Targeting the PI3K/AKT/mTOR pathway in biliary tract cancers: A review of current evidences and future perspectives

Biliary tract cancers (BTCs) are a group of invasive neoplasms, with increasing incidence and dismal prognosis. In advanced disease, the standard of care is represented by first-line chemotherapy with cisplatin and gemcitabine. In subsequent lines, no clear recommendations are currently available, highlighting the need for novel therapeutic approaches.The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, growth and survival, and is involved in BTCs carcinogenesis and progression. Mutations, gene copy number alterations and aberrant protein phosphorylation of PI3K, AKT, mTOR and PTEN have been thoroughly described in BTCs and correlate with poor survival outcomes.Several pre-clinical evidences state the efficacy of PI3K/AKT/mTOR pathway inhibitors in BTCs, both in vitro and in vivo. In the clinical setting, initial studies with rapamycin analogs have shown interesting activity with an acceptable toxicity profile. Novel strategies evaluating AKT and PI3K inhibitors have risen serious safety concerns, pointing out the need for improved patient selection and increased target specificity for the clinical development of these agents, both alone and in combination with chemotherapy.This review extensively describes the role of the PI3K/AKT/mTOR pathway in BTCs and examines the rationale of its targeting in these tumors, with particular focus on clinical activity, toxicities and perspectives on further development of PI3K/AKT/mTOR pathway inhibitors.     

Status of PI3K/Akt/mTOR Pathway Inhibitors in Lymphoma

The phosphatidylinositol-3-kinase (PI3K) pathway is well known to regulate a wide variety of essential cellular functions, including glucose metabolism, translational regulation of protein synthesis, cell proliferation, apoptosis, and survival. Aberrations in the PI3K pathway are among the most frequently observed in cancer, and include amplifications, rearrangements, mutations, and loss of regulators. As a net result of these anomalies, the PI3K pathway is activated in many malignancies, including in Hodgkin and non-Hodgkin lymphomas, and yields a competitive growth and survival advantage, increased metastatic ability, and resistance to conventional therapy. Numerous inhibitors targeting various nodes in the PI3K pathway are undergoing clinical development, and their current status in lymphoma will be the focus of this review.     

Mometasone furoate inhibits growth of acute leukemia cells in childhood by regulating PI3K signaling pathway

Objectives: Acute lymphoblastic leukemia (ALL) is the most common cancer before the age of 15 years, seriously endangering the health of children. The main treatment for Childhood ALL was pharmacotherapy. But these drugs have many side effects and some of them could develop drug resistance quickly. Mometasone furoate (MF) is an efficient glucocorticoid for topical treatment of inflammation on the skin, lung and nose.

Methods: In this study, we investigated whether the MF had effects on ALL cells proliferation and migration.

Results: The CCK-8 proliferation test showed that the cell viability was the lowest at 25?nM MF treatment and the increased OD value was time-dependent. In transwell assay, the number of CCRF-CEM cells was reduced in MF treated group. We found the expression of anti-apoptotic protein bcl-2 decreased the expression of pro-apoptotic protein caspase3 and bax increased in CCRF-CEM cell line treated with MF. The expression of p-AKT, p-mTOR, p70S6?K, vascular endothelial growth factor and CyclinD1 were decreased in MF treated group.

Conclusion: This study reveals that MF can inhibit proliferation and invasion/migration and induce apoptosis in Childhood ALL cells, which may be regulated by Phosphatidylinositol 3-kinase signaling pathway. These results suggest MF may be a potential new drug target for clinical ALL treatment.     

左归降糖解郁方对糖尿病并发抑郁症大鼠海马胰岛素抵抗的影响

目的研究左归降糖解郁方对糖尿病并发抑郁症大鼠海马胰岛素抵抗的调节作用。方法建立糖尿病并发抑郁症大鼠模型,并随机分为4组,模型组,阳性药组(二甲双胍0.18 g/kg+氟西汀1.8 mg/kg),左归降糖解郁方高、低剂量组(20.52、10.26g/kg),另设健康大鼠为对照组。各组大鼠ig给药28 d后,采用血糖仪及ELISA法检测空腹血糖及外周胰岛素抵抗程度。采用旷野实验和强迫游泳实验检测大鼠抑郁样行为。采用免疫荧光法和Western blotting法检测大鼠海马胰岛素受体磷酸化蛋白(p-IR)、磷酸化的胰岛素受体底物-1(p-IRS-1)的表达,采用Westernblotting法检测海马磷酸化的磷脂酰肌醇3-激酶(p-PI3K)、磷酸化蛋白激酶B(p-Akt)蛋白的表达。结果与对照组比较,模型组大鼠血糖显著升高并伴随明显的外周胰岛素抵抗,其在旷野实验中的活动次数显著降低、在强迫游泳实验中的不动时间显著延长;蛋白检测结果表明大鼠脑内p-IR、p-IRS-1、p-PI3K、p-Akt表达水平均显著降低。与模型组比较,左归降糖解郁方高剂量组大鼠血糖水平显著降低,外周胰岛素抵抗水平减轻,其在旷野实验中的活动次数显著增加、在强迫游泳实验中的不动时间显著缩短,而海马内p-IR、p-IRS-1、p-PI3K、p-Akt表达显著升高。结论左归降糖解郁方可有效调节糖尿病并发抑郁症大鼠海马胰岛素信号通路,从而改善动物脑内的胰岛素抵抗状态。     

