Hyperglycemia and Phosphatidylinositol 3-Kinase/Protein Kinase B/Mammalian Target of Rapamycin (PI3K/AKT/mTOR) Inhibitors in Phase I Trials: Incidence, Predictive Factors, and Management

Khan, Khurum; Wong, Mabel; Rihawi, Karim; Bodla, Shankar; Morganstein, Daniel L.; Banerji, Udai; Molife, L Rhoda

doi:10.1634/theoncologist.2015-0248

Cited by 55 publications

(49 citation statements)

References 30 publications

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“…We find that high insulin treatment triggered insulin resistant by the overexpression of IRS and mTOR, and galangin treatment downregulated IRS and mTOR phosphorylation ( Figure 4(a) ). This result is consistent with the conclusions that the activity of mTOR can be inhibited by downregulating the serine phosphorylation of IRS and upregulating its tyrosine phosphorylation [ 38 ]. Activated mTOR phosphorylates p70S6K, one of the most studied substrates of mTOR.…”

Section: Discussionsupporting

confidence: 92%

Galangin and Pinocembrin from Propolis Ameliorate Insulin Resistance in HepG2 Cells via Regulating Akt/mTOR Signaling

Liu

Liang

Zhang

et al. 2018

Evidence-Based Complementary and Alternative Medicine

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Insulin resistance has a critical role in type 2 diabetes. The aim of this study was to investigate the effect of pinobanksin, galangin, chrysin, and pinocembrin from propolis on insulin resistance. Our study shows that galangin and pinocembrin can ameliorate insulin resistance; on the contrary, pinobanksin and chrysin are ineffective. Galangin and pinocembrin treatments substantially increase glucose consumption and glycogen content by enhancing the activities of hexokinase and pyruvate kinase. Galangin treatment with 80 μM increased hexokinase and pyruvate kinase activities by 21.94% and 29.12%, respectively. Moreover, we hypothesize that galangin and pinocembrin may have a synergistic effect on the improvement of insulin resistance via Akt/mTOR signaling pathway, through distinctly upregulating the phosphorylation of IR, Akt, and GSK3β and remarkably downregulating the phosphorylation of IRS. Most notably, this is the first study to our knowledge to investigate pinocembrin about the alleviation of insulin resistance. Our results provide compelling evidence for the depth development of propolis products to ameliorate insulin resistance.

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Section: Discussionsupporting

confidence: 92%

Galangin and Pinocembrin from Propolis Ameliorate Insulin Resistance in HepG2 Cells via Regulating Akt/mTOR Signaling

Liu

Liang

Zhang

et al. 2018

Evidence-Based Complementary and Alternative Medicine

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“…Rapamycin has been reported to cause certain clinicopathologic changes when given to human patients at immunosuppressive doses (Brattstrom et al 1998;Khan et al 2016;Alexandre et al 1999), but this study provides the first comparable data for dogs given rapamycin in non-immunosuppressive doses. While the pharmacokinetics and pharmacodynamics of both orally and parenterally administered rapamycin in dogs are known (Paoloni et al 2010;Larson et al 2016), no data on its use for periods exceeding 7 days in companion dogs have been previously published.…”

Section: Side Effectsmentioning

confidence: 78%

“…Rapamycin is also used clinically for some rare forms of cancer (Xie et al 2016), to treat tuberous sclerosis complex, and in cardiac stents, to prevent restenosis (Kaeberlein 2013). Several side effects have been associated with rapamycin and rapamycin derivatives at the doses used in human medicine, including stomatitis (Boers-Doets et al 2013), impaired wound healing (Weinreich et al 2011), hyperlipidemia (Brattstrom et al 1998), hyperglycemia (Khan et al 2016), and thrombocytopenia (Alexandre et al 1999).…”

Section: Introductionmentioning

confidence: 99%

A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs

et al. 2017

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Age is the single greatest risk factor for most causes of morbidity and mortality in humans and their companion animals. As opposed to other model organisms used to study aging, dogs share the human environment, are subject to similar risk factors, receive comparable medical care, and develop many of the same age-related diseases humans do. In this study, 24 middle-aged healthy dogs received either placebo or a non-immunosuppressive dose of rapamycin for 10 weeks. All dogs received clinical and hematological exams before, during, and after the trial and echocardiography before and after the trial. Our results showed no clinical side effects in the rapamycin-treated group compared to dogs receiving the placebo. Echocardiography suggested improvement in both diastolic and systolic age-related measures of heart function (E/A ratio, fractional shortening, and ejection fraction) in the rapamycin-treated dogs. Hematological values remained within the normal range for all parameters studied; however, the mean corpuscular volume (MCV) was decreased in rapamycin-treated dogs. Based on these results, we will test rapamycin on a larger dog cohort for a longer period of time in order to validate its effects on cardiac function and to determine whether it can significantly improve healthspan and reduce mortality in companion dogs.

