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Toosendanin, a late-stage autophagy inhibitor, sensitizes triple-negative breast cancer to irinotecan chemotherapy
Zhang, Shuang1,2; Dong, Yu1,2; Chen, Xiuping1; Tan, Chris Soon Heng3; Li, Min4; Miao, Kai5; Lu, Jia Hong1,2
2022-05-06
Source PublicationChinese Medicine (United Kingdom)
ISSN1749-8546
Volume17Issue:1
Abstract

Background: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that develops resistance to chemotherapy frequently. Autophagy has been reported as a pro-survival response to chemotherapeutic drugs in TNBC, and suppression of autophagy can be a strategy to overcome drug resistance. Methods: The efficacy of toosendanin (TSN) in blocking autophagy flux was measured by western blot analysis of autophagy markers, and the fluorescent imaging of RFP-GFP-LC3 probe. The co-localization of autophagosomes and lysosomes was analyzed by fluorescent imaging. Then, lysosome function was determined by measuring the lysosomal pH value and the activity of lysosomal hydrolytic proteases. For in vitro study, human triple-negative breast cancer MDA-MB-231 and MDA-MB-436 cell lines were used for evaluating the anti-proliferative effect. For in vivo study, the RFP-GFP-LC3 MDA-MB-231 xenograft nude mice received intraperitoneal injection of irinotecan (10 mg/kg), TSN (0.5 mg/kg) or a combination, and the autophagy activity and cell apoptosis were determined in tumor tissue. The degree of pathological injury of tissue was evaluated by liver index. Results: The natural autophagy inhibitor TSN, a triterpenoid extracted from Melia toosenda Sieb. et Zucc, potently inhibited late-stage autophagy in TNBC cells. This effect was achieved via elevating lysosome pH rather than blocking the fusion of autophagosomes and lysosomes. We further investigated the effects of TSN on the in vitro and in vivo TNBC models, in combination with chemotherapeutic drug irinotecan (or its active metabolite 7-ethyl-10-hydroxycamptothecin), a topoisomerase I inhibitor showing therapeutic potential for TNBC. The data showed that TSN blocked 7-ethyl-10-hydroxycamptothecin (SN-38)/irinotecan-induced protective autophagy, and significantly induced apoptosis in TNBC cells and tumor xenograft models when compared to SN-38/irinotecan alone group. Graphical Abstract: [Figure not available: see fulltext.]

KeywordApoptosis Autophagy Inhibition Irinotecan Lysosome Sn-38 Toosendanin Triple-negative Breast Cancer
DOI10.1186/s13020-022-00605-8
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaIntegrative & Complementary Medicine ; Pharmacology & Pharmacy
WOS SubjectIntegrative & Complementary Medicine;pharmacology & Pharmacy
WOS IDWOS:000791789900002
Scopus ID2-s2.0-85129733112
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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, Taipa, SAR, 999078, Macao
2.Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, University of Macau, Taipa, SAR, 999078, Macao
3.Department of Chemistry, College of Science, Southern University of Science and Technology, Shenzhen, 518055, China
4.Mr. & Mrs. Ko Chi-Ming Centre for Parkinson’s Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong
5.MOE Frontier Science Centre for Precision Oncology, University of Macau, Taipa, SAR, Macao
First Author AffilicationInstitute of Chinese Medical Sciences;  University of Macau
Corresponding Author AffilicationInstitute of Chinese Medical Sciences;  University of Macau
Recommended Citation
GB/T 7714
Zhang, Shuang,Dong, Yu,Chen, Xiuping,et al. Toosendanin, a late-stage autophagy inhibitor, sensitizes triple-negative breast cancer to irinotecan chemotherapy[J]. Chinese Medicine (United Kingdom),2022,17(1).
APA Zhang, Shuang,Dong, Yu,Chen, Xiuping,Tan, Chris Soon Heng,Li, Min,Miao, Kai,&Lu, Jia Hong.(2022).Toosendanin, a late-stage autophagy inhibitor, sensitizes triple-negative breast cancer to irinotecan chemotherapy.Chinese Medicine (United Kingdom),17(1).
MLA Zhang, Shuang,et al."Toosendanin, a late-stage autophagy inhibitor, sensitizes triple-negative breast cancer to irinotecan chemotherapy".Chinese Medicine (United Kingdom) 17.1(2022).
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