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Effects of light-activated diazido-PtIV complexes on cancer cells in vitro
Patrick J Bednarski1, Katharina Korpis, Aron F Westendorf
1Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, 17487 Greifswald, Germany. bednarsk@uni-greifswalde.de
Abstract:
Various Pt(IV) diazides have been investigated over the years as light-activatable prodrugs that interfere with cell proliferation, accumulate in cancer cells and cause cell death. The potencies of the complexes vary depending on the substituted amines (pyridine=piperidine>ammine) as well as the coordination geometry (trans diazide>cis). Light-activated Pt(IV) diazides tend to be less specific than cisplatin at inhibiting cancer cell growth, but cells resistant to cisplatin show little cross-resistance to Pt(IV) diazides. Platinum is accumulated in the cancer cells to a similar level as cisplatin, but only when activated by light, indicating that reactive Pt species form photolytically. Studies show that Pt also becomes attached to cellular DNA upon the light activation of various Pt(IV) diazides. Structures of some of the photolysis products were elucidated by LC-MS/MS; monoaqua- and diaqua-Pt(II) complexes form that are reactive towards biomolecules such as calf thymus DNA. Platination of calf thymus DNA can be blocked by the addition of nucleophiles such as glutathione and chloride, further evidence that aqua-Pt(II) species form upon irradiation. Evidence is presented that reactive oxygen species may be generated in the first hours following photoactivation. Cell death does not take the usual apoptotic pathways seen with cisplatin, but appears to involve autophagy. Thus, photoactivated diazido-Pt(IV) complexes represent an interesting class of potential anti-cancer agents that can be selectively activated by light and kill cells by a mechanism different to the anti-cancer drug cisplatin.
Insights
Photoactivated platinum(IV) diazides are potential cancer drugs that accumulate in tumors and kill cells upon light exposure. These compounds offer an alternative to cisplatin, especially for resistant cancers, and induce cell death through novel mechanisms.
Area of Science:
- Medicinal Chemistry
- Photochemistry
- Cancer Biology
Background:
- Platinum(IV) diazides are investigated as light-activatable prodrugs for cancer therapy.
- Their efficacy and specificity are influenced by ligand substitution and coordination geometry.
Purpose of the Study:
- To investigate the mechanism of action and cellular effects of various photoactivated Pt(IV) diazides.
- To compare their properties with cisplatin, particularly in cisplatin-resistant cell lines.
Main Methods:
- Investigated Pt(IV) diazide complexes with varying amine ligands and coordination geometries.
- Utilized light activation to induce drug effects in cancer cells.
- Characterized photolysis products using LC-MS/MS.
- Assessed DNA binding and cellular responses, including cell death pathways.
Main Results:
- Pt(IV) diazides accumulate in cancer cells upon light activation, forming reactive Pt(II) species.
- These species bind to cellular DNA, similar to cisplatin.
- Cells resistant to cisplatin showed minimal cross-resistance to Pt(IV) diazides.
- Photoactivation led to reactive oxygen species generation and cell death via autophagy, distinct from cisplatin's apoptotic pathway.
Conclusions:
- Photoactivated Pt(IV) diazides are promising anti-cancer agents with light-selective activation.
- They offer a potential alternative for cisplatin-resistant cancers.
- Their unique mechanism of action, involving autophagy, warrants further investigation.
