• 1,4-Benzodioxane
• Anticancer
• Apoptosis
• Cell cycle analysis
• Molecular docking studies
• Molecular dynamics
• mTOR inhibitors

• Hydrazones/chemistry
• Hydrazones/pharmacology
• Hydrazones/chemical synthesis
• Humans
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/chemical synthesis
• Antineoplastic Agents/chemistry
• Animals
• Drug Design
• Mice
• Drug Screening Assays, Antitumor
• Cell Proliferation/drug effects
• Structure-Activity Relationship
• Skin Neoplasms/drug therapy
• Skin Neoplasms/pathology
• Skin Neoplasms/metabolism
• Molecular Structure
• Dose-Response Relationship, Drug
• Apoptosis/drug effects
• Molecular Docking Simulation
• Dioxanes/chemistry
• Dioxanes/pharmacology
• Dioxanes/chemical synthesis
• Cell Line, Tumor

• Cancer
• Rapamycin
• Targeted therapy
• mTOR inhibitors
• mTOR pathway
• mTORC1
• mTORC2

• Cancer
• anti-cancer drugs
• therapeutic targeting
• translation regulation

• Laryngeal squamous cell carcinoma
• Nuclear maspin
• Prognosis
• Tumor suppressors
• mTOR

• Antineoplastic Agents/therapeutic use
• Everolimus/therapeutic use
• Humans
• Indoles/therapeutic use
• Molecular Targeted Therapy/methods
• Neuroendocrine Tumors/drug therapy
• Pancreatic Neoplasms/drug therapy
• Pyrroles/therapeutic use
• Sunitinib

• Head and neck cancer
• Next generation DNA sequencing
• PI3K/MTOR inhibition
• Radiation

The Phosphatidyl inositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and c-Met signaling pathways are often deregulated in cancer. The two pathways are interconnected and at least c-Met has been implicated in drug resistance. The aim of the study was to assess in ovarian cancer preclinical models, the efficacy and tolerability of a dual PI3K mTOR inhibitor (PF-05212384 or gedatolisib) and a c-Met inhibitor (crizotinib) either as single agents or in combination. In vitro, both PF-05212384 and crizotinib showed a concentration dependent activity in the two ovarian cancer cell lines. The combination of the two did not result in synergistic activity. A subline resistant to gedatolisib was obtained and showed an increased expression of MDR-1 gene. In vivo results show that crizotinib alone did not display any activity in all the tumors investigated, while PF-05212384 alone had some marginal activity. The combination of the two resulted in all the experiments superior to single agents with a good tolerability. Considering that crizotinib did not show activity in the models used, the results indicate that crizotinib is able to potentiate the activity of PF-05212384. Although the activity of the combination was not striking in these three models of ovarian cancer, due to the good tolerability of the combination, the results would suggest the possibility to combine the two drugs in settings in which gedatolisib or crizotinib alone have already some significant activity.

Mammalian target of rapamycin (mTOR) is an attractive target for new anticancer drug development. We recently developed in silico models to distinguish mTOR inhibitors and non-inhibitors. In this study, we developed an integrated strategy for identifying new mTOR inhibitors using cascaded in silico screening models. With this strategy, fifteen new mTOR kinase inhibitors including four compounds with IC₅₀ values below 10 μM were discovered. In particular, compound 17 exhibited potent anticancer activities against four tumor cell lines, including MCF-7, HeLa, MGC-803, and C6, with IC₅₀ values of 1.90, 2.74, 3.50 and 11.05 μM. Furthermore, cellular studies and western blot analyses revealed that 17 induces cell death via apoptosis by targeting both mTORC1 and mTORC2 within cells and arrests the cell cycle of HeLa at the G₁/G₀-phase. Finally, multi-nanosecond explicit solvent simulations and MM/GBSA analyses were carried out to study the inhibitory mechanisms of 13, 17, and 40 for mTOR. The potent compounds presented here are worthy of further investigation.

• Chemokine
• Drug resistance
• Everolimus
• Pancreatic neuroendocrine tumor
• m-TOR pathway

Adipose tissue is responsible for triggering chronic systemic inflammatory response and these changes may be involved in the pathophysiology of preeclampsia.

To characterize the lipid profile in the placenta and plasma of patients with preeclampsia.

Samples were collected from placenta and plasma of 10 pregnant women with preeclampsia and 10 controls. Lipids were extracted using the Bligh–Dyer protocol and were analysed by MALDI TOF-TOF mass spectrometry.