Pre-clinical use of isogenic cell lines and tumours in vitro and in vivo for predictive biomarker discovery; impact of KRAS and PI3KCA mutation status on MEK inhibitor activity is model dependent

Studies to identify predictive biomarkers can be carried out in isogenic cancer cell lines, which enable interrogation of the effect of a specific mutation. We assessed the effects of four drugs, the PI3K–mammalian target of rapamycin inhibitor dactolisib, the PI3K inhibitor pictrelisib, and the MEK (MAPK/ERK Kinase) inhibitors PD 0325901 and selumetinib, in isogenic DLD1 parental, KRAS^+/−, KRAS^G13D/−, PIK3CA^+/− and PIK3CA^E545K/− colorectal carcinoma cell lines. Importantly, we found substantial differences in the growth of these cells and in their drug sensitivity depending on whether they were studied under 2D (standard tissue culture on plastic) or 3D (in vitro soft agar and in vivo xenograft) conditions. DLD1 KRAS^+/− and DLD1 PIK3CA^+/− cells were more sensitive to MEK inhibitors than parental, DLD1 KRAS^G13D/− and DLD1 PIK3CA^E545K/− cells under 2D conditions, whereas DLD1 KRAS^G13D/− and DLD1 PIK3CA^E545K/− xenografts were sensitive to 10 mg/kg daily ×14 PD 0325901 in vivo (p ≤ 0.02) but tumours derived from parental DLD1 cells were not. These findings indicate that KRAS and PIK3CA mutations can influence the response of DLD1 colorectal cancer cell lines to MEK and PI3K inhibitors, but that the effect is dependent on the experimental model used to assess drug sensitivity.     

Change of Pulsatility Index of the Fetal Middle Cerebral Artery after Auditory Stimulation in No Risk Pregnancies and in Pregnancies with Gestational Hypertension

Purpose: An aim was to determine the degree and the mode of variation of PI of middle cerebral artery in no risk pregnancies and in pregnancies with gestational hypertension, after the constant sound stimuli. Method: Study included 343 patients divided in two groups. Group 1: low risk pregnancies and group 2: gestational hypertension. Ultrasound prenatal auditory screening was performed after the 27th week of gestation. Results: The percentage of fetuses with increase of cerebral blood flow was slightly higher in the pregnancies with hypertension. Conclusion: An average change of PI of median cerebral artery was higher in this group.     

Cellular senescence determines endothelial cell damage induced by uremia

Renal dysfunction is closely associated with endothelial damage leading to cardiovascular disease. However, the extent to which endothelial damage induced by uremia is modulated by aging is poorly known. Aging can render endothelial cells more susceptible to apoptosis through an oxidative stress-dependent pathway. We examined whether senescence-associated to oxidative stress determines the injury induced by the uremia in endothelial cells.     

Salidroside protects PC12 cells from MPP-induced apoptosis via activation of the PI3K/Akt pathway

Oxidative stress plays an important role in the pathogenesis of Parkinson’s disease (PD). Salidroside (SAL), a phenylpropanoid glycoside isolated from Rhodiola rosea L., can exert potent antioxidant properties. In this study, we investigated the protective effects, and the possible mechanism of action, of SAL against 1-methyl-4-phenylpyridinium (MPP⁺)-induced cell damage in rat adrenal pheochromocytoma PC12 cells. Pretreatment of PC12 cells with SAL significantly reduced the ability of MPP⁺ to induce apoptosis in a dose and time-dependent manner. SAL significantly and dose-dependently inhibited MPP⁺-induced chromatin condensation and MPP⁺-induced release of lactate dehydrogenase by PC12 cells. SAL enhanced Akt phosphorylation in PC12 cells, and the protective effects of SAL against MPP⁺-induced apoptosis were abolished by LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K) phosphorylation. These findings suggest that SAL prevents MPP⁺-induced apoptosis in PC12 cells, at least in part through activation of the PI3K/Akt pathway.