诱导程序性细胞死亡的金属抗肿瘤药物研究

doi:10.12461/PKU.DXHX202406019

摘要/Abstract

摘要： 在生命体系中，细胞死亡是一个重要的过程，它涉及多种形式，这些死亡形式拥有不同的诱因、机制和特征。通过研究细胞各种死亡方式的分子机制，能够更好地干预并调控细胞死亡，这对癌症的治疗是极其重要的。自从顺铂被发现能够抑制癌细胞的增殖后，人们便开始重视并研究各类金属药物在抗肿瘤治疗中的作用。金属抗肿瘤药物诱导细胞死亡的方式是多样且复杂的，深入研究这些死亡方式有助于设计金属药物以诱导细胞发生特定形式的死亡，实现预期的治疗模式，达到理想的治疗效果。本文介绍了诱导细胞凋亡、坏死性凋亡、焦亡、铁死亡、铜死亡、胀亡和免疫原性死亡的金属药物及其近期研究进展。

关键词: 金属药物, 程序性细胞死亡, 抗肿瘤

Abstract: In biological systems, cell death represents a crucial biological process encompassing diverse modalities characterized by distinct triggers, molecular mechanisms, and phenotypic features. Elucidating the molecular pathways governing various cell death modalities enables targeted intervention and precise regulation of cellular demise, which holds paramount significance in cancer therapeutics. The discovery of cisplatin’s antiproliferative effects on cancer cells has catalyzed extensive investigation into metallic compounds for antitumor applications. The mechanisms through which metal-based antitumor agents induce cell death exhibit remarkable diversity and complexity. Systematic exploration of these death pathways facilitates the rational design of metallodrugs capable of triggering specific cell death modalities, thereby enabling tailored therapeutic strategies and optimized treatment outcomes. This review comprehensively summarizes recent advances in metal-based agents that induce apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, oncosis, and immunogenic cell death.

Key words: Metal drugs, Programmed cell death, Antitumor

曾家豪, 巢晖. 诱导程序性细胞死亡的金属抗肿瘤药物研究[J]. 大学化学, 2025, 40(6): 145-159.

Jiahao Zeng, Hui Chao. Research on Programmed Cell Death Induced by Metal Antitumor Drugs[J]. University Chemistry, 2025, 40(6): 145-159.

