Beyond gold: the chemoenhancing mechanism and therapeutic potential of auranofin in melanoma
Objective: The objective of the current study was to evaluate the chemosensitizing capacity of auranofin (AF), a gold (I) complex traditionally used in rheumatoid arthritis treatment, in potentiating the cytotoxic effects of doxorubicin (DOX) in melanoma cell models, specifically drug-sensitive (B16...
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| Format: | Article |
| Language: | English |
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China Anti-Cancer Association
2025-06-01
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| Series: | Cancer Biology & Medicine |
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| Online Access: | https://www.cancerbiomed.org/content/22/6/672 |
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| author | Xiaofeng Wang Yingnan Liu Wuqiong Zhang Zhongda Li Su Li Jiaxin Chen Qi Li Xiaoman Suo Yanqiao Zeng Guofang Zhang Yang Li |
| author_facet | Xiaofeng Wang Yingnan Liu Wuqiong Zhang Zhongda Li Su Li Jiaxin Chen Qi Li Xiaoman Suo Yanqiao Zeng Guofang Zhang Yang Li |
| author_sort | Xiaofeng Wang |
| collection | DOAJ |
| description | Objective: The objective of the current study was to evaluate the chemosensitizing capacity of auranofin (AF), a gold (I) complex traditionally used in rheumatoid arthritis treatment, in potentiating the cytotoxic effects of doxorubicin (DOX) in melanoma cell models, specifically drug-sensitive (B16F10) and multidrug-resistant (B16F10/ADR) variants. Methods: Experimental measurements, including in vitro cytotoxicity and apoptosis assays, surface plasmon resonance (SPR), immunoblotting assays, as well as theoretical calculations, such as molecular docking and molecular dynamics (MD) simulations, were used to systematically delineate the interaction dynamics between AF and thioredoxin reductase 1 (TrxR1). The anti-tumor efficacy of co-treatment with AF and DOX was assessed by examining cell viability and apoptotic rates. Results: Co-treatment with AF and DOX significantly increased anti-tumor efficacy, as evidenced by reduced cell viability and increased apoptotic rates. This synergistic effect was attributed to inhibition of TrxR1 by AF, which compromised tumor cell antioxidant defenses and elevated intracellular reactive oxygen species (ROS), thereby enhancing apoptotic pathways. Notably, AF treatment mitigated the heightened TrxR activity in DOX-resistant cells, intensifying the pro-oxidant effects of DOX, leading to increased ROS production and cell death. The data also showed that AF binds with high affinity to the selenocysteine residue within the catalytic site of TrxR1, which partially overlapped with the binding site of the endogenous substrate, thioredoxin (Trx), but with greater avidity. This unique binding configuration impedes the reduction of Trx by TrxR1, triggering an apoptotic response in cancer cells. Conclusions: This study underscores the chemosensitizing potential of AF in overcoming multidrug resistance in cancer therapy through redox modulation. The molecular mechanism of action underlying AF on TrxR1 demonstrated the unique binding configuration that impedes the reduction of Trx by TrxR1 and instigates an apoptotic response in cancer cells. These findings pave the way for the clinical application of AF as a chemosensitizer, offering a novel approach to augment the efficacy of existing chemotherapy regimens. |
| format | Article |
| id | doaj-art-d48ea3504d0c48879bba991ea1c55d76 |
| institution | Kabale University |
| issn | 2095-3941 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | China Anti-Cancer Association |
| record_format | Article |
| series | Cancer Biology & Medicine |
