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. 2016 Aug 19:16:657.
doi: 10.1186/s12885-016-2712-4.

VSports在线直播 - Dactolisib (NVP-BEZ235) toxicity in murine brain tumour models

I A Netland  1 , H E Førde  1 , L Sleire  1 , L Leiss  1   2 , M A Rahman  1 , B S Skeie  3 , C H Gjerde  1 , P Ø Enger  1   4   5 , D Goplen  6   7
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Dactolisib (NVP-BEZ235) toxicity in murine brain tumour models

I A Netland et al. BMC Cancer. .

VSports - Abstract

Background: Glioblastomas (GBMs) are highly malignant brain tumours with a poor prognosis, and current cytotoxic regimens provide only a limited survival benefit. The PI3K/Akt/mTOR pathway has been an attractive target for therapy due to its high activation in GBMs as well as other cancers VSports手机版. The dual pan-PI3K/mTOR kinase inhibitor dactolisib (NVP-BEZ235) is an anti-neoplastic compound currently under investigation. However, little is known about its efficacy in human GBMs. We aimed at evaluating the efficacy of dactolisib in human glioblastoma cells, as well as in murine models carrying human GBM xenografts. .

Methods: To assess the effect of dactolisib in vitro, MTS assay, manual cell count, BrdU incorporation and Annexin V staining experiments were used to observe growth and apoptosis V体育安卓版. Furthermore, Akt phosphorylation (S473), a downstream target of PI3K, was explored by western blotting. Animal studies utilizing orthotopic xenograft models of glioblastoma were performed in nude rats and NOD/SCID mice to monitor survival benefit or inhibition of tumor growth. .

Results: We found that dactolisib in vitro shows excellent dose dependent anti-growth properties and increase in apoptosis V体育ios版. Moreover, dose dependent inhibition of Akt phosphorylation (S473), a downstream effect of PI3K, was observed by western blotting. However, in two independent animal studies utilizing nude rats and NOD/SCID mice in orthotopic xenograft models of glioblastoma, we observed no survival benefit or inhibition of tumour growth. Severe side effects were observed, such as elevated levels of blood glucose and the liver enzyme alanine transaminase (ALT), in addition to diarrhoea, hair loss (alopecia), skin rash and accumulation of saliva in the oral cavity. .

Conclusion: Taken together, our results suggest that despite the anti-neoplastic efficacy of dactolisib in glioma treatment in vitro, its utility in vivo is questionable due to toxicity VSports最新版本. .

Keywords: BEZ235; Brain tumour; Dactolisib; Glioblastoma; PI3K; Patient-derived xenograft; Proliferation V体育平台登录. .

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Figures

Fig. 1
Fig. 1
a IC50 doses of dactolisib for P3 (left) and U87 (right) glioma cells, generated from MTS assay. b Relative cell number of P3 (left) and U87 (right) glioma cells exposed to dactolisib at doses indicated for 72 h. c Quantification of BrdU positive P3 (left) and U87 (right) glioma cells treated with dactolisib at doses indicated for 72 h and subsequently pulsed with BrdU. d Quantification of Annexin V- and PI-positive P3 (left) and U87 (right) glioma cells treated with dactolisib at doses indicated for 72 h and subsequently incubated with PI and Annexin V Alexa Fluor 488 conjugate. Error bars represent s.d. of three independent experiments. *P <0.05, **P < 0.01, ***P < 0,001, ****P < 0,0001
Fig. 2
Fig. 2
a Immunocytochemistry showing Akt phosphorylation in U87 cells after exposure to dactolisib at doses indicated for 72 h. Upper panel: Akt phosphorylated at site T308 (FITC, green). Middle panel: Akt phosphorylated at site S473 (FITC, green). Lower panel: Total Akt-levels (FITC, green). Nuclear counterstaining: DAPI (blue). b Left: Western blots showing levels of pAkt (T308), pAkt (S473) andtotal Akt in U87 cells exposed to dactolisib at doses indicated for 72 h. Right: Densitometric assessment of western blot, showing relative change in phosphorylation. c Left: Western blot showing levels of pAkt (T308), pAkt (S473) and total Akt in P3 cells exposed to dactolisib at doses indicated for 72 h. Right: Densitometric assessment of western blot, showing relative change in phosphorylation. Error bars represent s.d. of Error bars represent s.d. of three (a and b) and two (c) independent experiments. *P <0.05, **P < 0.01, ***P < 0,001
Fig. 3
Fig. 3
a Coat of nude rats before (left panel) and after (right panel) 1 week of treatment. One rat from the dactolisib treatment group (10 mg/kg) is shown in the upper panel, while one rat from the control group (vehicle only) is shown in the lower panel. b Maculopapular rash observed in some rats during dactolisib exposure. c Blood glucose levels in nude rats after 6 weeks of dactolisib treatment. *P <0.05. d Serum levels of ALT from rats exposed to dactolisib for 6 weeks. *P <0.05. E) Graphic presentation of adverse effects observed in nude rats exposed to dactolisib. (n = 6 for each group) F) Weight development in nude rats during dactolisib exposure (n = 4). Red arrow indicates dose increase from 10 mg/kg to 20 mg/kg
Fig. 4
Fig. 4
a Kaplan-Meyer survival curve for nude rats carrying orthotopic GBM xenografts (P3) (p-value 0.0845). (n = 6 for control group, n = 5 for dactolisib-group). b MRI-based assessment of all tumour volumes
Fig. 5
Fig. 5
a Weight development in healthy, non-tumour bearing NOD/SCID mice during dactolisib exposure (n = 6 for each group). b Kaplan Meyer survival curve for NOD/SCID mice carrying orthotopic GBM xenografts (P3). Left red arrow indicates treatment start of 45 mg/kg dactolisib (n = 7). Right red arrow indicates splitting of control group (n = 7) into one treatment group (25 mg/kg) (n = 3) and one control group (n = 4). Red line shows survival for mice in the treatment group of 45 mg/kg dactolisib, green line shows survival for mice in the treatment group of 25 mg/kg dactolisib, and black line shows survival for mice in the control group (vehicle only). (P-value 0.1788 for 25 mg/kg vs control). c MRI-based assessments of all tumour volumes
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