A Mechanism for Synergy with Combined mTOR and PI3 Kinase Inhibitors

Yang, Shujie; Xiao, Xue; Meng, Xiangjun; Leslie, Kimberly K.

doi:10.1371/journal.pone.0026343

Cited by 51 publications

(43 citation statements)

References 41 publications

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“…Selective inhibition of the Akt/mTOR signaling pathway reduces the level of macrophages and stabilizes vulnerable atherosclerotic plaques by promoting macrophage autophagy (35). The addition of a PI3K inhibitor overcomes cellular resistance to mTORC1 inhibitors, regardless of PTEN status, and therefore substantially expands the molecular phenotype of tumors likely to respond (16). Coordinated inhibition of the mTOR and autophagy pathways promotes apoptosis and may be a novel therapeutic paradigm for the treatment of melanoma (36).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies suggest that autophagy is important in the regulation of cancer development and progression and also in determining the response of tumor cells to anticancer therapy (11)(12)(13)(14). Several cell signaling pathways are implicated in regulating autophagy, including the phosphatidyl inositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway (15,16). The present study aimed to investigate the role of autophagy on DHA-and EPA-induced cell death in A549 cells, and the associated Akt/mTOR signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

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Role of autophagy in the ω-3 long chain polyunsaturated fatty acid-induced death of lung cancer A549 cells

Yao

Wang

et al. 2015

Oncology Letters

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Abstract. The present study identified that ω-3 long chain polyunsaturated fatty acids (ω-3 PUFAs), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) demonstrate anti-proliferative effects in lung cancer A549 cells. MTS and cytotoxicity assays were conducted to confirm that ω-3 PUFAs induced cell death. Autophagy-associated gene and signaling pathways were also detected. Microtubule-associated protein light chain 3 (LC3) expression was found to be increased subsequent to treatment with DHA and EPA, and the expression of LC3-II was particularly increased. mRFP-GFP-LC3 fluorescence staining and p62 expression levels were used to detect autophagic flux. The present results indicate that DHA and EPA block autophagic flux, suggesting autophagosome accumulation. Subsequent to treatment with DHA and EPA, which interfered with autophagosomes, the expression of Beclin 1 was significantly decreased, while the expression of phosphorylated Akt and phosphorylated mammalian target of rapamycin was significantly increased. Therefore, DHA and EPA exert anti-proliferative effects by inhibiting autophagy in A549 cells, which highlights the potential of DHA and EPA for use in the prevention or treatment of lung cancer. IntroductionLung cancer is the leading cause of cancer-associated mortality worldwide (1), and the five-year survival rate remains extremely poor (2). Overall, ~75-85% of lung cancers cases are non-small cell lung cancer (NSCLC), which includes squamous cell carcinoma, adenocarcinoma and large cell carcinoma. The treatment of lung cancer involves the use of medical therapies such as surgery, radiation, chemotherapy and palliative care (3) in an attempt to successfully treat or reduce the adverse impact of malignant neoplasms originating in lung tissue. Chemotherapeutic agents are the main treatment measures for NSCLC, but the side-effects are usually difficult to tolerate (4).Fish oils are an excellent source of long-chain ω-3 polyunsaturated fatty acids (ω-3 PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Fish oil supplements are increasingly recognized by clinical studies to be useful for the treatment of a variety of human afflictions, including cancer (5). Numerous studies reveal evidence for the capability of ω-3 PUFAs to decrease proliferation, exert a pro-apoptotic effect and inhibit angiogenesis in several in vitro models of colon cancer (6-9).A previous study indicated that DHA and EPA inhibit the proliferation of A549 cells and induce apoptosis, with autophagy also being observed under transmission electron microscopy (10). Autophagy is a type of programmed cell death and it is an important process that is involved in various human pathologies. Previous studies suggest that autophagy is important in the regulation of cancer development and progression and also in determining the response of tumor cells to anticancer therapy (11)(12)(13)(14). Several cell signaling pathways are implicated in regulating autophagy, including the phosphatidyl inositol 3-kinase (PI3K)/Akt/...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of autophagy in the ω-3 long chain polyunsaturated fatty acid-induced death of lung cancer A549 cells

