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

10.1186/s13020-022-00605-8

Chinese Medicine   影响因子和分区

1749-8546

1749-8546

["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 ofTSN 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."]

Autophagy inhibition Toosendanin Triple-negative breast cancer Lysosome Irinotecan SN-38 Apoptosis

SCI

英语

其他

Science and Technology Development Fund, Macau SAR["0110/2018/A3","0128/2019/A3"] ; 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund[2020B1212030006] ; University of Macau[MYRG2019-00129-ICMS]

Integrative & Complementary Medicine ; Pharmacology & Pharmacy

Integrative & Complementary Medicine ; Pharmacology & Pharmacy

WOS:000791789900002

BMC

2-s2.0-85129733112

Web of Science

1.Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Taipa 999078, Macao, Peoples R China
2.Univ Macau, Guangdong Hong Kong Macau Joint Lab Chinese Med &, Taipa 999078, Macao, Peoples R China
3.Southern Univ Sci & Technol, Coll Sci, Dept Chem, Shenzhen 518055, Peoples R China
4.Hong Kong Baptist Univ, Mr & Mrs Ko Chi Ming Ctr Parkinsons Dis Res, Sch Chinese Med, Hong Kong, Peoples R China
5.Univ Macau, MOE Frontier Sci Ctr Precis Oncol, Taipa, Macao, Peoples R China

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,2022,17(1).

Zhang, Shuang.,Dong, Yu.,Chen, Xiuping.,Tan, Chris Soon Heng.,Li, Min.,...&Lu, Jia-Hong.(2022).Toosendanin, a late-stage autophagy inhibitor, sensitizes triple-negative breast cancer to irinotecan chemotherapy.Chinese Medicine,17(1).

Zhang, Shuang,et al."Toosendanin, a late-stage autophagy inhibitor, sensitizes triple-negative breast cancer to irinotecan chemotherapy".Chinese Medicine 17.1(2022).