Approximately 200 lipid signals were quantified. The most prevalent lipid present in plasma of patients with preeclampsia was the main class Glycerophosphoserines-GP03 (PS) representing 52.30% of the total lipid composition, followed by the main classes Glycerophosphoethanolamines-GP02 (PEt), Glycerophosphocholines-GP01 (PC) and Flavanoids-PK12 (FLV), with 24.03%, 9.47% and 8.39% respectively. When compared to the control group, plasma samples of patients with preeclampsia showed an increase of PS (p<0.0001), PC (p<0.0001) and FLV (p<0.0001). Placental analysis of patients with preeclampsia, revealed the PS as the most prevalent lipid representing 56.28%, followed by the main class Macrolides/polyketides-PK04 with 32.77%, both with increased levels when compared with patients control group, PS (p<0.0001) and PK04 (p<0.0001).

Lipids found in placenta and plasma from patients with preeclampsia differ from those of pregnant women in the control group. Further studies are needed to clarify if these changes are specific and a cause or consequence of preeclampsia.

• Adult
• Age of Onset
• Female
• Humans
• Lipids/blood
• Obesity/blood
• Obesity/complications
• Obesity/pathology
• Placenta/metabolism
• Placenta/pathology
• Pre-Eclampsia/blood
• Pre-Eclampsia/etiology
• Pre-Eclampsia/pathology
• Pregnancy
• Systemic Inflammatory Response Syndrome/blood
• Systemic Inflammatory Response Syndrome/complications
• Systemic Inflammatory Response Syndrome/pathology

Malignant melanoma is the most lethal form of skin cancer, with a high propensity to metastasize to the brain. More than 60% of melanomas have the BRAF^V600E mutation, which activates the mitogen-activated protein kinase (MAPK) pathway [1]. In addition, increased PI3K (phosphoinositide 3-kinase) pathway activity has been demonstrated, through the loss of activity of the tumor suppressor gene, PTEN [2]. Here, we treated two melanoma brain metastasis cell lines, H1_DL2, harboring a BRAF^V600E mutation and PTEN loss, and H3, harboring WT (wild-type) BRAF and PTEN loss, with the MAPK (BRAF) inhibitor vemurafenib and the PI3K pathway associated mTOR inhibitor temsirolimus. Combined use of the drugs inhibited tumor cell growth and proliferation in vitro in H1_DL2 cells, compared to single drug treatment. Treatment was less effective in the H3 cells. Furthermore, a strong inhibitory effect on the viability of H1_DL2 cells, when grown as 3D multicellular spheroids, was seen. The treatment inhibited the expression of pERK1/2 and reduced the expression of pAKT and p-mTOR in H1_DL2 cells, confirming that the MAPK and PI3K pathways were inhibited after drug treatment. Microarray experiments followed by principal component analysis (PCA) mapping showed distinct gene clustering after treatment, and cell cycle checkpoint regulators were affected. Global gene analysis indicated that functions related to cell survival and invasion were influenced by combined treatment. In conclusion, we demonstrate for the first time that combined therapy with vemurafenib and temsirolimus is effective on melanoma brain metastasis cells in vitro. The presented results highlight the potential of combined treatment to overcome treatment resistance that may develop after vemurafenib treatment of melanomas.

Autophagy is a lysosomal-mediated catabolic process, which through degradation of different cytoplasmic components aids in maintaining cellular homeostasis and survival during exposure to extra- or intracellular stresses. Ammonia is a potential toxic and stress-inducing byproduct of glutamine catabolism, which has recently been found to induce autophagy in an MTOR independent way and support cancer cell survival. In this study, quantitative phosphoproteomics was applied to investigate the initial signaling events linking ammonia to the induction of autophagy. The MTOR inhibitor rapamycin was used as a reference treatment to emphasize the differences between an MTOR-dependent and -independent autophagy-induction. By this means 5901 phosphosites were identified of which 626 were treatment-specific regulated and 175 were coregulated. Investigation of the ammonia-specific regulated sites supported that MTOR activity was not affected, but indicated increased MAPK3 activity, regulation of proteins involved in Rho signal transduction, and a novel phosphorylation motif, serine-proline-threonine (SPT), which could be linked to cytoskeleton-associated proteins. MAPK3 could not be identified as the primary driver of ammonia-induced autophagy but instead the data suggested an upregulation of AMPK and the unfolded protein response (UPR), which might link ammonia to autophagy induction. Support of UPR induction was further obtained from the finding of increased protein levels of the ER stress markers DDIT3/CHOP and HSPA5 during ammonia treatment. The large-scale data set presented here comprises extensive high-quality quantitative information on phosphoprotein regulation in response to 2 very different autophagy inducers and should therefore be considered a general resource for the community.

