NVP-BEZ235 synergizes cisplatin sensitivity in osteosarcoma

Huang, Jincheng; Cui, Zhifei; Chen, Shui-Mu; Yang, Lianjun; Lian, Hongkai; Liu, Bin; Su, Zhihai; Liu, Jin-Shi; Wang, Min; Hu, Zhengbo; Ouyang, Jiahong; Li, Qing-Chu; Lü, Hai

doi:10.18632/oncotarget.23711

Cited by 17 publications

(13 citation statements)

References 54 publications

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“…Several reports have demonstrated that dactolisib exerts anti-proliferative and cytotoxic effects in vitro. Dactolisib was also shown to induce autophagy and enhance chemosensitivity [ 210 , 211 , 212 ]. In AML, dactolisib showed similar biological effects in vitro and inhibited the colony-forming capability of LSCs [ 213 , 214 ].…”

Section: Clinical Implications Of Pi3k/akt/mtor Inhibitors In Amlmentioning

confidence: 99%

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

Darici

Alkhaldi

Horne

et al. 2020

JCM

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Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy characterized by excessive proliferation and accumulation of immature myeloid blasts in the bone marrow. AML has a very poor 5-year survival rate of just 16% in the UK; hence, more efficacious, tolerable, and targeted therapy is required. Persistent leukemia stem cell (LSC) populations underlie patient relapse and development of resistance to therapy. Identification of critical oncogenic signaling pathways in AML LSC may provide new avenues for novel therapeutic strategies. The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathway, is often hyperactivated in AML, required to sustain the oncogenic potential of LSCs. Growing evidence suggests that targeting key components of this pathway may represent an effective treatment to kill AML LSCs. Despite this, accruing significant body of scientific knowledge, PI3K/Akt/mTOR inhibitors have not translated into clinical practice. In this article, we review the laboratory-based evidence of the critical role of PI3K/Akt/mTOR pathway in AML, and outcomes from current clinical studies using PI3K/Akt/mTOR inhibitors. Based on these results, we discuss the putative mechanisms of resistance to PI3K/Akt/mTOR inhibition, offering rationale for potential candidate combination therapies incorporating PI3K/Akt/mTOR inhibitors for precision medicine in AML.

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Section: Clinical Implications Of Pi3k/akt/mtor Inhibitors In Amlmentioning

confidence: 99%

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

Darici

Alkhaldi

Horne

et al. 2020

JCM

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“…Among the multifactorial mechanisms underlying chemoresistance, overexpression or activation of the Akt/mTOR pathway critically contributes to cisplatin resistance by attenuating p53 activity [18, 19]. The majority of studies have suggested that co-treatment with an mTOR inhibitor including rapamycin greatly enhanced the therapeutic activity of cisplatin against several cisplatin resistant cell lines, causing activation of autophagy and subsequent apoptosis [9, 14, 19–24]. As the broad action of rapamycin can cause unexpected side effects, seeking more specific inhibitor is considered to be an effective way to overcome cisplatin resistance.…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel S6K1 inhibitor, rosmarinic acid methyl ester, for treating cisplatin-resistant cervical cancer

