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

Zhenzhu Zhu,Zijian Guo,Changli Zhang,Zenghui Wang,Xiaoyong Wang,Yanjun Wang,Hongmei Zhang,Zhenji Gan

doi:10.1039/c8sc04871a

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.

Highlights

Lung cancer, non-small-cell lung cancer (NSCLC), is the most common lethal disease, accounting for ca. 85% of all lung cancer cases.[1]
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
A PtII complex with a mitochondrial-penetrating peptide was delivered to mitochondria of human cancer cells, inducing apoptosis by damaging mitochondrial DNA rather than nuclear DNA (nDNA),[22] which suggests that mtDNA is a potential target for platinum-based anticancer drugs

Summary

Introduction

Non-small-cell lung cancer (NSCLC), is the most common lethal disease, accounting for ca. 85% of all lung cancer cases.[1]. OPT induces remarkable changes in the ultrastructure and membrane of mitochondria, leading to more radical mitochondrial dysfunctions than cisplatin.

Results

Conclusion