RESUMO
Glioma is the most common primary intracranial tumor, in which glioblastoma (GBM) is the most malignant and lethal. However, the current chemotherapy drugs are still unsatisfactory for GBM therapy. As the natural products mainly extracted from Eucalyptus species, phloroglucinol-terpene adducts have the potential to be anti-cancer lead compounds that attracted increasing attention. In order to discover the new lead compounds with the anti-GBM ability, we isolated Eucalyptal A with a phloroglucinol-terpene skeleton from the fruit of E. globulus and investigated its anti-GBM activity in vitro and in vivo. Functionally, we verified that Eucalyptal A could inhibit the proliferation, growth and invasiveness of GBM cells in vitro. Moreover, Eucalyptal A had the same anti-GBM activity in tumor-bearing mice as in vitro and prolonged the overall survival time by maintaining mice body weight. Further mechanism research revealed that Eucalyptal A downregulated SRSF1 expression and rectified SRSF1-guided abnormal alternative splicing of MYO1B mRNA, which led to anti-GBM activity through the PDK1/AKT/c-Myc and PAK/Cofilin axes. Taken together, we identified Eucalyptal A as an important anti-GBM lead compound, which represents a novel direction for glioma therapy.
Assuntos
Neoplasias Encefálicas/metabolismo , Carcinogênese/efeitos dos fármacos , Eucaliptol/uso terapêutico , Glioma/metabolismo , Miosina Tipo I/metabolismo , Processamento de Proteína/efeitos dos fármacos , Fatores de Processamento de Serina-Arginina/biossíntese , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/prevenção & controle , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Eucaliptol/isolamento & purificação , Eucaliptol/farmacologia , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/prevenção & controle , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Miosina Tipo I/genética , Processamento de Proteína/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Processamento de Serina-Arginina/antagonistas & inibidores , Fatores de Processamento de Serina-Arginina/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
SUMMARY: Cellular senescence is a state of stable cell cycle arrest that has increasingly been linked with cellular, tissue, and organismal aging; targeted removal of senescent cells brings healthspan and lifespan benefits in animal models. Newly emerging approaches to specifically ablate or rejuvenate senescent cells are now the subject of intense study to explore their utility to provide novel treatments for the aesthetic signs and diseases of aging in humans. Here, we discuss different strategies that are being trialed in vitro, and more recently in vivo, for the targeted removal or reversal of senescent cells. Finally, we describe the evidence for a newly emerging molecular mechanism that may underpin senescence; dysregulation of alternative splicing. We will explore the potential of restoring splicing regulation as a novel "senotherapeutic" approach and discuss strategies by which this could be integrated into the established portfolio of skin aging therapeutics.