| spelling | doaj-art-d48ea3504d0c48879bba991ea1c55d762025-08-20T03:28:43ZengChina Anti-Cancer AssociationCancer Biology & Medicine2095-39412025-06-0122667268910.20892/j.issn.2095-3941.2025.0026Beyond gold: the chemoenhancing mechanism and therapeutic potential of auranofin in melanomaXiaofeng Wang0Yingnan Liu1Wuqiong Zhang2Zhongda Li3Su Li4Jiaxin Chen5Qi Li6Xiaoman Suo7Yanqiao Zeng8Guofang Zhang9Yang Li10Laboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518005, ChinaLaboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518005, ChinaLaboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518005, ChinaLaboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518005, ChinaLaboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518005, ChinaLaboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518005, ChinaLaboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518005, ChinaLaboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518005, ChinaLaboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518005, ChinaLaboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518005, ChinaLaboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518005, ChinaObjective: The objective of the current study was to evaluate the chemosensitizing capacity of auranofin (AF), a gold (I) complex traditionally used in rheumatoid arthritis treatment, in potentiating the cytotoxic effects of doxorubicin (DOX) in melanoma cell models, specifically drug-sensitive (B16F10) and multidrug-resistant (B16F10/ADR) variants. Methods: Experimental measurements, including in vitro cytotoxicity and apoptosis assays, surface plasmon resonance (SPR), immunoblotting assays, as well as theoretical calculations, such as molecular docking and molecular dynamics (MD) simulations, were used to systematically delineate the interaction dynamics between AF and thioredoxin reductase 1 (TrxR1). The anti-tumor efficacy of co-treatment with AF and DOX was assessed by examining cell viability and apoptotic rates. Results: Co-treatment with AF and DOX significantly increased anti-tumor efficacy, as evidenced by reduced cell viability and increased apoptotic rates. This synergistic effect was attributed to inhibition of TrxR1 by AF, which compromised tumor cell antioxidant defenses and elevated intracellular reactive oxygen species (ROS), thereby enhancing apoptotic pathways. Notably, AF treatment mitigated the heightened TrxR activity in DOX-resistant cells, intensifying the pro-oxidant effects of DOX, leading to increased ROS production and cell death. The data also showed that AF binds with high affinity to the selenocysteine residue within the catalytic site of TrxR1, which partially overlapped with the binding site of the endogenous substrate, thioredoxin (Trx), but with greater avidity. This unique binding configuration impedes the reduction of Trx by TrxR1, triggering an apoptotic response in cancer cells. Conclusions: This study underscores the chemosensitizing potential of AF in overcoming multidrug resistance in cancer therapy through redox modulation. The molecular mechanism of action underlying AF on TrxR1 demonstrated the unique binding configuration that impedes the reduction of Trx by TrxR1 and instigates an apoptotic response in cancer cells. These findings pave the way for the clinical application of AF as a chemosensitizer, offering a novel approach to augment the efficacy of existing chemotherapy regimens.https://www.cancerbiomed.org/content/22/6/672auranofintrxr1anti-cancerdrug resistancemolecular dynamics simulation |
| spellingShingle | Xiaofeng Wang Yingnan Liu Wuqiong Zhang Zhongda Li Su Li Jiaxin Chen Qi Li Xiaoman Suo Yanqiao Zeng Guofang Zhang Yang Li Beyond gold: the chemoenhancing mechanism and therapeutic potential of auranofin in melanoma Cancer Biology & Medicine auranofin trxr1 anti-cancer drug resistance molecular dynamics simulation |
| title | Beyond gold: the chemoenhancing mechanism and therapeutic potential of auranofin in melanoma |
| title_full | Beyond gold: the chemoenhancing mechanism and therapeutic potential of auranofin in melanoma |
| title_fullStr | Beyond gold: the chemoenhancing mechanism and therapeutic potential of auranofin in melanoma |
| title_full_unstemmed | Beyond gold: the chemoenhancing mechanism and therapeutic potential of auranofin in melanoma |
| title_short | Beyond gold: the chemoenhancing mechanism and therapeutic potential of auranofin in melanoma |
| title_sort | beyond gold the chemoenhancing mechanism and therapeutic potential of auranofin in melanoma |
| topic | auranofin trxr1 anti-cancer drug resistance molecular dynamics simulation |
| url | https://www.cancerbiomed.org/content/22/6/672 |
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