Toosendanin, a late-stage autophagy inhibitor, sensitizes triple-negative breast cancer to irinotecan chemotherapy
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 ov...
| Main Authors: | , , , , , , |
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| Format: | Article |
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BMC
2022-05-01
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| Series: | Chinese Medicine |
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| Online Access: | https://doi.org/10.1186/s13020-022-00605-8 |
| _version_ | 1817985484917309440 |
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| author | Shuang Zhang Yu Dong Xiuping Chen Chris Soon Heng TAN Min Li Kai Miao Jia-Hong Lu |
| author_facet | Shuang Zhang Yu Dong Xiuping Chen Chris Soon Heng TAN Min Li Kai Miao Jia-Hong Lu |
| author_sort | Shuang Zhang |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-04-13T23:57:51Z |
| format | Article |
| id | doaj.art-c3f86beebc584ef0a9b7452a26b3cff2 |
| institution | Directory Open Access Journal |
| issn | 1749-8546 |
| language | English |
| last_indexed | 2024-04-13T23:57:51Z |
| publishDate | 2022-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Chinese Medicine |
| spelling | doaj.art-c3f86beebc584ef0a9b7452a26b3cff22022-12-22T02:23:49ZengBMCChinese Medicine1749-85462022-05-0117111410.1186/s13020-022-00605-8Toosendanin, a late-stage autophagy inhibitor, sensitizes triple-negative breast cancer to irinotecan chemotherapyShuang Zhang0Yu Dong1Xiuping Chen2Chris Soon Heng TAN3Min Li4Kai Miao5Jia-Hong Lu6State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauDepartment of Chemistry, College of Science, Southern University of Science and TechnologyMr. & Mrs. Ko Chi-Ming Centre for Parkinson’s Disease Research, School of Chinese Medicine, Hong Kong Baptist UniversityMOE Frontier Science Centre for Precision Oncology, University of MacauState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauAbstract 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 Abstracthttps://doi.org/10.1186/s13020-022-00605-8Autophagy inhibitionToosendaninTriple-negative breast cancerLysosomeIrinotecanSN-38 |
| spellingShingle | Shuang Zhang Yu Dong Xiuping Chen Chris Soon Heng TAN Min Li Kai Miao Jia-Hong Lu Toosendanin, a late-stage autophagy inhibitor, sensitizes triple-negative breast cancer to irinotecan chemotherapy Chinese Medicine Autophagy inhibition Toosendanin Triple-negative breast cancer Lysosome Irinotecan SN-38 |
| title | Toosendanin, a late-stage autophagy inhibitor, sensitizes triple-negative breast cancer to irinotecan chemotherapy |
| title_full | Toosendanin, a late-stage autophagy inhibitor, sensitizes triple-negative breast cancer to irinotecan chemotherapy |
| title_fullStr | Toosendanin, a late-stage autophagy inhibitor, sensitizes triple-negative breast cancer to irinotecan chemotherapy |
| title_full_unstemmed | Toosendanin, a late-stage autophagy inhibitor, sensitizes triple-negative breast cancer to irinotecan chemotherapy |
| title_short | Toosendanin, a late-stage autophagy inhibitor, sensitizes triple-negative breast cancer to irinotecan chemotherapy |
| title_sort | toosendanin a late stage autophagy inhibitor sensitizes triple negative breast cancer to irinotecan chemotherapy |
| topic | Autophagy inhibition Toosendanin Triple-negative breast cancer Lysosome Irinotecan SN-38 |
| url | https://doi.org/10.1186/s13020-022-00605-8 |
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