链接本文: https://www.dxhx.pku.edu.cn/CN/10.12461/PKU.DXHX202406019

https://www.dxhx.pku.edu.cn/CN/Y2025/V40/I6/145

参考文献

[1] Ndagi, U.; Mhlongo, N.; Soliman, M. E. Drug Des. Dev. Ther. 2017, 11, 599.
[2] Rosenberg, B.; Vancamp, L.; Trosko, J. E.; Mansour, V. H. Nature 1969, 222 (5191), 385.
[3] Jungwirth, U.; Kowol, C. R.; Keppler, B. K.; Hartinger, C. G.; Berger, W.; Heffeter, P. Antioxid. Redox Signal. 2011, 15 (4), 1085.
[4] Tang, D.; Kang, R.; Berghe, T. V.; Vandenabeele, P.; Kroemer, G. Cell Res. 2019, 29 (5), 347.
[5] Peng, F.; Liao, M.; Qin, R.; Zhu, S.; Peng, C.; Fu, L.; Chen, Y.; Han, B. Signal Transduction Targeted Ther. 2022, 7 (9), 3283.
[6] Galluzzi, L.; Vitale, I.; Aaronson, S. A.; Abrams, J. M.; Adam, D.; Agostinis, P.; Alnemri, E. S.; Altucci, L.; Amelio, I.; Andrews, D. W.; et al. Cell Death Differ. 2018, 25 (3), 486.
[7] Peng, K.; Zheng, Y.; Xia, W.; Mao, Z.-W. Chem. Soc. Rev. 2023, 52 (8), 2790.
[8] Kerr, J. F.; Wyllie, A. H.; Currie, A. R. Br. J. Cancer 1972, 26 (4), 239.
[9] Ghosh, S. Bioorg. Chem. 2019, 88, 102925.
[10] König, M.; Siegmund, D.; Raszeja, L. J.; Prokop, A.; Metzler-Nolte, N. MedChemComm 2018, 9 (1), 173.
[11] Plaks, V.; Kong, N.; Werb, Z. Cell Stem Cell 2015, 16 (3), 225.
[12] Eskandari, A.; Kundu, A.; Johnson, A.; Karmakar, S.; Ghosh, S.; Suntharalingam, K. Dalton Trans. 2020, 49 (14), 4211.
[13] Medici, S.; Peana, M.; Nurchi, V. M.; Lachowicz, J. I.; Crisponi, G.; Zoroddu, M. A. Coord. Chem. Rev. 2015, 284, 329.
[14] Liu, J. P.; Prentice, A. W.; Clarkson, G. J.; Woolley, J. M.; Stavros, V. G.; Paterson, M. J.; Sadler, P. J. Adv. Mater. 2023, 35 (19), 2210363.
[15] Wong, R. S. J. Exp. Clin. Cancer Res. 2011, 30, 1.
[16] Hadian, K.; Stockwell, B. R. Nat. Rev. Drug Discov. 2023, 22 (9), 723.
[17] Su, Z.; Yang, Z.; Xie, L.; DeWitt, J.; Chen, Y. Cell Death Differ. 2016, 23 (5), 748.
[18] Wu, Y.; Dong, G.; Sheng, C. Acta Pharm. Sin. B 2020, 10 (9), 1601.
[19] Wang, Y.; Zhang, Q.; Wang, B.; Li, P.; Liu, P. Neurochem. Res. 2017, 42, 2363.
[20] Suntharalingam, K.; Awuah, S. G.; Bruno, P. M.; Johnstone, T. C.; Wang, F.; Lin, W.; Zheng, Y.-R.; Page, J. E.; Hemann, M. T.; Lippard, S. J. J. Am. Chem. Soc. 2015, 137 (8), 2967.
[21] Passeri, G.; Northcote-Smith, J.; Perera, R.; Gubic, N.; Suntharalingam, K. Molecules 2022, 27 (10), 3277.
[22] Xiong, K.; Qian, C.; Yuan, Y.; Wei, L.; Liao, X.; He, L.; Rees, T. W.; Chen, Y.; Wan, J.; Ji, L. Angew. Chem. Int. Ed. 2020, 59 (38), 16631.
[23] Cookson, B. T.; Brennan, M. A. Trends Microbiol. 2001, 9 (3), 113.