• MTOR
• ammonia
• autophagy
• phosphoproteomics
• rapamycin
• unfolded protein response

Aberrant PI3K/AKT/mTOR signaling has been linked to oncogenesis and therapy resistance in various malignancies including leukemias. In Philadelphia chromosome (Ph) positive leukemias, activation of PI3K by dysregulated BCR-ABL tyrosine kinase (TK) contributes to the pathogenesis and development of resistance to ABL-TK inhibitors (TKI). The PI3K pathway thus is an attractive therapeutic target in BCR-ABL positive leukemias, but its role in BCR-ABL negative ALL is conjectural. Moreover, the functional contribution of individual components of the PI3K pathway in ALL has not been established.

We compared the activity of the ATP-competitive pan-PI3K inhibitor NVP-BKM120, the allosteric mTORC1 inhibitor RAD001, the ATP-competitive dual PI3K/mTORC1/C2 inhibitors NVP-BEZ235 and NVP-BGT226 and the combined mTORC1 and mTORC2 inhibitors Torin 1, PP242 and KU-0063794 using long-term cultures of ALL cells (ALL-LTC) from patients with B-precursor ALL that expressed the BCR-ABL or TEL-ABL oncoproteins or were BCR-ABL negative.

Dual PI3K/mTOR inhibitors profoundly inhibited growth and survival of ALL cells irrespective of their genetic subtype and their responsiveness to ABL-TKI. Combined suppression of PI3K, mTORC1 and mTORC2 displayed greater antileukemic activity than selective inhibitors of PI3K, mTORC1 or mTORC1 and mTORC2.

Inhibition of the PI3K/mTOR pathway is a promising therapeutic approach in patients with ALL. Greater antileukemic activity of dual PI3K/mTORC1/C2 inhibitors appears to be due to the redundant function of PI3K and mTOR. Clinical trials examining dual PI3K/mTORC1/C2 inhibitors in patients with B-precursor ALL are warranted, and should not be restricted to particular genetic subtypes.

• Adult
• Aged
• Aged, 80 and over
• Antigens, CD/metabolism
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/pathology
• Carcinoma, Squamous Cell/surgery
• Cohort Studies
• Disease-Free Survival
• Endoglin
• ErbB Receptors/metabolism
• Female
• Head and Neck Neoplasms/metabolism
• Head and Neck Neoplasms/pathology
• Head and Neck Neoplasms/surgery
• Humans
• Immunohistochemistry
• Laryngeal Neoplasms/metabolism
• Laryngeal Neoplasms/pathology
• Laryngeal Neoplasms/surgery
• Male
• Middle Aged
• Neovascularization, Pathologic/metabolism
• Neovascularization, Pathologic/pathology
• Prognosis
• Proto-Oncogene Mas
• Receptors, Cell Surface/metabolism
• Retrospective Studies
• Signal Transduction
• Squamous Cell Carcinoma of Head and Neck
• TOR Serine-Threonine Kinases/metabolism

Rapamycin is an allosteric inhibitor of mammalian target of rapamycin, and inhibits tumor growth and angiogenesis. Recent studies suggested a possibility that rapamycin renormalizes aberrant tumor vasculature and improves tumor oxygenation. The longitudinal effects of rapamycin on angiogenesis and tumor oxygenation were evaluated in murine squamous cell carcinoma (SCCVII) by electron paramagnetic resonance imaging (EPRI) and magnetic resonance imaging (MRI) to identify an optimal time after rapamycin treatment for enhanced tumor radioresponse. Rapamycin treatment was initiated on SCCVII solid tumors 8 days after implantation (500–750 mm³) and measurements of tumor pO₂ and blood volume were conducted from day 8 to 14 by EPRI/MRI. Microvessel density was evaluated over the same time period by immunohistochemical analysis. Tumor blood volume as measured by MRI significantly decreased 2 days after rapamycin treatment. Tumor pO₂ levels modestly but significantly increased 2 days after rapamycin treatment; whereas, it decreased in non-treated control tumors. Furthermore, the fraction of hypoxic area (pixels with pO₂<10 mm Hg) in the tumor region decreased 2 days after rapamycin treatments. Immunohistochemical analysis of tumor microvessel density and pericyte coverage revealed that microvessel density decreased 2 days after rapamycin treatment, but pericyte coverage did not change, similar to what was seen with anti-angiogenic agents such as sunitinib which cause vascular renormalization. Collectively, EPRI/MRI co-imaging can provide non-invasive evidence of rapamycin-induced vascular renormalization and resultant transient increase in tumor oxygenation. Improved oxygenation by rapamycin treatment provides a temporal window for anti-cancer therapies to realize enhanced response to radiotherapy.

