Abstract
A number of artificial cation ionophores (or transporters) have been developed for basic research and biomedical applications. However, their mechanisms of action and the putative correlations between changes in intracellular cation concentrations and induced cell death remain poorly understood. Here, we show that three hemispherand-strapped calix[4]pyrrole-based ion-pair receptors act as efficient Na+/K+ exchangers in the presence of Cl− in liposomal models and promote Na+ influx and K+ efflux (Na+/K+ exchange) in cancer cells to induce apoptosis. Mechanistic studies reveal that these cation exchangers induce endoplasmic reticulum (ER) stress in cancer cells by perturbing intracellular cation homeostasis, promote generation of reactive oxygen species, and eventually enhance mitochondria-mediated apoptosis. However, they neither induce osmotic stress nor affect autophagy. This study provides support for the notion that synthetic receptors, which perturb cellular cation homeostasis, may provide new small molecules with potentially useful apoptotic activity.
| Original language | English |
|---|---|
| Pages (from-to) | 3325-3339 |
| Number of pages | 15 |
| Journal | Chem |
| Volume | 7 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 2021 Dec 9 |
Bibliographical note
Funding Information:The work at Yonsei University was supported financially by the National Research Foundation of Korea (NRF) (grant no. 2020R1A2C3003462 to I.S.). The research at Hunan University was funded by the National Natural Science Foundation of China ( 21901069 and 22071050 to Q.H.), the Science and Technology Plan Project of Hunan Province, China (grant number 2019RS1018 to Q.H.), and Fundamental Research Funds for the Central Universities (Startup Funds to Q.H.). D.A.M., A.J.K., E.N.W.H., and P.A.G. acknowledge and pay respect to the Gadigal people of the Eora Nation, the traditional owners of the land on which we research, teach, and collaborate at the University of Sydney. P.A.G. thanks the Australian Research Council , Australia ( DP200100453 ) and the University of Sydney for funding, and Xin Wu and Lijun Chen for help with the preparation of this manuscript. The work in Austin was supported initially by the National Institutes of Health (grant R01GM103790 to J.L.S.) with subsequent support provided by the Robert A. Welch Foundation ( F-0018 to J.L.S.).
Funding Information:
The work at Yonsei University was supported financially by the National Research Foundation of Korea (NRF) (grant no. 2020R1A2C3003462 to I.S.). The research at Hunan University was funded by the National Natural Science Foundation of China (21901069 and 22071050 to Q.H.), the Science and Technology Plan Project of Hunan Province, China (grant number 2019RS1018 to Q.H.), and Fundamental Research Funds for the Central Universities (Startup Funds to Q.H.). D.A.M. A.J.K. E.N.W.H. and P.A.G. acknowledge and pay respect to the Gadigal people of the Eora Nation, the traditional owners of the land on which we research, teach, and collaborate at the University of Sydney. P.A.G. thanks the Australian Research Council, Australia (DP200100453) and the University of Sydney for funding, and Xin Wu and Lijun Chen for help with the preparation of this manuscript. The work in Austin was supported initially by the National Institutes of Health (grant R01GM103790 to J.L.S.) with subsequent support provided by the Robert A. Welch Foundation (F-0018 to J.L.S.). Q.H. P.A.G. J.L.S. and I.S. designed and supervised the project. S.-H.P. performed biological studies. Q.H. I.-H.W. S.X. and M.D.K. designed and synthesized the compounds and performed ion-binding studies in solution. Q.H. and V.M.L. carried out the X-ray single-crystal structure analysis. Q.H. carried out the DFT calculations. P.A.G. D.A.M. A.J.K. and E.N.W.H. designed and performed the ion-transport studies in liposomes. S.-H.P. Q.H. and D.A.M. wrote the manuscript. I.S. J.L.S. and P.A.G. helped with writing the manuscript. The authors declare no competing interests.
Publisher Copyright:
© 2021 Elsevier Inc.
All Science Journal Classification (ASJC) codes
- Chemistry(all)
- Biochemistry
- Environmental Chemistry
- Chemical Engineering(all)
- Biochemistry, medical
- Materials Chemistry
