Therapeutic Discovery Trans,trans,trans-[Pt(N3)2(OH)2(py)(NH3)]: A Light-Activated Antitumor Platinum Complex That Kills Human Cancer Cells by an Apoptosis-Independent Mechanism

Photoactivatable Pt diazido complexes have unusual photobiologic properties. We show here that trans, trans,trans-[Pt(N3)2(OH)2(py)(NH3)] complex 3 is a potent photoactivated cytotoxin toward human cancer cells in culture, with an average IC50 value in 13 cell lines of 55 28 mmol/L after 30 minutes (0.12 mW/cm) photoactivation with UVA, although visible light was also effective. Photoactivated complex 3 was noncrossresistant to cisplatin in 3 of 4 resistant cell lines. Cell swelling but very little blebbing was seen for HL60 cells treatedwith irradiated complex 3. Unlike cisplatin and etoposide, both of which cause apoptosis inHL60 cells, no apoptosis was observed for UVA-activated complex 3 by the Annexin V/propidium iodide flow cytotometry assay. Changes in the levels of the autophagic proteins LC3B-II and p62 inHL60 cells treatedwith UVAactivated complex 3 indicate autophagy is active during cell death. In a clonogenic assaywith the SISO human cervix cancer cell line, 3 inhibited colony formation when activated by UVA irradiation. Antitumor activity of complex 3 in mice bearing xenografted OE19 esophageal carcinoma tumors was photoaugmented by visible light. Insights into thenovel reactionpathways of complex 3havebeenobtained fromN{H}nuclearmagnetic resonance studies, which show that photoactivation pathways can involve release of free azide in buffered solution. Density functional theory (DFT) and time-dependent DFT calculations revealed the dissociative character of singlet and triplet excited states of complex 3,which gives rise to reactive, possibly cytotoxic azidyl radicals. Mol Cancer Ther; 11(9); 1894–904. 2012 AACR.