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. 2019 Jan 22;10(10):3089-3095.
doi: 10.1039/c8sc04871a. eCollection 2019 Mar 14.

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

Zhenzhu Zhu  1 , Zenghui Wang  2 , Changli Zhang  3 , Yanjun Wang  1 , Hongmei Zhang  1 , Zhenji Gan  4 , Zijian Guo  2 , Xiaoyong Wang  1
Affiliations

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

Zhenzhu Zhu et al. Chem Sci. .

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.

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Figures

Fig. 1
Fig. 1. Structures of pyriplatin, OPT, MPT and PPT.
Fig. 2
Fig. 2. Cytotoxic profiles of the complexes against A549 (A) and HL-7702 cells (B) at 48 h, A549 tumor progression of mice treated with OPT (5 mg kg–1) (C), and changes of tumor volume after 19 d treatment (D). Cytotoxicity is presented as the mean ± S.D. of three independent experiments; tumor volume is presented as the average volume ± S.D. of 5 mice, *p < 0.1, **p < 0.01, ***p < 0.001, and ****p < 0.0001. Cisplatin and saline are used as controls.
Fig. 3
Fig. 3. Content of nDNA-bound Pt in A549 cells after incubation with OPT, MPT, PPT, pyriplatin and cisplatin (10 μM), respectively, for 24 h (A), and damage to the D-loop region of mtDNA in A549 cells caused by OPT, MPT, PPT and cisplatin, respectively (B). Data are expressed as mean ± S.D. of at least three independent experiments.
Fig. 4
Fig. 4. Mitochondrial bioenergetics in A549 cells. (A) OCR variations, (B) key parameters of mitochondrial respiration, (C) metabolic phenotypes and (D) intracellular citrate levels after treatment with OPT, MPT, PPT, and cisplatin (10 μM), respectively, for 24 h, presented as mean ± S.D. (n = 5).
Fig. 5
Fig. 5. Representative images of A549 cells after incubation with OPT, cisplatin, and pyriplatin (10 μM) for 12 h, respectively, detected by fluorescence microscopy using a JC-1 probe.
Fig. 6
Fig. 6. TEM images of the mitochondrial structure in A549 cells treated with OPT (10 μM) for 24 h and without treatment.
Fig. 7
Fig. 7. (A) Western blotting analysis of Cyto c released from the mitochondria of A549 cells after treatment with the complexes using β-actin (42 kDa) as a reference, and relative intensity of Cyto c analyzed by Image J (mean ± S.D., n = 3). (B) Flow cytometric analysis of A549 cells after incubation with OPT or cisplatin (10 μM) for 24 h and subsequent staining with Annexin V-FITC and PI.
Fig. 8
Fig. 8. Proposed mechanism of action for OPT.
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