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Natural autophagy blockers, dauricine (DAC) and daurisoline (DAS), sensitize cancer cells to camptothecin-induced toxicity
Wu, Ming-Yue1; Wang, Sheng-Fang1; Cai, Cui-Zan1; Tan, Jie-Qiong2; Li, Min3; Lu, Jin-Jian1; Chen, Xiu-Ping1; Wang, Yi-Tao1; Zheng, Wei4; Lu, Jia-Hong1
2017-09-29
Source PublicationONCOTARGET
ISSN1949-2553
Volume8Issue:44Pages:77673-77684
Abstract

Autophagy is a cellular bulk degradation pathway implicated in various diseases. Inhibition of autophagy has been regarded as a new therapeutic strategy for cancer treatment, especially in combination with chemotherapy. In our study, we identified two natural compounds, dauricine (DAC) and daurisoline (DAS), as two potent autophagy blockers through a high-content screening. DAC and DAS are alkaloids isolated from traditional Chinese medicine Rhizoma Menispermi. We systematically examined the effects of DAC and DAS on autophagy function in HeLa cells and found that DAC and DAS induced massive formation of autophagic vacuoles and lipidation of LC3. The accumulation of autophagic vacuoles and LC3 lipidation are due to blockage of autophagosome maturation as evidenced by interrupted colocalization of autophagsosome and lysosome, increased GFP-LC3/RFP-LC3 ratio and accumulation of autophagic substrate p62. Moreover, DAC and DAS impaired lysosomal function, as indicated by reduced lysosomal protease activity and increased lysosomal pH values. Importantly, we showed that DAC and DAS strongly inhibited the lysosome V-type ATPase activity. For the therapeutic potential, we found that DAC and DAS blocked the campothecin (CPT)-induced protective autophagy in HeLa cells, and dramatically sensitized the multiple cancer cells to CPT-induced cell death. In conclusion, our result shows that DAC and DAS are autophagy inhibitors which inhibit the lysosomal degradation of auophagic vacuoles, and sensitize the CPT-induced cancer cell death. The study implies the therapeutic potential of DAC and DAS in the treatment of cancers in combination of chemotherapy by inhibiting autophagy.

KeywordDauricine Daurisoline Autophagy Blocker Cancer Cells Cell Toxicity
DOIhttp://doi.org/10.18632/oncotarget.20767
URLView the original
Indexed BySCI
Language英语
WOS Research AreaOncology ; Cell Biology
WOS SubjectOncology ; Cell Biology
WOS IDWOS:000412066700149
PublisherIMPACT JOURNALS LLC
The Source to ArticleWOS
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Cited Times [WOS]:4   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorLu, Jia-Hong
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China
2.State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha, Hunan, China
3.Mr. and Mrs. Ko Chi Ming Centre for Parkinson’s Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
4.Department of Thyroid and Breast Surgery, The Third People’s Hospital of Shenzhen, Shenzhen, Guangdong, China
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Wu, Ming-Yue,Wang, Sheng-Fang,Cai, Cui-Zan,et al. Natural autophagy blockers, dauricine (DAC) and daurisoline (DAS), sensitize cancer cells to camptothecin-induced toxicity[J]. ONCOTARGET,2017,8(44):77673-77684.
APA Wu, Ming-Yue.,Wang, Sheng-Fang.,Cai, Cui-Zan.,Tan, Jie-Qiong.,Li, Min.,...&Lu, Jia-Hong.(2017).Natural autophagy blockers, dauricine (DAC) and daurisoline (DAS), sensitize cancer cells to camptothecin-induced toxicity.ONCOTARGET,8(44),77673-77684.
MLA Wu, Ming-Yue,et al."Natural autophagy blockers, dauricine (DAC) and daurisoline (DAS), sensitize cancer cells to camptothecin-induced toxicity".ONCOTARGET 8.44(2017):77673-77684.
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