of survivin and Ran was assessed by proximity-linked ligation assay and their subcellular distribution by confocal immunofluorescence microscopy. Expression of survivin, Ran and proteins important for OXPHOS and glycolysis was determined by Western blot, hexokinase activity by enzymatic assay, interaction of survivin with HIF-1α by co-IP, and OXPHOS and glycolysis by extracellular flux analyzer.ResultsHigh mRNA expression of survivin and Ran is correlated with poor patient survival. LLP-3 decreases viability, induces apoptosis, and inhibits clonogenic and anchorage-independent growth in NB cell lines, including those with MYCN amplification, and mutations of p53 and ALK. LLP-3 inhibits interaction of survivin with Ran, decreasing their concentration both in the cytoplasm and the nucleus. LLP-3 impairs flexibility of energy metabolism by inhibiting both OXPHOS and glycolysis. Metabolic inhibition is associated with mitochondrial dysfunction and attenuated hexokinase activity but is independent of HIF-1α.ConclusionLLP-3 attenuates interaction and concentration of survivin and Ran in NB cells. It controls NB cells with diverse genetic alterations, associated with inhibition of OXPHOS, aerobic glycolysis, mitochondrial function and HK activity. Thus, LLP-3 warrants further studies as a novel drug against NB.

Project description:The prognosis for patients with relapsed or refractory high-risk neuroblastoma remains dismal and novel therapeutic options are urgently needed. The RIST treatment protocol has a multimodal metronomic therapy design combining molecular-targeted drugs (Rapamycin and Dasatinib) with chemotherapy backbone (Irinotecan and Temozolomide), which is currently verified in a phase II clinical trial (NCT01467986). With the availability of novel and more potent ATP competitive mTOR inhibitors, we expect to improve the RIST combination therapy. By comparing the IC50 values of Torin-1, Torin-2, AZD3147 and PP242 we established that only Torin-2 inhibited cell viability of all three MycN-amplified neuroblastoma cell lines tested at nanomolar concentration. Single treatment of both mTOR inhibitors induced a significant G1 cell cycle arrest and combination treatment with Dasatinib reduced the expression of cell cycle regulator cyclin D1 or increased the expression of cell cycle inhibitor p21. The combinatorial index depicted for both mTOR inhibitors a synergistic effect with Dasatinib. Interestingly, compared to Rapamycin, the combination treatment with Torin-2 resulted in a broader mTOR pathway inhibition as indicated by reduced phosphorylation of AKT (Thr308, Ser473), 4E-BP (Ser65), and S6K (Thr389). Furthermore, substituting Rapamycin in the modified multimodal RIST protocol with Torin-2 reduced cell viability and induced apoptosis despite a significant lower Torin-2 drug concentration applied. The efficacy of nanomolar concentrations may significantly reduce unwanted immunosuppression associated with Rapamycin. However, at this point we cannot rule out that Torin-2 has increased toxicity due to its potency in more complex systems. Nonetheless, our results suggest that including Torin-2 as a substitute for Rapamycin in the RIST protocol may represent a valid option to be evaluated in prospective clinical trials for relapsed or treatment-refractory high-risk neuroblastoma.

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The combination of the novel glycolysis inhibitor 3-BrOP and rapamycin is effective against neuroblastoma.

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The combination of the novel glycolysis inhibitor 3-BrOP and rapamycin is effective against neuroblastoma.

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