A Cyclometalated Ruthenium(II) Complex Induces Oncosis for Synergistic Activation of Innate and Adaptive Immunity
Tao Feng
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510006 P. R. China
Search for more papers by this authorZixin Tang
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510006 P. R. China
Search for more papers by this authorJun Shu
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510006 P. R. China
Search for more papers by this authorXianbo Wu
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510006 P. R. China
Search for more papers by this authorHui Jiang
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510006 P. R. China
Search for more papers by this authorZhuoli Chen
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510006 P. R. China
Search for more papers by this authorDr. Yu Chen
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510006 P. R. China
Search for more papers by this authorProf. Liangnian Ji
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510006 P. R. China
Search for more papers by this authorCorresponding Author
Prof. Dr. Hui Chao
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510006 P. R. China
MOE Key Laboratory of Theoretical Organic Chemistry and Functional Molecule, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, 400201 P. R. China
Search for more papers by this authorTao Feng
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510006 P. R. China
Search for more papers by this authorZixin Tang
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510006 P. R. China
Search for more papers by this authorJun Shu
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510006 P. R. China
Search for more papers by this authorXianbo Wu
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510006 P. R. China
Search for more papers by this authorHui Jiang
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510006 P. R. China
Search for more papers by this authorZhuoli Chen
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510006 P. R. China
Search for more papers by this authorDr. Yu Chen
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510006 P. R. China
Search for more papers by this authorProf. Liangnian Ji
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510006 P. R. China
Search for more papers by this authorCorresponding Author
Prof. Dr. Hui Chao
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510006 P. R. China
MOE Key Laboratory of Theoretical Organic Chemistry and Functional Molecule, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, 400201 P. R. China
Search for more papers by this authorAbstract
An optimal cancer chemotherapy regimen should effectively address the drug resistance of tumors while eliciting antitumor-immune responses. Research has shown that non-apoptotic cell death, such as pyroptosis and ferroptosis, can enhance the immune response. Despite this, there has been limited investigation and reporting on the mechanisms of oncosis and its correlation with immune response. Herein, we designed and synthesized a Ru(II) complex that targeted the nucleus and mitochondria to induce cell oncosis. Briefly, the Ru(II) complex disrupts the nucleus and mitochondria DNA, which active polyADP-ribose polymerase 1, accompanied by ATP consumption and porimin activation. Concurrently, mitochondrial damage and endoplasmic reticulum stress result in the release of Ca2+ ions and increased expression of Calpain 1. Subsequently, specific pore proteins porimin and Calpain 1 promote cristae destruction or vacuolation, ultimately leading to cell membrane rupture. The analysis of RNA sequencing demonstrates that the Ru(II) complex can initiate the oncosis-associated pathway and activate both innate and adaptive immunity. In vivo experiments have confirmed that oncosis promotes dendritic cell maturation and awakens adaptive cytotoxic T lymphocytes but also activates the innate immune by inducing the polarization of macrophages towards an M1 phenotype.
Conflict of interests
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available in the supplementary material of this article.
Supporting Information
As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.
| Filename | Description |
|---|---|
| ange202405679-sup-0001-misc_information.pdf7.9 MB | Supporting Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1
- 1aN. Vasan, J. Baselga, D. M. Hyman, Nature 2019, 575, 299–309;
- 1bC. Guo, R. Wan, Y. He, S. H. Lin, J. Cao, Y. Qiu, T. Zhang, Q. Zhao, Y. Niu, Y. Jin, H.-Y. Huang, X. Wang, L. Tan, R. K. Thomas, H. Zhang, L. Chen, K.-K. Wong, L. Hu, H. Ji, Nat. Can. 2022, 3, 614–628.
- 2
- 2aL. K. Boroughs, R. J. DeBerardinis, Nat. Cell Biol. 2015, 17, 351–359;
- 2bS. Rottenberg, C. Disler, P. Perego, Nat. Rev. Cancer 2021, 21, 37–50;
- 2cL. Ma, L. Li, G. Zhu, Inorg. Chem. Front. 2022, 9, 2424–2453.
- 3K. Peng, Y. Zheng, W. Xia, Z. W. Mao, Chem. Soc. Rev. 2023, 52, 2790–2832.
- 4
- 4aM. J. Chow, C. Licona, G. Pastorin, G. Mellitzer, W. H. Ang, C. Gaiddon, Chem. Sci. 2016, 7, 4117–4124;
- 4bH. Yuan, Z. Han, Y. Chen, F. Qi, H. Fang, Z. Guo, S. Zhang, W. He, Angew. Chem. Int. Ed. 2021, 60, 8174–8181.
- 5G. Majno, I. Joris, Am. J. Pathol. 1995, 146, 3–15.