• Cancer treatment
• Cell proliferation
• Mammalian target of rapamycin inhibition
• Mammalian target of rapamycin pathway
• Protooncogenes
• Transplant patients
• Tumor suppressors

• Animals
• Biomarkers, Pharmacological/analysis
• Cell Line, Tumor
• Disease Progression
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Female
• Infusions, Intravenous
• Mammary Neoplasms, Experimental/drug therapy
• Mice
• Mice, Transgenic
• Protein Kinase Inhibitors/administration & dosage
• Protein Kinase Inhibitors/pharmacokinetics
• Protein Kinase Inhibitors/pharmacology
• Signal Transduction/drug effects
• Sirolimus/administration & dosage
• Sirolimus/analogs & derivatives
• Sirolimus/pharmacokinetics
• Sirolimus/pharmacology
• TOR Serine-Threonine Kinases/analysis
• TOR Serine-Threonine Kinases/antagonists & inhibitors
• Translational Research, Biomedical/methods
• Tumor Burden/drug effects
• Xenograft Model Antitumor Assays

• Animals
• Humans
• Lipid Metabolism
• Male
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Multiprotein Complexes
• Nuclear Proteins/metabolism
• Phosphatidate Phosphatase
• Proteins/metabolism
• Signal Transduction
• Sterol Regulatory Element Binding Protein 1/metabolism
• Sterol Regulatory Element Binding Protein 2/metabolism
• TOR Serine-Threonine Kinases

• R01 CA103866 NCI NIH HHS
• R01 CA103866-09 NCI NIH HHS
• R01 GM089652-01 NIGMS NIH HHS
• Howard Hughes Medical Institute
• R01 AI47389 NIAID NIH HHS
• R01 DK078187 NIDDK NIH HHS
• R01 CA103866-08 NCI NIH HHS
• R01 CA129105 NCI NIH HHS
• R01 CA129105-04 NCI NIH HHS
• R01 CA129105-05 NCI NIH HHS
• R37 AI047389 NIAID NIH HHS
• R01 GM089652 NIGMS NIH HHS

A challenge in cancer therapy has been to identify targets whose function is essential for survival of malignant cells but not normal cells. This Perspective discusses recent evidence that novel inhibitors of the kinase TOR can provide an unprecedented balance of anti-cancer efficacy and tolerability.

The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation. mTOR signaling is frequently dysregulated in oncogenic cells, and thus an attractive target for anticancer therapy. Using CellDesigner, a modeling support software for graphical notation, we present herein a comprehensive map of the mTOR signaling network, which includes 964 species connected by 777 reactions. The map complies with both the systems biology markup language (SBML) and graphical notation (SBGN) for computational analysis and graphical representation, respectively. As captured in the mTOR map, we review and discuss our current understanding of the mTOR signaling network and highlight the impact of mTOR feedback and crosstalk regulations on drug-based cancer therapy. This map is available on the Payao platform, a Web 2.0 based community-wide interactive process for creating more accurate and information-rich databases. Thus, this comprehensive map of the mTOR network will serve as a tool to facilitate systems-level study of up-to-date mTOR network components and signaling events toward the discovery of novel regulatory processes and therapeutic strategies for cancer.

Cutaneous malignant melanoma is the most lethal form of skin cancer and an increasingly common disease worldwide. It remains one of the most treatment-refractory malignancies. The current treatment options for patients with metastatic melanoma are limited and in most cases non-curative. This review focuses on conventional chemotherapeutic drugs for melanoma treatment, by a single or combinational agent approach, but also summarizes some potential novel phytoagents discovered from dietary vegetables or traditional herbal medicines as alternative options or future medicine for melanoma prevention. We explore the mode of actions of these natural phytoagents against metastatic melanoma.