Using bio-orthogonally catalyzed lethality strategy to generate mitochondria-targeting anti-tumor metallodrugs in vitro and in vivo
© The Author(s) 2020. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd..
Synthetic lethality was proposed nearly a century ago by geneticists and recently applied to develop precision anti-cancer therapies. To exploit the synthetic lethality concept in the design of chemical anti-cancer agents, we developed a bio-orthogonally catalyzed lethality (BCL) strategy to generate targeting anti-tumor metallodrugs both in vitro and in vivo. Metallodrug Ru-rhein was generated from two non-toxic species Ru-N3 and rhein-alkyne via exclusive endogenous copper-catalyzed azide alkyne cycloaddition (CuAAC) reaction without the need of an external copper catalyst. The non-toxic species Ru-arene complex Ru-N3 and rhein-alkyne were designed to perform this strategy, and the mitochondrial targeting product Ru-rhein was generated in high yield (>83%) and showed high anti-tumor efficacy in vitro. This BCL strategy achieved a remarkable tumor suppression effect on the tumor-bearing mice models. It is interesting that the combination of metal-arene complexes with rhein via CuAAC reaction could transform two non-toxic species into a targeting anti-cancer metallodrug both in vitro and in vivo, while the product Ru-rhein was non-toxic towards normal cells. This is the first example that exclusive endogenous copper was used to generate metal-based anti-cancer drugs for cancer treatment. The anti-cancer mechanism of Ru-rhein was studied and autophagy was induced by increased reactive oxygen species and mitochondrial damage. The generality of this BCL strategy was also studied and it could be extended to other metal complexes such as Os-arene and Ir-arene complexes. Compared with the traditional methods for cancer treatment, this work presented a new approach to generating targeting metallodrugs in vivo via the BCL strategy from non-toxic species in metal-based chemotherapy.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
|---|---|
| Enthalten in: |
National science review - 8(2021), 9 vom: 07. Sept., Seite nwaa286 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Xue, Xuling [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Bio-orthogonal reaction |
|---|
| Anmerkungen: |
Date Revised 26.10.2021 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.1093/nsr/nwaa286 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM332318257 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM332318257 | ||
| 003 | DE-627 | ||
| 005 | 20231225215334.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1093/nsr/nwaa286 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1107.xml |
| 035 | |a (DE-627)NLM332318257 | ||
| 035 | |a (NLM)34691728 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Xue, Xuling |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Using bio-orthogonally catalyzed lethality strategy to generate mitochondria-targeting anti-tumor metallodrugs in vitro and in vivo |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 26.10.2021 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © The Author(s) 2020. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd. | ||
| 520 | |a Synthetic lethality was proposed nearly a century ago by geneticists and recently applied to develop precision anti-cancer therapies. To exploit the synthetic lethality concept in the design of chemical anti-cancer agents, we developed a bio-orthogonally catalyzed lethality (BCL) strategy to generate targeting anti-tumor metallodrugs both in vitro and in vivo. Metallodrug Ru-rhein was generated from two non-toxic species Ru-N3 and rhein-alkyne via exclusive endogenous copper-catalyzed azide alkyne cycloaddition (CuAAC) reaction without the need of an external copper catalyst. The non-toxic species Ru-arene complex Ru-N3 and rhein-alkyne were designed to perform this strategy, and the mitochondrial targeting product Ru-rhein was generated in high yield (>83%) and showed high anti-tumor efficacy in vitro. This BCL strategy achieved a remarkable tumor suppression effect on the tumor-bearing mice models. It is interesting that the combination of metal-arene complexes with rhein via CuAAC reaction could transform two non-toxic species into a targeting anti-cancer metallodrug both in vitro and in vivo, while the product Ru-rhein was non-toxic towards normal cells. This is the first example that exclusive endogenous copper was used to generate metal-based anti-cancer drugs for cancer treatment. The anti-cancer mechanism of Ru-rhein was studied and autophagy was induced by increased reactive oxygen species and mitochondrial damage. The generality of this BCL strategy was also studied and it could be extended to other metal complexes such as Os-arene and Ir-arene complexes. Compared with the traditional methods for cancer treatment, this work presented a new approach to generating targeting metallodrugs in vivo via the BCL strategy from non-toxic species in metal-based chemotherapy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a bio-orthogonal reaction | |
| 650 | 4 | |a bio-orthogonally catalyzed lethality | |
| 650 | 4 | |a cancer therapy | |
| 650 | 4 | |a metallodrug | |
| 650 | 4 | |a mitochondrial targeting | |
| 700 | 1 | |a Qian, Chenggen |e verfasserin |4 aut | |
| 700 | 1 | |a Tao, Qin |e verfasserin |4 aut | |
| 700 | 1 | |a Dai, Yuanxin |e verfasserin |4 aut | |
| 700 | 1 | |a Lv, Mengdi |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, Jingwen |e verfasserin |4 aut | |
| 700 | 1 | |a Su, Zhi |e verfasserin |4 aut | |
| 700 | 1 | |a Qian, Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Hong-Ke |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Zijian |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t National science review |d 2014 |g 8(2021), 9 vom: 07. Sept., Seite nwaa286 |w (DE-627)NLM243751931 |x 2053-714X |7 nnns |
| 773 | 1 | 8 | |g volume:8 |g year:2021 |g number:9 |g day:07 |g month:09 |g pages:nwaa286 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1093/nsr/nwaa286 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 8 |j 2021 |e 9 |b 07 |c 09 |h nwaa286 | ||