[24] Shi, J.; Zhao, Y.; Wang, K.; Shi, X.; Wang, Y.; Huang, H.; Zhuang, Y.; Cai, T.; Wang, F.; Shao, F. Nature 2015, 526 (7575), 660.
[25] Wang, Q.; Wang, Y.; Ding, J.; Wang, C.; Zhou, X.; Gao, W.; Huang, H.; Shao, F.; Liu, Z. Nature 2020, 579 (7799), 421.
[26] Zhang, Z.; Zhang, Y.; Xia, S.; Kong, Q.; Li, S.; Liu, X.; Junqueira, C.; Meza-Sosa, K. F.; Mok, T. M. Y.; Ansara, J.; et al. Nature 2020, 579 (7799), 415.
[27] Su, X.; Wang, W. J.; Cao, Q.; Zhang, H.; Liu, B.; Ling, Y.; Zhou, X.; Mao, Z. W. Angew. Chem. Int. Ed. 2022, 61 (8), e202115800.
[28] Murthy, A. M.; Robinson, N.; Kumar, S. Cell Death Differ. 2020, 27 (11), 2989.
[29] Ling, Y. Y.; Xia, X. Y.; Hao, L.; Wang, W. J.; Zhang, H.; Liu, L. Y.; Liu, W.; Li, Z. Y.; Tan, C. P.; Mao, Z. W. Angew. Chem. Int. Ed. 2022, 134 (43), e202210988.
[30] Fan, R.; Lin, R.; Zhang, S.; Deng, A.; Hai, Y.; Zhuang, J.; Liu, Y.; Cheng, M.; Wei, G. Acta Pharm. Sin. B 2024, 14 (4), 1742.
[31] Dixon, S. J.; Lemberg, K. M.; Lamprecht, M. R.; Skouta, R.; Zaitsev, E. M.; Gleason, C. E.; Patel, D. N.; Bauer, A. J.; Cantley, A. M.; Yang, W. S.; et al. Cell 2012, 149 (5), 1060.
[32] Li, S.; Yuan, H.; Chen, Y.; Guo, Z. Fundam. Res. 2023, 3 (4), 525.
[33] Tang, D.; Chen, X.; Kang, R.; Kroemer, G. Cell Res. 2021, 31 (2), 107.
[34] Liu, K.; Huang, L.; Qi, S.; Liu, S.; Xie, W.; Du, L.; Cui, J.; Zhang, X.; Zhang, B.; Liu, L. Adv. Healthcare Mater. 2023, 12 (12), 2203085.
[35] Ling, Y. Y.; Wang, W. J.; Hao, L.; Wu, X. W.; Liang, J. H.; Zhang, H.; Mao, Z. W.; Tan, C. P. Small 2022, 18 (49), 2203659.
[36] Wang, W. J.; Ling, Y. Y.; Zhong, Y. M.; Li, Z. Y.; Tan, C. P.; Mao, Z. W. Angew. Chem. Int. Ed. 2022, 61 (16), e202115247.
[37] Yuan, H.; Han, Z.; Chen, Y. C.; Qi, F.; Fang, H. B.; Guo, Z. J.; Zhang, S. R.; He, W. J. Angew. Chem. Int. Ed. 2021, 60 (15), 8174.
[38] Ke, L. B.; Wei, F. M.; Xie, L. N.; Karges, J.; Chen, Y.; Ji, L. N.; Chao, H. Angew. Chem. Int. Ed. 2022, 61 (28), e202205429.
[39] Lai, Y.; Lu, N.; Ouyang, A.; Zhang, Q.; Zhang, P. Chem. Sci. 2022, 13 (34), 9921.
[40] Tsvetkov, P.; Coy, S.; Petrova, B.; Dreishpoon, M.; Verma, A.; Abdusamad, M.; Rossen, J.; Joesch-Cohen, L.; Humeidi, R.; Spangler, R. D. Science 2022, 375 (6586), 1254.
[41] Xie, J.; Yang, Y.; Gao, Y.; He, J. Mol. Cancer 2023, 22 (1), 46.
[42] Xue, Q.; Kang, R.; Klionsky, D. J.; Tang, D.; Liu, J.; Chen, X. Autophagy 2023, 19 (8), 2175.
[43] Ji, P.; Wang, P.; Chen, H.; Xu, Y.; Ge, J.; Tian, Z.; Yan, Z. Pharmaceuticals 2023, 16 (2), 234.
[44] Tang, D.; Kroemer, G.; Kang, R. Nat. Rev. Clin. Oncol. 2024, 21(5), 370.
[45] Zhou, J.; Yu, Q.; Song, J.; Li, S.; Li, X. L.; Kang, B.; Chen, H. Y.; Xu, J. J. Angew. Chem. Int. Ed. 2023, 62 (12), e202213922.
