NVP-BEZ235, a dual PI3K/mTOR inhibitor synergistically potentiates the antitumor effects of cisplatin in bladder cancer cells

Moon, Du Geon; Lee, Sangeun; Oh, Mi Mi; Jeong, Seong Jin; Hong, Sung Kyu; Yoon, Cheol Yong; Byun, Seok Soo; Park, Hong S.; Cheon, Jun

doi:10.3892/ijo.2014.2505

Cited by 56 publications

(50 citation statements)

References 38 publications

(31 reference statements)

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“…31 Indeed, protein synthesis, which is required for cell growth and cell cycle progression, is regulated by mTORC1, while PI3K-Akt as well as mTORC2 activation is also important for cell survival. 32,33 Interestingly, in consistent with recent studies, 34,35 we found that NVP-BEZ235 caused increased phosphorylation of MEK/Erk, although it appeared to be less significant compared with mTOR or PI3K inhibitors. 34,35 It has been suggested that activation of MEK/Erk signaling is a resistance mechanism in mTOR inhibitor-based therapy.…”

Section: Discussionsupporting

confidence: 90%

“…32,33 Interestingly, in consistent with recent studies, 34,35 we found that NVP-BEZ235 caused increased phosphorylation of MEK/Erk, although it appeared to be less significant compared with mTOR or PI3K inhibitors. 34,35 It has been suggested that activation of MEK/Erk signaling is a resistance mechanism in mTOR inhibitor-based therapy. Consequently MAPK/Erk inhibitors can improve antitumor effect of PI3K-mTOR inhibitors.…”

Section: Discussionsupporting

confidence: 90%

“…Consequently MAPK/Erk inhibitors can improve antitumor effect of PI3K-mTOR inhibitors. [34][35][36] Here we observed that MEK/ Erk inhibitors enhanced the activity of NVP-BEZ235 both in vivo and in vitro. Thus these findings suggest that concomitant targeting of MAPK/Erk signaling is a promising strategy to enhance antitumor effect of NVP-BEZ235 against osteosarcoma and possible other cancers.…”

Section: Discussionmentioning

confidence: 63%

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Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against osteosarcoma

Zhu¹,

Min

Fang³

et al. 2015

Cancer Biology & Therapy

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Keywords: MEK/Erk and chemo-resistance, NVP-BEZ235, osteosarcoma, PI3K-Akt-mTOR signaling Abbreviations: mammalian target of rapamycin (mTOR); mTOR complex 1 (mTORC1); mTOR complex 2 (mTORC2); phosphoinositide-dependent protein kinase-1 (PDK1); phosphatidylinositol 3-kinase (PI3K); receptor tyrosine kinases (RTKs).Recent studies have identified that constitutively active phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is an important feature of osteosarcoma, where it promotes cell proliferation, survival, and chemo-resistance. Here, we studied the therapeutic potential of NVP-BEZ235, a novel dual PI3K/mTOR dual inhibitor, on osteosarcoma cells in vivo and in vitro. NVP-BEZ235 was cytotoxic and cytostatic to a panel of osteosarcoma lines (MG-63, U2OS and SaOs-2), where it induce apoptosis and cell-cycle arrest. At the molecular level, NVP-BEZ235 inhibited PI3K-AKT-mTORC1 activation and downregulated cyclin D1/cyclin B1 expressions, while increasing MEK/Erk phosphorylation in osteosarcoma cells. MEK/Erk inhibitors PD98059 and MEK-162 increased NVP-BEZ235 activity on osteosarcoma cells. In vivo, oral NVP-BEZ235 inhibited U2OS xenograft in SCID mice, and its antitumor efficiency was further enhanced by MEK-162 co-administration. Taken together, our findings indicate that dual inhibition of PI3K and mTOR with NVP-BEZ235, either alone or in combination with MEK/Erk inhibitors, may be an efficient treatment for osteosarcoma.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 63%

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Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against osteosarcoma

Zhu¹,

Min

Fang³

et al. 2015

Cancer Biology & Therapy

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“…In order to overcome chemotherapy resistance, BEZ235 had been developed and showed effective inhibition on cell growth of various cancers in the presence of cisplatin resistance. 26,27 In conclusion, this study demonstrated that tunicamycin could stimulate ERS and downregulate relevant proteins of the PI3K/AKT/mTOR signaling pathway in time-and dose-dependent manners and that ERS increased autophagy and apoptosis of MCF-7 cells as well as chemosensitivity of MCF-7 cells to cisplatin through inhibition of the PI3K/ AKT/mTOR signaling pathway. Nevertheless, the relationship between ERS and MCF-7 cells has not been clearly explained.…”

Section: Discussionmentioning

confidence: 60%

Effects of endoplasmic reticulum stress on the autophagy, apoptosis, and chemotherapy resistance of human breast cancer cells by regulating the PI3K/AKT/mTOR signaling pathway

Zhong

Wang

et al. 2017

Tumour Biol.