Yao

Wang

et al. 2015

Oncology Letters

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“…Thus, the safety and effectiveness of autophagy activators or inhibitors must be taken into account before clinical therapy development. A combination of mTOR and PI3 kinase inhibitors showed a synergistic antitumor effect [124] . Another study showed that the combination of the mTOR inhibitor rapamycin and the IMPase inhibitor lithium ameliorates toxicity of polyglutamine-expanded huntingtin [125] .…”

Section: Therapeutic Implications For Autophagy Regulatorsmentioning

confidence: 99%

Application and interpretation of current autophagy inhibitors and activators

et al. 2013

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Autophagy is the major intracellular degradation system, by which cytoplasmic materials are delivered to and degraded in the lysosome. As a quality control mechanism for cytoplasmic proteins and organelles, autophagy plays important roles in a variety of human diseases, including neurodegenerative diseases, cancer, cardiovascular disease, diabetes and infectious and inflammatory diseases. The discovery of ATG genes and the dissection of the signaling pathways involved in regulating autophagy have greatly enriched our knowledge on the occurrence and development of this lysosomal degradation pathway. In addition to its role in degradation, autophagy may also promote a type of programmed cell death that is different from apoptosis, termed type II programmed cell death. Owing to the dual roles of autophagy in cell death and the specificity of diseases, the exact mechanisms of autophagy in various diseases require more investigation. The application of autophagy inhibitors and activators will help us understand the regulation of autophagy in human diseases, and provide insight into the use of autophagy-targeted drugs. In this review, we summarize the latest research on autophagy inhibitors and activators and discuss the possibility of their application in human disease therapy.

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“…Fujiwara et al (2007) reported PI3K/Akt inhibition increased radiosensitivity by inducing autophagic cell death. The combination of BEZ235, the dual PI3K/mTOR inhibitor, with temsirolimus resulted in cell death due to autophagy (Yang et al, 2011). Inhibition of autophagy has also enhanced the effect of PI3K/mTOR inhibition in neurological tumours (Ghadimi et al, 2012) and lung cancer (Xu et al, 2011).…”

Section: Tablementioning

confidence: 99%

Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype

Bhattacharya

Low

Soh

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEThe testing of anticancer compounds in vitro is usually performed in hyperglycaemic cell cultures, although many tumours and their in vivo microenvironments are hypoglycaemic. Here, we have assessed, in cultures of tumour cells, the effects of reduced glucose levels on resistance to anticancer drugs and investigated the underlying cellular mechanisms. EXPERIMENTAL APPROACHPIK3CA mutant (AGS, HGC27), and wild-type (MKN45, NUGC4) gastric cancer cells were cultured in high-glucose (HG, 25 mM) or low-glucose (LG, 5 mM) media and tested for sensitivity to two cytotoxic compounds, 5-fluorouracil (5-FU) and carboplatin, the PI3K/mTOR inhibitor, PI103 and the mTOR inhibitor, Ku-0063794. KEY RESULTSAll cells had increased resistance to 5-FU and carboplatin when cultured in LG compared with HG conditions despite having similar growth and cell cycle characteristics. On treatment with PI103 or Ku-0063794, only the PIK3CA mutant cells displayed increased resistance in LG conditions. The PIK3CA mutant LG cells had selectively increased p-mTOR, p-S6, p-4EBP1, GLUT1 and lactate production, and reduced reactive oxygen species, consistent with increased glycolysis. Combination analysis indicated PI103 and Ku-0063794 were synergistic in PIK3CA mutant LG cells only. Synergism was accompanied by reduced mTOR signalling and increased autophagy. CONCLUSIONS AND IMPLICATIONSHypoglycaemia increased resistance to cytotoxic agents, especially in tumour cells with a high dependence on glycolysis. Dual inhibition of the PI3K/mTOR pathway may be able to attenuate such hypoglycaemia-associated resistance. Abbreviations

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A Mechanism for Synergy with Combined mTOR and PI3 Kinase Inhibitors

Cited by 51 publications

References 41 publications

Role of autophagy in the ω-3 long chain polyunsaturated fatty acid-induced death of lung cancer A549 cells

Role of autophagy in the ω-3 long chain polyunsaturated fatty acid-induced death of lung cancer A549 cells

Application and interpretation of current autophagy inhibitors and activators

Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype

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