[46] Xu, Y.; Liu, S. Y.; Zeng, L.; Ma, H.; Zhang, Y.; Yang, H.; Liu, Y.; Fang, S.; Zhao, J.; Xu, Y. Adv. Mater. 2022, 34 (43), 2204733.
[47] Lv, H.; Liu, X.; Zeng, X.; Liu, Y.; Zhang, C.; Zhang, Q.; Xu, J. Front. Pharmacol. 2022, 13, 930041.
[48] Guo, B.; Yang, F.; Zhang, L.; Zhao, Q.; Wang, W.; Yin, L.; Chen, D.; Wang, M.; Han, S.; Xiao, H. Adv. Mater. 2023, 35 (22), 2212267.
[49] Weerasinghe, P.; Buja, L. M. Exp. Mol. Pathol. 2012, 93 (3), 302.
[50] Guan, R.; Chen, Y.; Zeng, L.; Rees, T. W.; Jin, C.; Huang, J.; Chen, Z.-S.; Ji, L.; Chao, H. Chem. Sci. 2018, 9 (23), 5183.
[51] Yao, H.; Chen, S.; Deng, Z.; Tse, M.-K.; Matsuda, Y.; Zhu, G. Inorg. Chem. 2020, 59 (16), 11823.
[52] Xiong, K.; Lin, X.; Kou, J.; Wei, F.; Shen, J.; Chen, Y.; Ji, L.; Chao, H. Adv. Healthcare Mater. 2024, 13 (5), 2302564.
[53] Feng, T.; Tang, Z.; Shu, J.; Wu, X.; Jiang, H.; Chen, Z.; Chen, Y.; Ji, L.; Chao, H. Angew. Chem. Int. Ed. 2024, 63 (31), e202405679.
[54] Casares, N.; Pequignot, M. O.; Tesniere, A.; Ghiringhelli, F.; Roux, S.; Chaput, N.; Schmitt, E.; Hamai, A.; Hervas-Stubbs, S.; Obeid, M.; et al. J. Exp. Med., 2005, 202 (12), 1691.
[55] Zhang, L. P.; Montesdeoca, N.; Karges, J.; Xiao, H. H. Angew. Chem. Int. Ed. 2023, 62 (21), e202300662.
[56] Galluzzi, L.; Buqué, A.; Kepp, O.; Zitvogel, L.; Kroemer, G. Nat. Rev. Immunol. 2017, 17 (2), 97.
[57] Tesniere, A.; Schlemmer, F.; Boige, V.; Kepp, O.; Martins, I.; Ghiringhelli, F.; Aymeric, L.; Michaud, M.; Apetoh, L.; Barault, L.; et al. Oncogene 2010, 29 (4), 482.
[58] Trondl, R.; Heffeter, P.; Kowol, C. R.; Jakupec, M. A.; Berger, W.; Keppler, B. K. Chem. Sci. 2014, 5 (8), 2925.
[59] Wernitznig, D.; Kiakos, K.; Del Favero, G.; Harrer, N.; Machat, H.; Osswald, A.; Jakupec, M. A.; Wernitznig, A.; Sommergruber, W.; Keppler, B. K. Metallomics 2019, 11 (6), 1044.
[60] Zhang, L.; Montesdeoca, N.; Karges, J.; Xiao, H. Angew. Chem. Int. Ed. 2023, 62 (21), e202300662.
[61] Sen, S.; Won, M.; Levine, M. S.; Noh, Y.; Sedgwick, A. C.; Kim, J. S.; Sessler, J. L.; Arambula, J. F. Chem. Soc. Rev. 2022, 51 (4), 1212.
[62] Wang, L. L.; Guan, R. L.; Xie, L. N.; Liao, X. X.; Xiong, K.; Rees, T. W.; Chen, Y.; Ji, L. N.; Chao, H. Angew. Chem. Int. Ed. 2021, 60 (9), 4657.
[63] Sen, S.; Hufnagel, S.; Maier, E. Y.; Aguilar, I.; Selvakumar, J.; DeVore, J. E.; Lynch, V. M.; Arumugam, K.; Cui, Z.; Sessler, J. L. J. Am. Chem. Soc. 2020, 142 (49), 20536.
[64] Sun, Y.; Yin, E.; Tan, Y.; Yang, T.; Song, D.; Jin, S.; Guo, Z.; Wang, X. Dalton Trans. 2021, 50 (10), 3516.