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“…mTOR is a major node in the pathway; approximately 50% of solid tumours are associated with the activation of the PI3K–Akt–mTOR pathway ( Liu P. et al, 2009 ). Khan et al (2016) found that hyperglycaemia is common in patients treated with PI3K–Akt–mTOR inhibitors; the agents targeting this pathway are associated with hyperglycaemia due to their interaction with the insulin–glucose regulatory axis. Recently, it was reported that NLRC3 is an inhibitory sensor of the PI3K–mTOR pathway in cancer ( Karki et al, 2016 ); however, the relationship between NLRC3 and PI3K–Akt–AS160–GLUT4, NLRC3 and PI3K–Akt–mTOR signalling pathway in DM is not known.…”

Section: Discussionmentioning

confidence: 99%

Semen Cassiae Extract Improves Glucose Metabolism by Promoting GlUT4 Translocation in the Skeletal Muscle of Diabetic Rats

Zhang

Liang

et al. 2018

Front. Pharmacol.

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Diabetes mellitus is a clinical syndrome characterised by hyperglycaemia; its complications lead to disability and even death. Semen Cassiae is a traditional Chinese medicine, which has anti-hypertensive, anti-hyperlipidaemia, anti-oxidation, and anti-ageing properties. Our study was designed to evaluate the action of total anthraquinones of Semen Cassiae extract (SCE) on the improvement of glucose metabolism in diabetic rats and to elucidate the underlying mechanism. First, we evaluated the effect of SCE on normal rats. Next, we observed the effect of SCE using a rat model of diabetes, which was established by feeding rats with high-energy diet for 4 weeks and a single intraperitoneal injection of streptozotocin (STZ; 30 mg/kg) 3 weeks after starting the high-energy diet. Rats in different SCE groups (administered 54, 108, and 324 mg/kg/day of SCE) and metformin group (162 mg/kg/day, positive control drug) were treated with the corresponding drugs 1 week before starting high-energy diet and treatment continued for 5 weeks; meanwhile, rats in the control group were administered the same volume of sodium carboxymethyl cellulose solution (vehicle solution). One week after STZ injection, fasting blood glucose (FBG), oral glucose tolerance (OGT), fasting serum insulin (FSI) and serum lipids were quantified. Finally, the expression of proteins in the phosphatidylinositol-3-kinase (PI3K)–Akt–AS160–glucose transporter isoform 4 (GLUT4) signalling pathway was detected by western blotting. The data indicated that the levels of FBG and serum lipids were significantly lowered, and OGT and FSI were markedly increased in diabetic rats treated with SCE (108 mg/kg/day); however, SCE did not cause hypoglycaemia in normal rats. The molecular mechanisms were explored in the skeletal muscle. SCE markedly restored the decreased translocation of GLUT4 in diabetic rats. Moreover, the protein expressions of phosphorylated-AS160 (Thr642), phosphorylated-Akt (Ser473) and PI3K were significantly increased after SCE treatment in the skeletal muscle. These results indicate that SCE exerts an anti-hyperglycaemic effect by promoting GLUT4 translocation through the activation of the PI3K–Akt–AS160 signalling pathway. Our findings suggest that treatment with SCE, containing anthraquinones, could be an effective approach to enhance diabetes therapy.

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Hyperglycemia and Phosphatidylinositol 3-Kinase/Protein Kinase B/Mammalian Target of Rapamycin (PI3K/AKT/mTOR) Inhibitors in Phase I Trials: Incidence, Predictive Factors, and Management

Cited by 55 publications

References 30 publications

Galangin and Pinocembrin from Propolis Ameliorate Insulin Resistance in HepG2 Cells via Regulating Akt/mTOR Signaling

Galangin and Pinocembrin from Propolis Ameliorate Insulin Resistance in HepG2 Cells via Regulating Akt/mTOR Signaling

A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs

Semen Cassiae Extract Improves Glucose Metabolism by Promoting GlUT4 Translocation in the Skeletal Muscle of Diabetic Rats

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