St-N, a novel alkaline derivative of stevioside, reverses docetaxel resistance by targeting lysosomes in vitro and in vivo.
Drug resistance of cancers remains a major obstacle due to limited therapeutics. Lysosome targeting is an effective method for overcoming drug resistance in cancer cells. St-N (ent-13-hydroxy-15-kaurene-19-acid N-methylpiperazine ethyl ester) is a novel alkaline stevioside derivative with an amine g...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2024-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0316268 |
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| author | Yanxia Guo Shikang Wang Qun Liu Yan Dong Yongqing Liu |
| author_facet | Yanxia Guo Shikang Wang Qun Liu Yan Dong Yongqing Liu |
| author_sort | Yanxia Guo |
| collection | DOAJ |
| description | Drug resistance of cancers remains a major obstacle due to limited therapeutics. Lysosome targeting is an effective method for overcoming drug resistance in cancer cells. St-N (ent-13-hydroxy-15-kaurene-19-acid N-methylpiperazine ethyl ester) is a novel alkaline stevioside derivative with an amine group. In this study, we found that docetaxel (Doc)-resistant prostate cancer (PCa) cells were sensitive to St-N. Mechanistically, the alkaline characteristic of St-N led to targeting lysosomes, as evidenced by lysosomal swelling and rupture through transmission electron microscopy and Lyso-tracker Red staining. St-N destabilized lysosomal membrane by impairing lysosomal membrane proteins and acid sphingomyelinase. As a result, St-N caused cathepsins to release from the lysosomes into the cytosol, eventually triggering apoptotic and necrotic cell death. Meanwhile, the cytoprotective role of lysosomal activation under docetaxel treatment was interrupted by St-N, leading to significant synergistic cytotoxicity of docetaxel and St-N. In docetaxel-resistant PCa homograft mice, St-N significantly inhibited the growth of RM-1/Doc homografts and enhanced the anticancer effects of docetaxel, but did not show significant toxicity. Taken together, these findings demonstrated that St-N reversed docetaxel resistance in vitro and in vivo by destabilizing lysosomal membranes to promote cell death, thus providing a strong rationale for applying St-N in docetaxel-resistant PCa. |
| format | Article |
| id | doaj-art-24392c42cd8a4d9e84c70bcccc99a280 |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-24392c42cd8a4d9e84c70bcccc99a2802025-08-20T02:44:12ZengPublic Library of Science (PLoS)PLoS ONE1932-62032024-01-011912e031626810.1371/journal.pone.0316268St-N, a novel alkaline derivative of stevioside, reverses docetaxel resistance by targeting lysosomes in vitro and in vivo.Yanxia GuoShikang WangQun LiuYan DongYongqing LiuDrug resistance of cancers remains a major obstacle due to limited therapeutics. Lysosome targeting is an effective method for overcoming drug resistance in cancer cells. St-N (ent-13-hydroxy-15-kaurene-19-acid N-methylpiperazine ethyl ester) is a novel alkaline stevioside derivative with an amine group. In this study, we found that docetaxel (Doc)-resistant prostate cancer (PCa) cells were sensitive to St-N. Mechanistically, the alkaline characteristic of St-N led to targeting lysosomes, as evidenced by lysosomal swelling and rupture through transmission electron microscopy and Lyso-tracker Red staining. St-N destabilized lysosomal membrane by impairing lysosomal membrane proteins and acid sphingomyelinase. As a result, St-N caused cathepsins to release from the lysosomes into the cytosol, eventually triggering apoptotic and necrotic cell death. Meanwhile, the cytoprotective role of lysosomal activation under docetaxel treatment was interrupted by St-N, leading to significant synergistic cytotoxicity of docetaxel and St-N. In docetaxel-resistant PCa homograft mice, St-N significantly inhibited the growth of RM-1/Doc homografts and enhanced the anticancer effects of docetaxel, but did not show significant toxicity. Taken together, these findings demonstrated that St-N reversed docetaxel resistance in vitro and in vivo by destabilizing lysosomal membranes to promote cell death, thus providing a strong rationale for applying St-N in docetaxel-resistant PCa.https://doi.org/10.1371/journal.pone.0316268 |
| spellingShingle | Yanxia Guo Shikang Wang Qun Liu Yan Dong Yongqing Liu St-N, a novel alkaline derivative of stevioside, reverses docetaxel resistance by targeting lysosomes in vitro and in vivo. PLoS ONE |
| title | St-N, a novel alkaline derivative of stevioside, reverses docetaxel resistance by targeting lysosomes in vitro and in vivo. |
| title_full | St-N, a novel alkaline derivative of stevioside, reverses docetaxel resistance by targeting lysosomes in vitro and in vivo. |
| title_fullStr | St-N, a novel alkaline derivative of stevioside, reverses docetaxel resistance by targeting lysosomes in vitro and in vivo. |
| title_full_unstemmed | St-N, a novel alkaline derivative of stevioside, reverses docetaxel resistance by targeting lysosomes in vitro and in vivo. |
| title_short | St-N, a novel alkaline derivative of stevioside, reverses docetaxel resistance by targeting lysosomes in vitro and in vivo. |
| title_sort | st n a novel alkaline derivative of stevioside reverses docetaxel resistance by targeting lysosomes in vitro and in vivo |
| url | https://doi.org/10.1371/journal.pone.0316268 |
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