- 6
- 6aD. R. Green, T. Ferguson, L. Zitvogel, G. Kroemer, Nat. Rev. Immunol. 2009, 9, 353–363;
- 6bJ. Pracharova, V. Novohradsky, H. Kostrhunova, P. Štarha, Z. Trávníček, J. Kasparkova, V. Brabec, Dalton Trans. 2018, 47, 12197–12208;
- 6cE. Ortega-Forte, S. Hernández-García, G. Vigueras, P. Henarejos-Escudero, N. Cutillas, J. Ruiz, F. Gandía-Herrero, Cell. Mol. Life Sci. 2022, 79, 510;
- 6dK. N. Wang, X. Shao, Z. Tian, L. Y. Liu, C. Zhang, C.-P. Tan, J. Zhang, P. Ling, F. Liu, Q. Chen, J. Diao, Z. W. Mao, Adv. Sci. 2021, 8, 2004566.
- 7
- 7aR. Guan, Y. Chen, L. Zeng, T. W. Rees, C. Jin, J. Huang, Z. S. Chen, L. Ji, H. Chao, Chem. Sci. 2018, 9, 5183–5190;
- 7bP. J. Jarman, F. Noakes, S. Fairbanks, K. Smitten, I. K. Griffiths, H. K. Saeed, J. A. Thomas, C. Smythe, J. Am. Chem. Soc. 2019, 141, 2925–2937;
- 7cH. Yao, S. Chen, Z. Deng, M. K. Tse, Y. Matsuda, G. Zhu, Inorg. Chem. 2020, 59, 11823–11833;
- 7dS. Ji, X. Yang, X. Chen, A. Li, D. Yan, H. Xu, H. Fei, Chem. Sci. 2020, 11, 9126–9133;
- 7eM. Ye, W. Q. Huang, Z. X. Li, C. X. Wang, T. Liu, Y. Chen, C. H. H. Hor, W. L. Man, W. X. Ni, Chem. Commun. 2022, 58, 2468–2471;
- 7fW. Wang, P. Wang, X. Liao, B. Yang, C. Gao, J. Yang, J. Med. Chem. 2023, 66, 13103–13115;
- 7gJ. Kasparkova, A. Hernández-García, H. Kostrhunova, M. Goicuría, V. Novohradsky, D. Bautista, L. Markova, M. D. Santana, V. Brabec, J. Ruiz, J. Med. Chem. 2024, 67, 691–708;
- 7hK. Xiong, X. Lin, J. Kou, F. Wei, J. Shen, Y. Chen, L. Ji, H. Chao, Adv. Healthcare Mater. 2024, 13, 2302564.
- 8
- 8aD. Slade, M. S. Dunstan, E. Barkauskaite, R. Weston, P. Lafite, N. Dixon, M. Ahel, D. Leys, I. Ahel, Nature 2011, 477, 616–620.
- 9Y. Sun, J. Yu, X. Liu, C. Zhang, J. Cao, G. Li, X. Liu, Y. Chen, H. Huang, Biomed. Pharmacother. 2018, 102, 699–710.
- 10
- 10aF. Ma, C. Zhang, K. V. S. Prasad, G. J. Freeman, S. F. Schlossman, Proc. Nat. Acad. Sci. 2001, 98, 9778–9783;
- 10bC. Zhang, Y. Xu, J. Gu, S. F. Schlossman, Proc. Nat. Acad. Sci. 1998, 95, 6290–6295.
- 11X. Liu, T. Van Vleet, R. G. Schnellmann, Annu. Rev. Pharmacol. Toxicol. 2004, 44, 349–370.
- 12M. Leist, B. Single, A. F. Castoldi, S. Kühnle, P. Nicotera, J. Exp. Med. 1997, 185, 1481–1486.
- 13
- 13aT. Mishchenko, I. Balalaeva, A. Gorokhova, M. Vedunova, D. V. Krysko, Cell Death Dis. 2022, 13, 455;
- 13bM. Lv, Y. Zheng, J. Wu, Z. Shen, B. Guo, G. Hu, Y. Huang, J. Zhao, Y. Qian, Z. Su, C. Wu, X. Xue, H. K. Liu, Z. W. Mao, Angew. Chem. Int. Ed. 2023, 62, e202312897;
- 13cX. Zhao, X. Wang, W. Zhang, T. Tian, J. Zhang, J. Wang, W. Wei, Z. Guo, J. Zhao, X. Wang, Angew. Chem. Int. Ed. 2024, 63, e202400829;
- 13dY. Wang, L. Cai, H. Li, H. Chen, T. Yang, Y. Tan, Z. Guo, X. Wang, Angew. Chem. Int. Ed. 2023, 62, e202309043;
- 13eJ. Karges, Angew. Chem. Int. Ed. 2022, 61, e202112236;
- 13fK. Xiong, F. Wei, Y. Chen, L. Ji, H. Chao, Small Methods 2023, 7, 2201403.