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Nowadays, although chemotherapy is an established therapy for breast cancer, the molecular mechanisms of chemotherapy resistance in breast cancer remain poorly understood. This study aims to explore the effects of endoplasmic reticulum stress on autophagy, apoptosis, and chemotherapy resistance in human breast cancer cells by regulating PI3K/AKT/mTOR signaling pathway. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to detect the cell viability of six human breast cancer cell lines (MCF-7, ZR-75-30, T47D, MDA-MB-435s, MDA-MB-453, and MDA-MB-231) treated with tunicamycin (5 µM), after which MCF-7 cells were selected for further experiment. Then, MCF-7 cells were divided into the control (without any treatment), tunicamycin (8 µ), BEZ235 (5 µ), and tunicamycin + BEZ235 groups. Cell viability of each group was testified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Western blotting was applied to determine the expressions of endoplasmic reticulum stress and PI3K/AKT/mTOR pathwayrelated proteins and autophagy-and apoptosis-related proteins. Monodansylcadaverine and Annexin V-fluorescein isothiocyanate/propidium iodide staining were used for determination of cell autophagy and apoptosis. Furthermore, MCF-7 cells were divided into the control (without any treatment), tunicamycin (5 µM), cisplatin (16 µM), cisplatin (16 µM) + BEZ235 (5 µM), tunicamycin (5 µM) + cisplatin (16 µM), and tunicamycin (5 µM) + cisplatin (16 µM) + BEZ235 groups. Cell viability and apoptosis were also evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and Annexin V-fluorescein isothiocyanate/propidium iodide staining. In MCF-7 cells treated with tunicamycin, cell viability decreased significantly, but PEAK, eIF2, and CHOP were upregulated markedly and p-PI3K, p-AKT, and p-MTOR were downregulated in dose-and time-dependent manners. In the tunicamycin + BEZ235 group, the cell viability was lower and the apoptosis rate was higher than those of the control and monotherapy groups. Compared with the cisplatin group, the tunicamycin + cisplatin group showed a relatively higher growth inhibition rate; the growth inhibition rate substantially increased in the tunicamycin + cisplatin + BEZ235 group than the tunicamycin + cisplatin group. The apoptosis rate was highest in tunicamycin + cisplatin + BEZ235 group, followed by tunicamycin + cisplatin group and then cisplatin group. Our study provide evidence that endoplasmic reticulum stress activated by tunicamycin could promote breast cancer cell autophagy and apoptosis and enhance chemosensitivity of MCF-7 cells by inhibiting the PI3K/AKT/ mTOR signaling pathway.

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“…The ERK pathway parallels the PI3K/mTOR pathway, which is important in cardiomyocyte survival during stress (Das et al, 2009). ERK signaling is enhanced after treatment with BEZ (Moon et al, 2014), which essentially redirects signaling away from PI3K into RAS, leading to cardiomyocyte survival. In addition, inhibition of mTORC1 with rapamycin protects the heart against ischemia-reperfusion injury through activation of JAK2/STAT3 (Das et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Targeted Inhibition of Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Sensitizes Pancreatic Cancer Cells to Doxorubicin without Exacerbating Cardiac Toxicity

et al. 2015

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Pancreatic cancer has the lowest 5-year survival rate of all major cancers despite decades of effort to design and implement novel, more effective treatment options. In this study, we tested whether the dual phosphoinositide 3-kinase/mechanistic target of rapamycin inhibitor BEZ235 (BEZ) potentiates the antitumor effects of doxorubicin (DOX) against pancreatic cancer. Cotreatment of BEZ235 with DOX resulted in dose-dependent inhibition of the phosphoinositide 3-kinase/mechanistic target of rapamycin survival pathway, which corresponded with an increase in poly ADP ribose polymerase cleavage. Moreover, BEZ cotreatment significantly improved the effects of DOX toward both cell viability and cell death in part through reduced Bcl-2 expression and increased expression of the shorter, more cytotoxic forms of BIM. BEZ also facilitated intracellular accumulation of DOX, which led to enhanced DNA damage and reactive oxygen species generation. Furthermore, BEZ in combination with gemcitabine reduced MiaPaca2 cell proliferation but failed to increase reactive oxygen species generation or BIM expression, resulting in reduced necrosis and apoptosis. Treatment with BEZ and DOX in mice bearing tumor xenographs significantly repressed tumor growth as compared with BEZ, DOX, or gemcitabine. Additionally, in contrast to the enhanced expression seen in MiaPaca2 cells, BEZ and DOX cotreatment reduced BIM expression in H9C2 cardiomyocytes. Also, the Bcl-2/Bax ratio was increased, which was associated with a reduction in cell death. In vivo echocardiography showed decreased cardiac function with DOX treatment, which was not improved by combination treatment with BEZ. Thus, we propose that combining BEZ with DOX would be a better option for patients than current standard of care by providing a more effective tumor response without the associated increase in toxicity.

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NVP-BEZ235, a dual PI3K/mTOR inhibitor synergistically potentiates the antitumor effects of cisplatin in bladder cancer cells

Cited by 56 publications

References 38 publications

Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against osteosarcoma

Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against osteosarcoma

Effects of endoplasmic reticulum stress on the autophagy, apoptosis, and chemotherapy resistance of human breast cancer cells by regulating the PI3K/AKT/mTOR signaling pathway

Targeted Inhibition of Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Sensitizes Pancreatic Cancer Cells to Doxorubicin without Exacerbating Cardiac Toxicity

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