Cascade Specific Endogenous Fe Interference and Catalysis for Tumor Therapy with Stemness Suppression

Overview

Journal Natl Sci Rev

Date 2025 Feb 19

PMID 39967605

Authors

Jiajie Chen

Yitong Wang

Jian Huang

Zhibo Yang

Huicong Niu

Xiaolian Su

Jimin Huang

Hongshi Ma

Yufang Zhu

Chengtie Wu

Jianlin Shi

Affiliations

Soon will be listed here.

Abstract

Cancer stem-like cells (CSCs), featuring high tumorigenicity and invasiveness, are one of the critical factors leading to the failure of clinical cancer treatment such as metastasis and recurrence. However, current strategies suffer from the low stemness-inhibiting efficacy on CSCs by conventional molecular agents and the poor lethal effects against bulk tumor cells. Here we engineer a coordination nanomedicine by 2,5-dihydroxyterephthalic acid (DHT) complexing zinc ions (Zn) as a double-effect nanodisrupter of tumor iron (Fe) and redox homeostasis for catalysis-boosted tumor therapy with stemness inhibition. Taking advantage of the much higher binding force of DHT toward Fe, this nanomedicine can specifically chelate endogenous Fe into its nanostructure and release Zn, and the formed hexacoordinated Fe-DHT conformation is of much enhanced reducibility in order to promote reactive oxygen species (ROS) production in tumors. The nanomedicine-mediated Fe depletion and ROS generation collectively induce CSC differentiation downregulating the Wnt signaling and inducing forkhead box O3 (FoxO3) activation, respectively. Notably, the combined tumor-selective ROS generation and Zn-induced antioxidation dysfunction potently trigger intratumoral oxidative damage leading to both cellular apoptosis and ferroptosis. This nanomedicine, capable of synchronously treating CSCs and bulk tumor cells, has been demonstrated to effectively inhibit the growth, postoperative recurrence and metastasis of orthotopic triple-negative breast tumors , offering an encouraging candidate of cancer therapeutic agents for treating CSCs-enriched malignancy.

References

Torti S, Torti F . Iron and Cancer: 2020 Vision. Cancer Res. 2020; 80(24):5435-5448. PMC: 8118237. DOI: 10.1158/0008-5472.CAN-20-2017. View

Wang K, Zhang T, Dong Q, Nice E, Huang C, Wei Y . Redox homeostasis: the linchpin in stem cell self-renewal and differentiation. Cell Death Dis. 2013; 4:e537. PMC: 3613828. DOI: 10.1038/cddis.2013.50. View

Huo T, Chen L, Nie H, Li W, Lin C, Akhtar M . Mitochondrial Dysfunction and Antioxidation Dyshomeostasis-Enhanced Tumor Starvation Synergistic Chemotherapy Achieved using a Metal-Organic Framework-Based Nano-Enzyme Reactor. ACS Appl Mater Interfaces. 2022; 14(3):3675-3684. DOI: 10.1021/acsami.1c18654. View

Beck B, Blanpain C . Unravelling cancer stem cell potential. Nat Rev Cancer. 2013; 13(10):727-38. DOI: 10.1038/nrc3597. View

Marie-Egyptienne D, Lohse I, Hill R . Cancer stem cells, the epithelial to mesenchymal transition (EMT) and radioresistance: potential role of hypoxia. Cancer Lett. 2012; 341(1):63-72. DOI: 10.1016/j.canlet.2012.11.019. View

Nieto M, Huang R, Jackson R, Thiery J . EMT: 2016. Cell. 2016; 166(1):21-45. DOI: 10.1016/j.cell.2016.06.028. View

Beug H . Breast cancer stem cells: eradication by differentiation therapy?. Cell. 2009; 138(4):623-5. DOI: 10.1016/j.cell.2009.08.007. View

Huo M, Wang L, Wang Y, Chen Y, Shi J . Nanocatalytic Tumor Therapy by Single-Atom Catalysts. ACS Nano. 2019; 13(2):2643-2653. DOI: 10.1021/acsnano.9b00457. View

Zheng X, Cui D, Xu S, Brabant G, Derwahl M . Doxorubicin fails to eradicate cancer stem cells derived from anaplastic thyroid carcinoma cells: characterization of resistant cells. Int J Oncol. 2010; 37(2):307-15. DOI: 10.3892/ijo_00000679. View

10.

Lin H, Chen Y, Shi J . Nanoparticle-triggered in situ catalytic chemical reactions for tumour-specific therapy. Chem Soc Rev. 2018; 47(6):1938-1958. DOI: 10.1039/c7cs00471k. View

11.

Ninomiya T, Ohara T, Noma K, Katsura Y, Katsube R, Kashima H . Iron depletion is a novel therapeutic strategy to target cancer stem cells. Oncotarget. 2017; 8(58):98405-98416. PMC: 5716739. DOI: 10.18632/oncotarget.21846. View

12.

Clarke M . Clinical and Therapeutic Implications of Cancer Stem Cells. N Engl J Med. 2019; 380(23):2237-2245. DOI: 10.1056/NEJMra1804280. View

13.

Yang B, Chen Y, Shi J . Reactive Oxygen Species (ROS)-Based Nanomedicine. Chem Rev. 2019; 119(8):4881-4985. DOI: 10.1021/acs.chemrev.8b00626. View

14.

Pan Y, Ma X, Liu C, Xing J, Zhou S, Parshad B . Retinoic Acid-Loaded Dendritic Polyglycerol-Conjugated Gold Nanostars for Targeted Photothermal Therapy in Breast Cancer Stem Cells. ACS Nano. 2021; 15(9):15069-15084. DOI: 10.1021/acsnano.1c05452. View

15.

Yang B, Yao H, Tian H, Yu Z, Guo Y, Wang Y . Intratumoral synthesis of nano-metalchelate for tumor catalytic therapy by ligand field-enhanced coordination. Nat Commun. 2021; 12(1):3393. PMC: 8184762. DOI: 10.1038/s41467-021-23710-y. View

16.

Bystrom L, Guzman M, Rivella S . Iron and reactive oxygen species: friends or foes of cancer cells?. Antioxid Redox Signal. 2012; 20(12):1917-24. PMC: 3967355. DOI: 10.1089/ars.2012.5014. View

17.

Shaw F, Harrison H, Spence K, Ablett M, Simoes B, Farnie G . A detailed mammosphere assay protocol for the quantification of breast stem cell activity. J Mammary Gland Biol Neoplasia. 2012; 17(2):111-7. DOI: 10.1007/s10911-012-9255-3. View

18.

Pracht J, Boenigk J, Isenbeck-Schroter M, Keppler F, Scholer H . Abiotic Fe(III) induced mineralization of phenolic substances. Chemosphere. 2001; 44(4):613-9. DOI: 10.1016/s0045-6535(00)00490-2. View

19.

Song S, Christova T, Perusini S, Alizadeh S, Bao R, Miller B . Wnt inhibitor screen reveals iron dependence of β-catenin signaling in cancers. Cancer Res. 2011; 71(24):7628-39. DOI: 10.1158/0008-5472.CAN-11-2745. View

20.

Sunayama J, Sato A, Matsuda K, Tachibana K, Watanabe E, Seino S . FoxO3a functions as a key integrator of cellular signals that control glioblastoma stem-like cell differentiation and tumorigenicity. Stem Cells. 2011; 29(9):1327-37. DOI: 10.1002/stem.696. View