RESUMO
Endoplasmic reticulum (ER) stress and the subsequent adaptive cellular response, termed the unfolded protein response (UPR), have been implicated in several diseases, including cancer. In this review, I present a brief introduction to ER stress and the UPR and then summarize the importance of the IRE1α-XBP1 branch as a target for anticancer drug discovery. In addition, I introduce our approach to the identification of inhibitors against the IRE1α-XBP1 branch from microbial cultures. As a result of our screening, toyocamycin has been identified and toyocamycin showed anticancer activity against multiple myeloma.
Assuntos
Antineoplásicos/farmacologia , Estresse do Retículo Endoplasmático/fisiologia , Endorribonucleases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteína 1 de Ligação a X-Box/antagonistas & inibidores , Animais , Antibióticos Antineoplásicos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endorribonucleases/antagonistas & inibidores , Humanos , Lactamas Macrocíclicas/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Rifabutina/análogos & derivados , Rifabutina/farmacologia , Toiocamicina/farmacologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Resposta a Proteínas não Dobradas/fisiologiaRESUMO
CONTEXT: Molecular pathogenesis of chronic alcoholism is linked to increased endoplasmic reticulum stress. Ethanol is a competitive inhibitor of vitamin A metabolism and vitamin A supplementation aggravates existing liver problems. Hence, we probed into the impact of supplementation of all trans retinoic acid (ATRA), the active metabolite of vitamin A on ethanol-induced endoplasmic reticulcum stress. METHODS: Male Sprague-Dawley rats were divided into four groups - I: Control; II: Ethanol; III: ATRA; IV: ATRA + Ethanol. After 90 days the animals were sacrificed to study markers of lipid peroxidation in hepatic microsomal fraction and expression of ER stress proteins and apoptosis in liver. RESULTS AND CONCLUSION: Ethanol caused hepatic hyperlipidemia, enhanced microsomal lipid peroxidation, upregulated expression of unfolded protein response associated proteins and that of apoptosis. Ethanol also led to downregulation of retinoid receptors. ATRA supplementation reversed all these alterations indicating the decrease in ethanol-induced endoplasmic reticulum stress.