Transtranstrans-PtIV(N3)2(OH)2(py)(NH3): a light activated antitumor platinum complex that kills human cancer cells by an apoptosis independent mechanism

摘要

Photoactivatable Pt^IV diazido complexes have unusual photobiological properties. We demonstrate here that trans,trans,trans-[Pt^IV(N3)2(OH)2(py)(NH3)] >3 is a potent photoactivated cytotoxin towards human cancer cells in culture, with an average IC50 value in 13 cell lines of 55 ± 28 µM after 30 min (0.12 mW/cm²) photoactivation with UVA, although visible light was also effective. Photoactivated >3 was non-cross-resistant to cisplatin in 3 of 4 resistant cell lines. Cell swelling but very little blebbing was seen for HL60 cells treated with irradiated >3. Unlike cisplatin and etoposide, both of which cause apoptosis in HL60 cells, no apoptosis was observed for UVA-activated >3 by the Annexin V/propidium iodide flow cytotometry assay. Changes in the levels of the autophagic proteins LC3B-II and p62 in HL60 cells treated with UVA-activated 3 indicate autophagy is active during cell death. In a clonogenic assay with the SISO human cervix cancer cell line, >3 inhibited colony formation when activated by UVA irradiation. Antitumor activity of >3 in mice bearing xenografted OE19 esophageal carcinoma tumors was photoaugmented by visible light. Insights into the novel reaction pathways of >3 have been obtained from ¹⁴N{¹H} NMR studies, which show that photoactivation pathways can involve release of free azide in buffered solution. Density functional theory (DFT) and time-dependent DFT (TDDFT) calculations revealed the dissociative character of singlet and triplet excited states of >3, which give rises to reactive, possibly cytotoxic azidyl radicals.