Artesunate induces mitochondria-mediated apoptosis of human retinoblastoma cells by upregulating Kruppel-like factor 6
| Autor: | Yihui Wu, Qianying Gao, Jing Zhuang, Jieting Zeng, Jin Qiu, Haoting Chen, Kin Chiu, Xiaobing Qian, Nandan Wu, Ying Yang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Transcriptional Activation
Cancer Research Immunology Artesunate Apoptosis Article Eye cancer Cellular and Molecular Neuroscience Antimalarials Mice In vivo Cell Line Tumor medicine Kruppel-Like Factor 6 Gene silencing Animals Humans Viability assay lcsh:QH573-671 Cell Proliferation Retinoblastoma business.industry Cell growth lcsh:Cytology Drug Repositioning Cell Biology medicine.disease eye diseases Mitochondria Rats Gene Expression Regulation Neoplastic Disease Models Animal KLF6 Cell culture Drug delivery Cancer research Heterografts business |
| Zdroj: | Cell Death & Disease Cell Death and Disease, Vol 10, Iss 11, Pp 1-12 (2019) |
| ISSN: | 2041-4889 |
| Popis: | Retinoblastoma (RB) is the most common primary intraocular malignancy in children. Intravitreal chemotherapy achieves favorable clinical outcomes in controlling RB vitreous seeds, which are a common reason for treatment failure. Thus, a novel, effective and safe intravitreal chemotherapeutic drug is urgently required. The malaria drug artesunate (ART) recently demonstrated remarkable anticancer effects with mild side effects. The purpose of this study is to investigate the anti-RB efficacy, the underlying mechanism and the intraocular safety of ART. Herein, we verified that ART inhibits RB cell viability and induces cell apoptosis in a dose- and time-dependent manner. Microarray analysis revealed that Kruppel-like factor 6 (KLF6) was upregulated after ART treatment, and this was further confirmed by real-time PCR and western blot assays. Silencing of KLF6 expression significantly reversed ART-induced RB cell growth inhibition and apoptosis. Furthermore, ART activated mitochondria-mediated apoptosis of RB cells, while silencing KLF6 expression significantly inhibited this effect. In murine xenotransplantation models of RB, we further confirmed that ART inhibits RB tumor growth, induces tumor cell apoptosis and upregulates KLF6 expression. In addition, KLF6 silencing attenuates ART-mediated inhibition of tumor growth in vivo. Furthermore, we proved that intravitreal injection of ART in Sprague-Dawley (SD) rats is safe, with no obvious retinal function damage or structural disorders observed by electrophysiology (ERG), fundal photographs, fundus fluorescein angiography (FFA) or optical coherence tomography (OCT) examinations. Collectively, our study revealed that ART induces mitochondrial apoptosis of RB cells via upregulating KLF6, and our results may extend the application of ART to the clinic as an effective and safe intravitreal chemotherapeutic drug to treat RB, especially RB with vitreous seeds. |
| Databáze: | OpenAIRE |
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