RESUMO
Vincristine, a widely used chemotherapeutic agent for treating different cancer, often induces severe peripheral neuropathic pain. A common symptom of vincristine-induced peripheral neuropathic pain is mechanical allodynia and hyperalgesia. However, mechanisms underlying vincristine-induced mechanical allodynia and hyperalgesia are not well understood. In the present study, we show with behavioral assessment in rats that vincristine induces mechanical allodynia and hyperalgesia in a PIEZO2 channel-dependent manner since gene knockdown or pharmacological inhibition of PIEZO2 channels alleviates vincristine-induced mechanical hypersensitivity. Electrophysiological results show that vincristine potentiates PIEZO2 rapidly adapting (RA) mechanically-activated (MA) currents in rat dorsal root ganglion (DRG) neurons. We have found that vincristine-induced potentiation of PIEZO2 MA currents is due to the enhancement of static plasma membrane tension (SPMT) of these cells following vincristine treatment. Reducing SPMT of DRG neurons by cytochalasin D (CD), a disruptor of the actin filament, abolishes vincristine-induced potentiation of PIEZO2 MA currents, and suppresses vincristine-induced mechanical hypersensitivity in rats. Collectively, enhancing SPMT and subsequently potentiating PIEZO2 MA currents in primary afferent neurons may be an underlying mechanism responsible for vincristine-induced mechanical allodynia and hyperalgesia in rats. Targeting to inhibit PIEZO2 channels may be an effective analgesic method to attenuate vincristine-induced mechanical hypersensitivity.
RESUMO
Migration and invasion are the most important characteristics of human malignancies which limit cancer drug therapies in the clinic. Tongue squamous cell carcinoma (TSCC) is one of the rarest types of cancer, although it is characterized by a higher incidence, rapid growth and greater potential for metastasis compared with other oral neoplasms worldwide. Studies have demonstrated that the phenolic compound obovatol exhibits antitumor effects. However, the potential mechanisms underlying obovatolmediated signaling pathways have not been completely elucidated in TSCC. The present study investigated the antitumor effects and potential molecular mechanisms mediated by obovatol in TSCC cells and tissues. The results of the present study demonstrated that obovatol exerted cytotoxicity in SCC9 TSCC cells, and inhibited their migration and invasion. In addition, obovatol induced apoptosis in SCC9 TSCC cells by increasing caspase 9/3 and apoptotic protease enhancing factor 1 expression levels. Western blot analysis demonstrated that obovatol inhibited the expression of proepidermal growth factor (EGF), Janus kinase (JAK), and signal transducer and activator of transcription (STAT) in SCC9 TSCC cells. A study of the molecular mechanisms demonstrated that depletion of EGF reversed the obovatolmediated inhibition of SCC9 TSCC cell growth and aggressiveness. Animal experiments indicated that obovatol significantly inhibited TSCC tumor growth and increased the number of apoptotic cells in tumor tissues. In conclusion, the results of the present study provided scientific evidence that obovatol inhibited TSCC cell growth and aggressiveness through the EGFmediated JAKSTAT signaling pathway, suggesting that obovatol may be a potential antiTSCC agent.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Compostos de Bifenilo/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Fator de Crescimento Epidérmico/genética , Janus Quinases/genética , Éteres Fenílicos/farmacologia , Fatores de Transcrição STAT/genética , Neoplasias da Língua/tratamento farmacológico , Animais , Antígenos CD , Proteína Quinase CDC2/genética , Proteína Quinase CDC2/metabolismo , Caderinas/genética , Caderinas/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Janus Quinases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Neoplasias da Língua/genética , Neoplasias da Língua/metabolismo , Neoplasias da Língua/patologia , Vimentina/genética , Vimentina/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hepatocellular carcinoma (HCC) is the fifth most prevalent malignancy and the third leading cause of cancer-related deaths worldwide. More effective cures for HCC patients are urgently needed, of which gene therapy is among those with the most potential. We previously developed a novel gene carrier by conjugating low molecular weight chitosan with TAT (transactivator of transcription) peptide and LHRH (luteinizing hormone-releasing hormone) analog, with the resultant TAT-LHRH-chitosan conjugate (TLC) demonstrating high selectivity for hepatoma cells in vitro. However, it remains unclear whether TLC can deliver the genes to the target organs and tissues in vivo, which is one of the critical features determining their medical application potential. The current study further investigated the in vivo distribution of TLC/DNA nanoparticles (TLCDNPs) in the nude mice with subcutaneous hepatoma xenografts. It was found that TLCDNPs delayed the renal clearance of DNA and prolonged its circulation time as compared with CS/DNA complexes (CDNPs) and naked DNA, but failed to demonstrate enhanced accumulation of DNA in the hepatoma xenografts. The mechanisms regarding the failure of TLCDNPs' tumor targeting in the mice bearing subcutaneous hepatoma xenografts remain unclear and need to be further addressed. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2394-2400, 2016.
