Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drug combinations may provide a therapeutic benefit in treating cancer patients. However when considering a drug combination, it is important to assess how the molecular impact of the combination relates to the effects manifested by each drug alone and whether or not it varies depending on the tumor type. In this study, we have analyzed the molecular impact on a human leiomyosarcoma cell line (SK-LMS-1) of a combination consisting of the mTOR inhibitor rapamycin and either the anti-metabolite drug gemcitabine (Gemzar) or the protein tyrosine kinase inhibitor imatinib mesylate (Gleevec, STI571). We show that imatinib mesylate depolarizes the mitochondrial membrane potential (DeltaPhim) and inhibits protein tyrosine phosphorylation, but displays only minor effects on cell proliferation when added alone or in combin-ation with rapamycin. Gemcitabine or rapamycin, when added alone, inhibit protein tyrosine phosphorylation as well as phosphorylation of the MAP kinases ERK1/2. Both drugs also affect the cell cycle, arresting the cells at the S or G1 phase respectively. Rapamycin elevates significantly DeltaPhim but produces only a moderate effect on cell growth. Gemcitabine inhibits considerably cell growth but exerts no effect on DeltaPhim. Combining gemcitabine and rapamycin produces a major effect on the cell cycle, elevates the DeltaPhim even further and maintains the molecular impacts exerted by each single drug. Therefore, consistent with our clinical observation, these results suggest that combining gemcitabine and rapamycin may be beneficial in treating leiomyosarcoma patients.
 ...
PMID:Molecular impacts of rapamycin-based drug combinations: combining rapamycin with gemcitabine or imatinib mesylate (Gleevec) in a human leiomyosarcoma model. 1754 26

Autophagy is a critical regulator of cellular homeostasis, dysregulation of which is associated with diverse diseases. Here we show therapeutic effects of a novel autophagy enhancer identified by high-throughput screening of a chemical library against metabolic syndrome. An autophagy enhancer increases LC3-I to LC3-II conversion without mTOR inhibition. MSL, an autophagy enhancer, activates calcineurin, and induces dephosphorylation/nuclear translocation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy gene expression. MSL accelerates intracellular lipid clearance, which is reversed by lalistat 2 or Tfeb knockout. Its administration improves the metabolic profile of ob/ob mice and ameliorates inflammasome activation. A chemically modified MSL with increased microsomal stability improves the glucose profile not only of ob/ob mice but also of mice with diet-induced obesity. Our data indicate that our novel autophagy enhancer could be a new drug candidate for diabetes or metabolic syndrome with lipid overload.
 ...
PMID:A novel autophagy enhancer as a therapeutic agent against metabolic syndrome and diabetes. 3122 85