A Photoactive Platinum(IV) Anticancer Complex Inhibits Thioredoxin–Thioredoxin Reductase System Activity by Induced Oxidization of the Protein

Abstract

Thioredoxin (Trx) is an important enzyme in the redox signaling pathway and is usually overexpressed in tumor cells. We demonstrate herein that the photoactive platinum(IV) anticancer complex trans,trans,trans-[Pt(N)(OH)(Py)] (1) can bind to His, Glu, and Gln residues of Trx upon the irradiation of blue light. More importantly, complex 1 can also induce the oxidation of Met, Trp, and the Cys catalytic sites to form disulfide bonds by generating reactive oxygen species (ROS) upon photoactivation. These eventually lead to inhibition of activity of Trx enzyme and the Trx system and further increase in the cellular ROS level. We speculate that the oxidative damage not only inhibits Trx activity but also greatly contributes to the anticancer action of complex 1.

New Designs for Phototherapeutic Transition Metal Complexes

“…In addition to platinum‐mediated toxicity, nitrogen/oxygen radical species generated upon irradiation can also contribute to the cytotoxicity of these complexes. Inhibition of thioredoxin following treatment with 18 , trans ‐[Pt(N 3 ) 2 (OH) 2 (pyridine) 2 ], and irradiation, has been attributed to oxidation rather than platination suggesting an important role for ROS in the toxicity . Furthermore, a significant production of RNS/ROS is observed for 6 h after irradiation of cancer cells treated with 16 or 18 .…”

Diazido platinum(iv) complexes for photoactivated anticancer chemotherapy

“…107 Platination of His, Glu (glutamic acid), and Gln (glutamine) residues of Trx and oxidation of Met, Trp, and the Cys catalytic sites induced by 13 upon irradiation can inhibit the activity of Trx enzyme and Trx system, and further increase the cellular ROS level. 108…”

Inorganic Coordination Chemistry: Where We Stand in Cancer Treatment?

“…Upon irradiation with blue light, it binds to amino acid residues of thioredoxin, a multifunctional enzyme that regulates gene transcription, redox signaling, and cell growth, inhibiting cell apoptosis, overexpressed in several cancers, leading to an increase oxidative stress persistent for more than 48 h in vitro, with a potent antiproliferative activity. The complex might be suitable for treatment of peripheral cancers such as bladder and esophageal [10,31].…”