PMID- 31723124
OWN - NLM
STAT- MEDLINE
DCOM- 20200826
LR  - 20210110
IS  - 2041-4889 (Electronic)
VI  - 10
IP  - 11
DP  - 2019 Nov 13
TI  - Artesunate induces mitochondria-mediated apoptosis of human retinoblastoma cells 
      by upregulating Kruppel-like factor 6.
PG  - 862
LID - 10.1038/s41419-019-2084-1 [doi]
LID - 862
AB  - 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.
FAU - Yang, Ying
AU  - Yang Y
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen 
      University, Guangzhou, 510060, P. R. China.
FAU - Wu, Nandan
AU  - Wu N
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen 
      University, Guangzhou, 510060, P. R. China.
FAU - Wu, Yihui
AU  - Wu Y
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen 
      University, Guangzhou, 510060, P. R. China.
FAU - Chen, Haoting
AU  - Chen H
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen 
      University, Guangzhou, 510060, P. R. China.
FAU - Qiu, Jin
AU  - Qiu J
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen 
      University, Guangzhou, 510060, P. R. China.
FAU - Qian, Xiaobing
AU  - Qian X
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen 
      University, Guangzhou, 510060, P. R. China.
FAU - Zeng, Jieting
AU  - Zeng J
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen 
      University, Guangzhou, 510060, P. R. China.
FAU - Chiu, Kin
AU  - Chiu K
AD  - Department of Ophthalmology, The University of Hong Kong, Hong Kong SAR, P. R. 
      China.
FAU - Gao, Qianying
AU  - Gao Q
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen 
      University, Guangzhou, 510060, P. R. China. gaoqy@hotmail.com.
AD  - Department of Ophthalmology, The 2nd Affiliate Hospital, Wenzhou Medical 
      University, Wenzhou, 325000, P. R. China. gaoqy@hotmail.com.
FAU - Zhuang, Jing
AU  - Zhuang J
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen 
      University, Guangzhou, 510060, P. R. China. zhuangj@mail.sysu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191113
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Antimalarials)
RN  - 0 (KLF6 protein, human)
RN  - 0 (Kruppel-Like Factor 6)
RN  - 60W3249T9M (Artesunate)
SB  - IM
MH  - Animals
MH  - Antimalarials/pharmacology
MH  - Apoptosis/drug effects
MH  - Artesunate/*pharmacology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Disease Models, Animal
MH  - Drug Repositioning
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Heterografts
MH  - Humans
MH  - Kruppel-Like Factor 6/*genetics
MH  - Mice
MH  - Mitochondria/drug effects
MH  - Rats
MH  - Retinoblastoma/*drug therapy/genetics/pathology
MH  - Transcriptional Activation/drug effects
PMC - PMC6853908
COIS- The authors declare that they have no conflict of interest.
EDAT- 2019/11/15 06:00
MHDA- 2020/08/28 06:00
PMCR- 2019/11/13
CRDT- 2019/11/15 06:00
PHST- 2019/04/11 00:00 [received]
PHST- 2019/10/17 00:00 [accepted]
PHST- 2019/09/29 00:00 [revised]
PHST- 2019/11/15 06:00 [entrez]
PHST- 2019/11/15 06:00 [pubmed]
PHST- 2020/08/28 06:00 [medline]
PHST- 2019/11/13 00:00 [pmc-release]
AID - 10.1038/s41419-019-2084-1 [pii]
AID - 2084 [pii]
AID - 10.1038/s41419-019-2084-1 [doi]
PST - epublish
SO  - Cell Death Dis. 2019 Nov 13;10(11):862. doi: 10.1038/s41419-019-2084-1.