- 14T. Vanden Berghe, M. Kalai, G. Denecker, A. Meeus, X. Saelens, P. Vandenabeele, Cell. Signalling 2006, 18, 328–335.
- 15
- 15aM. L. Escobar, G. H. Vázquez-Nin, O. M. Echeverría, Cell Death in Mammalian Ovary 2011, pp. 103–110;
10.1007/978-94-007-1134-1_6 Google Scholar
- 15bT. Bergsbaken, S. L. Fink, B. T. Cookson, Nat. Rev. Microbiol. 2009, 7, 99–109.
- 16
- 16aX. Wang, X. Wang, S. Jin, N. Muhammad, Z. Guo, Chem. Rev. 2019, 119, 1138–1192;
- 16bB. Englinger, C. Pirker, P. Heffeter, A. Terenzi, C. R. Kowol, B. K. Keppler, W. Berger, Chem. Rev. 2019, 119, 1519–1624;
- 16cH. Jiang, Y. Guo, C. Wei, P. Hu, J. Shi, Adv. Mater. 2021, 33, 2008065.
- 17
- 17aL. Zeng, P. Gupta, Y. Chen, E. Wang, L. Ji, H. Chao, Z. S. Chen, Chem. Soc. Rev. 2017, 46, 5771–5804;
- 17bM. Małecka, A. Skoczyńska, D. M. Goodman, C. G. Hartinger, E. Budzisz, Coord. Chem. Rev. 2021, 436, 213849;
- 17cM. Orsi, B. Shing Loh, C. Weng, W. H. Ang, A. Frei, Angew. Chem. Int. Ed. 2024, 63, e202317901;
- 17dI. A. Shutkov, Y. N. Okulova, V. Y. Tyurin, E. V. Sokolova, D. A. Babkov, A. A. Spasov, Y. A. Gracheva, C. Schmidt, K. I. Kirsanov, A. A. Shtil, O. M. Redkozubova, E. F. Shevtsova, E. R. Milaeva, I. Ott, A. A. Nazarov, Int. J. Mol. Sci. 2021, 22, 13468.
- 18
- 18aK. Połeć-Pawlak, J. K. Abramski, J. Ferenc, L. S. Foteeva, A. R. Timerbaev, B. K. Keppler, M. Jarosz, J. Chromatogr. A 2008, 1192, 323–326;
- 18bA. K. Bytzek, G. Koellensperger, B. K. Keppler, C. G. Hartinger, J. Inorg. Biochem. 2016, 160, 250–255.
- 19
- 19aH. Huang, P. Zhang, B. Yu, Y. Chen, J. Wang, L. Ji, H. Chao, J. Med. Chem. 2014, 57, 8971–8983;
- 19bH. Huang, P. Zhang, H. Chen, L. Ji, H. Chao, Chem. Eur. J. 2015, 21, 715–725;
- 19cK. Xiong, C. Ouyang, J. Liu, J. Karges, X. Lin, X. Chen, Y. Chen, J. Wan, L. Ji, H. Chao, Angew. Chem. Int. Ed. 2022, 61, e202204866.
- 20B. E. Trump, I. K. Berezesky, S. H. Chang, P. C. Phelps, Toxicol. Pathol. 1997, 25, 82–88.
- 21J. B. Spinelli, M. C. Haigis, Nat. Cell Biol. 2018, 20, 745–754.
- 22C. L. Edelstein, E. D. Wieder, M. M. Yaqoob, P. E. Gengaro, T. J. Burke, R. A. Nemenoff, R. W. Schrier, Proc. Nat. Acad. Sci. 1995, 92, 7662–7666.
- 23S. M. O'Cathail, T. D. Pokrovska, T. S. Maughan, K. D. Fisher, L. W. Seymour, M. A. Hawkins, Front. Oncol. 2017, 7, 153.
- 24S. Ji, L. Huang, S. Chang, X. Sun, H. Liu, A. Li, Y. Jin, H. Fei, Biomaterials 2023, 301, 122269.
- 25P. Weerasinghe, S. Hallock, R. E. Brown, D. S. Loose, L. M. Buja, Exp. Mol. Pathol. 2013, 94, 289–300.
Citing Literature
This is the
German version
of Angewandte Chemie.
Note for articles published since 1962:
Do not cite this version alone.
Take me to the International Edition version with citable page numbers, DOI, and citation export.
We apologize for the inconvenience.
