RESUMO
Paclitaxel resistance is associated with a poor prognosis in non-small cell lung cancer (NSCLC) patients, and currently, there is no promising drug for paclitaxel resistance. In this study, we investigated the molecular mechanisms underlying the chemoresistance in human NSCLC-derived cell lines. We constructed paclitaxel-resistant NSCLC cell lines (A549/PR and H460/PR) by long-term exposure to paclitaxel. We found that triptolide, a diterpenoid epoxide isolated from the Chinese medicinal herb Tripterygium wilfordii Hook F, effectively enhanced the sensitivity of paclitaxel-resistant cells to paclitaxel by reducing ABCB1 expression in vivo and in vitro. Through high-throughput sequencing, we identified the SHH-initiated Hedgehog signaling pathway playing an important role in this process. We demonstrated that triptolide directly bound to HNF1A, one of the transcription factors of SHH, and inhibited HNF1A/SHH expression, ensuing in attenuation of Hedgehog signaling. In NSCLC tumor tissue microarrays and cancer network databases, we found a positive correlation between HNF1A and SHH expression. Our results illuminate a novel molecular mechanism through which triptolide targets and inhibits HNF1A, thereby impeding the activation of the Hedgehog signaling pathway and reducing the expression of ABCB1. This study suggests the potential clinical application of triptolide and provides promising prospects in targeting the HNF1A/SHH pathway as a therapeutic strategy for NSCLC patients with paclitaxel resistance. Schematic diagram showing that triptolide overcomes paclitaxel resistance by mediating inhibition of the HNF1A/SHH/ABCB1 axis.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Diterpenos , Resistencia a Medicamentos Antineoplásicos , Compostos de Epóxi , Proteínas Hedgehog , Fator 1-alfa Nuclear de Hepatócito , Neoplasias Pulmonares , Paclitaxel , Fenantrenos , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Humanos , Fenantrenos/farmacologia , Fenantrenos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Hedgehog/metabolismo , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , Animais , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Camundongos Nus , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Camundongos , Camundongos Endogâmicos BALB C , Células A549RESUMO
BACKGROUND: This study will assess the effectiveness and safety of acupuncture for the treatment of patients with diabetic peripheral neuropathy (DPN). METHODS: We will comprehensively search electronic databases of MEDLINE, EMBASE, Cochrane Library, Web of Science, Chinese Biomedical Literature Database, Chinese Scientific Journal Database, and China National Knowledge Infrastructure from their inception to July 1, 2019. We will also search grey literature to avoid missing any potential studies. Randomized controlled trials related to acupuncture for the treatment of DPN will be included. All record literatures are searched without language limitation. Two researchers will independently carry out research selection, data extraction, and research quality evaluation. We will perform RevMan 5.3 software for statistical analysis. RESULTS: Primary outcomes consist of severity of neuropathy and pain intensity. Secondary outcomes include diabetes mellitus duration, body mass index, HbA1c level, blood glucose levels, and adverse events. CONCLUSION: The findings of this study will summarize recent evidence for the effectiveness and safety of acupuncture for the treatment of patients with DPN. ETHICS AND DISSEMINATION: We will not analyze individual data, thus no ethic approval is needed. The results of this study are expected to be published at a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019139635.