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1.
ACS Chem Biol ; 17(12): 3290-3297, 2022 12 16.
Artículo en Inglés | MEDLINE | ID: mdl-36469692

RESUMEN

Autophagy is a conserved metabolic pathway that is central to many diseases. Recently, there has been a lot of interest in targeting autophagy with small molecule inhibitors as a possible therapeutic strategy. However, many of the compounds used for autophagy are nonselective. Here, we explored the inhibition of autophagy in pancreatic cancer cells using established selective small molecule inhibitors and discovered an unexpected link between the autophagy pathway and progression through the cell cycle. Our findings revealed that treatments with inhibitors that have different autophagy pathway targets block cell replication and activate other metabolic pathways to compensate for the blockade in autophagy. An unbiased screen looking for known drugs that might synergize with autophagy inhibition revealed new combination treatments that might provide a blueprint for therapeutic approaches to pancreatic cancer. The drugs quizartinib and THZ1 showed a strong synergistic effect in pancreatic cells with autophagy inhibition.


Asunto(s)
Autofagia , Ciclo Celular , Neoplasias Pancreáticas , Humanos , Autofagia/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Combinación de Medicamentos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas
2.
Eur J Pharmacol ; 554(1): 30-3, 2007 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-17112507

RESUMEN

The itch-associated responses evoked by intradermal injection of 12(S)-HPETE and leukotriene B4 were compared in ICR-mice. 12(S)-HPETE and leukotriene B4 (0.01-0.2 nmol/site) induced scratching of the injected site, respectively; the dose-responses were a peak at 0.05 nmol/site (12(S)-HPETE) or 0.03 nmol/site (leukotriene B4). The scratching response by 12(S)-HPETE (0.05 nmol/site) started within 1 min, peaked in the first 10 min period, had almost subsided by 25 min whereas the effect of leukotriene B4 peaked in the second 10 min. The effect of leukotriene B4 is slightly stronger than that of 12(S)-HPETE in 40 min of count. The scratching induced by 12(S)-HPETE was inhibited by capsaicin, naltrexon, and LY255283. These results suggest the possibility that 12-lipoxygenase product can be added to a new member of an endogenous itch mediator in the skin.


Asunto(s)
Prurito/inducido químicamente , Animales , Capsaicina/farmacología , Relación Dosis-Respuesta a Droga , Leucotrieno B4/farmacología , Leucotrienos/farmacología , Masculino , Ratones , Ratones Endogámicos ICR , Naltrexona/farmacología , Receptores de Leucotrieno B4/antagonistas & inhibidores
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