Dactolisib (NVP-BEZ235) toxicity in murine brain tumour models

Netland, Inger Anne; Førde, Hilde Elise; Sleire, Linda; Leiss, Lina; Rahman, Mohummad Aminur; Skeie, Bente Sandvei; Gjerde, Christiane H.; Enger, Per Øyvind; Goplen, Dorota

doi:10.1186/s12885-016-2712-4

Cited by 23 publications

(14 citation statements)

References 41 publications

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“…2b ). This is consistent with the results by Netland and coworkers who found no survival benefit or inhibition of tumour growth in orthotopic xenograft models of GB developed in nude rats and NOD/SCID mice [ 19 ]. Accordingly, the simultaneous treatment with NVP-BEZ235 and the MAPK inhibitor AZD6244 did not lead to synergistic radiosensitization of tumor cells, questioning a radiosensitizing effect of both inhibitors [ 30 ].…”

Section: Discussionsupporting

confidence: 93%

“…was chosen due to significant toxicity of higher doses towards our animals (data not shown). Consistently, in two independent animal studies utilizing nude rats and NOD/SCID mice in orthotopic xenograft models of GB, Netland and coworkers have found severe side effects of doses of NVP-BEZ235 higher than 25 mg/ml [ 19 ]. The early termination of recent NVP-BEZ235 clinical trials due to elevated toxicity may confirm that safety dosing of NVP-BEZ235 should be thoroughly investigated prior to use [ 20 , 21 ].…”

Section: Discussionmentioning

confidence: 76%

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ATR kinase inhibitors NVP-BEZ235 and AZD6738 effectively penetrate the brain after systemic administration

et al. 2018

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Ataxia Telangiectasia and Rad3 related protein (ATR) is a central mediator of the response to DNA damage that may cause the quiescent resistance of cancer initiating cells to genotoxic radiotherapy. NVP-BEZ235 is a dual PI3K/mTOR inhibitor that also effectively targets ATR with IC50 = 21 × 10− 9 M in cells. AZD6738 does not target significantly PI3K/mTOR-related kinases but specifically inhibits ATR with IC50 = 74 × 10− 9 M in cells. Both drugs have been proposed as radiosensitizers of different tumors including glioblastoma (GB), the most malignant brain tumor. In order to study the radiosensitizing properties of ATR inhibitors NVP-BEZ235 and AZD6738 towards GB, we have preliminarily investigated their capacity to penetrate the brain after systemic administration. Tumor-free CD-1 mice were inoculated i.p. with 25 mg/Kg body weight of NVP-BEZ235 or AZD6738. 1, 2, 6 and 8 h later, blood was collected by retro-orbital bleeding after which the mice were euthanized and the brains explanted. Blood and brain samples were then extracted and NVP-BEZ235 and AZD6738 concentrations determined by High Performance Liquid Chromatography/Mass Spectrometry. We found for NVP-BEZ235 and especially for AZD6738, elevated bioavailability and effective brain penetration after intraperitoneal administration. Albeit low drug and radiation dosages were used, a trend to toxicity of NVP-BEZ235 followed by ionizing radiation (IR) towards mice bearing primary glioma initiating cells (GIC)-driven orthotopic tumors was yet observed, as compared to AZD6738 + IR and vehicle+IR. Survival was never improved with median values of 99, 86 and 101 days for vehicle+IR, NVP-BEZ235 + IR and AZD6738 + IR-treated mice, respectively. Although the present results indicate favorable pharmacokinetics properties of ATR inhibitors NVP-BEZ235 and AZD6738, they do not lend support to their use as radiosensitizers of GB.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 76%

ATR kinase inhibitors NVP-BEZ235 and AZD6738 effectively penetrate the brain after systemic administration

et al. 2018

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“…Employment of new drugs and therapeutic strategies may cause additional side effects. Our data showed weight loss around 7% in animals treated with BEZ235, while other studies have reported weight loss greater than 15% [56]. Studies have shown that the loss of body weight, after oral administration of BEZ235, occurs in a dose-dependent manner in several model systems [14,57,58].…”

Section: Discussionsupporting

confidence: 45%

Combinatorial Effect of Abiraterone Acetate and NVP-BEZ235 on Prostate Tumor Progression in Rats

et al. 2018

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Use of drug combinations that target different pathways involved in the development and progression of prostate cancer (PCa) has emerged as an alternative to overcome the resistance caused by drug monotherapies. The antiandrogen abiraterone acetate and the PI3K/Akt inhibitor NVP-BEZ235 (BEZ235) may be suitable options for the prevention of drug resistance and the inhibition of PCa progression. The aim of the present study was to evaluate whether abiraterone acetate and BEZ235 achieve superior therapeutic effects to either drug administered as monotherapy, in the early stages of PCa in an androgen-dependent system. Our study showed that each drug might impair tumor growth by reducing proliferation and increasing cell death when administered as monotherapy. However, tumor growth continued to progress with each drug monotherapy and some important side effects were related to BEZ. Conversely, when used in combination, the drugs impaired the inflammatory response, decreased hyperplastic lesions, and blocked tumor progression from premalignant to a malignant stage. Our data showed that the strategy to block the androgenic and PI3K/AKT/mTOR pathway is an effective therapeutic option and should be investigated including distinct PI3K pathway inhibitors.

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“…Recent studies have highlighted conflicting results regarding the effectiveness of this agent in vivo where BEZ235 demonstrated antitumor efficacy with improved survival against U87MG orthotopic gliomas in one study [ 67 ]. However, very little to no efficacy was observed in another independent orthotopic xenograft model study [ 68 ]. It is important to note that many PI3K/mTOR inhibitors demonstrate weak affinities for ABC transporters, but in spite of this, can still achieve target inhibition in GBM albeit with modest single-agent efficacy.…”

Section: Hif Transcription Factorsmentioning

confidence: 99%

The Role of Hypoxia in Glioblastoma Invasion

Monteiro

Hill

Pilkington

et al. 2017

Cells

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Glioblastoma multiforme (GBM), a grade IV astrocytoma, is the most common and deadly type of primary malignant brain tumor, with a patient’s median survival rate ranging from 15 to 17 months. The current treatment for GBM involves tumor resection surgery based on MRI image analysis, followed by radiotherapy and treatment with temozolomide. However, the gradual development of tumor resistance to temozolomide is frequent in GBM patients leading to subsequent tumor regrowth/relapse. For this reason, the development of more effective therapeutic approaches for GBM is of critical importance. Low tumor oxygenation, also known as hypoxia, constitutes a major concern for GBM patients, since it promotes cancer cell spreading (invasion) into the healthy brain tissue in order to evade this adverse microenvironment. Tumor invasion not only constitutes a major obstacle to surgery, radiotherapy, and chemotherapy, but it is also the main cause of death in GBM patients. Understanding how hypoxia triggers the GBM cells to become invasive is paramount to developing novel and more effective therapies against this devastating disease. In this review, we will present a comprehensive examination of the available literature focused on investigating how GBM hypoxia triggers an invasive cancer cell phenotype and the role of these invasive proteins in GBM progression.

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Dactolisib (NVP-BEZ235) toxicity in murine brain tumour models

Cited by 23 publications

References 41 publications

ATR kinase inhibitors NVP-BEZ235 and AZD6738 effectively penetrate the brain after systemic administration

ATR kinase inhibitors NVP-BEZ235 and AZD6738 effectively penetrate the brain after systemic administration

Combinatorial Effect of Abiraterone Acetate and NVP-BEZ235 on Prostate Tumor Progression in Rats

The Role of Hypoxia in Glioblastoma Invasion

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