Nam

et al. 2019

BMC Cancer

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Background The mTOR/S6K1 signaling pathway is often activated in cervical cancer, and thus considered a molecular target for cervical cancer therapies. Inhibiting mTOR is cytotoxic to cervical cancer cells and creates a synergistic anti-tumor effect with conventional chemotherapy agents. In this study, we identified a novel S6K1 inhibitor, rosmarinic acid methyl ester (RAME) for the use of therapeutic agent against cervical cancer. Methods Combined structure- and ligand-based virtual screening was employed to identify novel S6K1 inhibitors among the in house natural product library. In vitro kinase assay and immunoblot assay was used to examine the effects of RAME on S6K1 signaling pathway. Lipidation of LC3 and mRNA levels of ATG genes were observed to investigate RAME-mediated autophagy. PARP cleavage, mRNA levels of apoptotic genes, and cell survival was measured to examine RAME-mediated apoptosis. Results RAME was identified as a novel S6K1 inhibitor through the virtual screening. RAME, not rosmarinic acid, effectively reduced mTOR-mediated S6K1 activation and the kinase activity of S6K1 by blocking the interaction between S6K1 and mTOR. Treatment of cervical cancer cells with RAME promoted autophagy and apoptosis, decreasing cell survival rate. Furthermore, we observed that combination treatment with RAME and cisplatin greatly enhanced the anti-tumor effect in cisplatin-resistant cervical cancer cells, which was likely due to mTOR/S6K1 inhibition-mediated autophagy and apoptosis. Conclusions Our findings suggest that inhibition of S6K1 by RAME can induce autophagy and apoptosis in cervical cancer cells, and provide a potential option for cervical cancer treatment, particularly when combined with cisplatin. Electronic supplementary material The online version of this article (10.1186/s12885-019-5997-2) contains supplementary material, which is available to authorized users.

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“…Chemotherapy drugs which target signaling pathways with a known association to PC tumor progression, including mTOR, PI3K-Akt, MAPK, AMPK, and p53 signaling, are used to induce PC cancer cell death. This is exemplified by BEZ235, a phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor that blocks AKT phosphorylation (Thr308/Ser473) and can prevent breast [6, 7], glioma [8], and non-small-cell lung cancer growth [9, 10]. Combining BEZ235 with abiraterone acetate, which blocks cytochrome P450 17 alpha-hydroxylase to significantly reduce androgen production, improves therapeutic outcomes in PC [11].…”

Section: Introductionmentioning

confidence: 99%

Bloom Syndrome Protein Activates AKT and PRAS40 in Prostate Cancer Cells

Chen

Zhao

2019

Oxidative Medicine and Cellular Longevity

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Purpose. Prostate cancer (PC) is a common malignant tumor and a leading cause of cancer-related death in men worldwide. In order to design new therapeutic interventions for PC, an understanding of the molecular events underlying PC tumorigenesis is required. Bloom syndrome protein (BLM) is a RecQ-like helicase, which helps maintain genetic stability. BLM dysfunction has been implicated in tumor development, most recently during PC tumorigenesis. However, the molecular basis for BLM-induced PC progression remains poorly characterized. In this study, we investigated whether BLM modulates the phosphorylation of an array of prooncogenic signaling pathways to promote PC progression. Methods. We analyzed differentially expressed proteins (DEPs) using iTRAQ technology. Site-directed knockout of BLM in PC-3 prostate cancer cells was performed using CRISPR/Cas9-mediated homologous recombination gene editing to confirm the effects of BLM on DEPs. PathScan® Antibody Array Kits were used to analyze the phosphorylation of nodal proteins in PC tissue. Immunohistochemistry and automated western blot (WES) analyses were used to validate these findings. Results. We found that silencing BLM in PC-3 cells significantly reduced their proliferative capacity. In addition, BLM downregulation significantly reduced levels of phosphorylated protein kinase B (AKT (Ser473)) and proline-rich AKT substrate of 40 kDa (PRAS40 (Thr246)), and this was accompanied by enhanced ROS (reactive oxygen species) levels. In addition, we found that AKT and PRAS40 inhibition reduced BLM, increased ROS levels, and induced PC cell apoptosis. Conclusions. We demonstrated that BLM activates AKT and PRAS40 to promote PC cell proliferation and survival. We further propose that ROS act in concert with BLM to facilitate PC oncogenesis, potentially via further enhancing AKT signaling and downregulating PTEN expression. Importantly, inhibiting the BLM-AKT-PRAS40 axis induced PC cell apoptosis. Thus, we highlight new avenues for novel anti-PC treatments.

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NVP-BEZ235 synergizes cisplatin sensitivity in osteosarcoma

Cited by 17 publications

References 54 publications

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

Identification of a novel S6K1 inhibitor, rosmarinic acid methyl ester, for treating cisplatin-resistant cervical cancer

Bloom Syndrome Protein Activates AKT and PRAS40 in Prostate Cancer Cells

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