Issue 10, 2019

Mitochondrion-targeted platinum complexes suppressing lung cancer through multiple pathways involving energy metabolism

Abstract

Mitochondria are potential therapeutic targets for anticancer drugs. A series of mitochondrion-targeted monofunctional platinum complexes, [Pt(ortho-PPh3CH2Py)(NH3)2Cl](NO3)2 (OPT), [Pt(meta-PPh3CH2Py)(NH3)2Cl](NO3)2 (MPT), and [Pt(para-PPh3CH2Py)(NH3)2Cl](NO3)2 (PPT) (PPh3 = triphenylphosphonium, Py = pyridine), are studied in this article. The antitumor activity and mechanism of action have been investigated in vitro and in vivo as well as on molecular levels. OPT exhibits higher efficacy than cisplatin against A549 lung cancer cells; furthermore, it shows a strong inhibition towards the growth of non-small-cell lung cancer in nude mice. The DNA binding ability of these complexes follows an order of PPT > OPT > MPT. Cellular uptake and distribution studies show that OPT accumulates mainly in mitochondria, while MPT and PPT accumulate more preferentially in nuclei than in mitochondria. As a result, OPT induces remarkable changes in the ultrastructure and membrane of mitochondria, leading to more radical mitochondrial dysfunctions than cisplatin. The release of cytochrome c from mitochondria is more evident for cells treated with OPT than with cisplatin, though the apoptosis of A549 cells induced by OPT is similar to that induced by cisplatin. Disruption to mitochondrial oxidative phosphorylation and glycolysis is involved in the antitumor mechanism of these compounds. The results indicate that in addition to DNA binding, bioenergetic pathways also play crucial roles in the antitumor activity of mitochondrion-targeted monofunctional platinum complexes.

Graphical abstract: Mitochondrion-targeted platinum complexes suppressing lung cancer through multiple pathways involving energy metabolism

Supplementary files

Article information

Article type
Edge Article
Submitted
01 11 2018
Accepted
16 1 2019
First published
22 1 2019
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2019,10, 3089-3095

Mitochondrion-targeted platinum complexes suppressing lung cancer through multiple pathways involving energy metabolism

Z. Zhu, Z. Wang, C. Zhang, Y. Wang, H. Zhang, Z. Gan, Z. Guo and X. Wang, Chem. Sci., 2019, 10, 3089 DOI: 10.1039/C8SC04871A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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