Ferroptosis Inducing Co(III) Polypyridine Sulfasalazine Complex for Therapeutically Enhanced Anticancer Therapy

• Published in: Angewandte Chemie International Edition 2024-11, Vol.63 (48), p.e202412585-n/a
• Main Authors: Montesdeoca, Nicolás, Johannknecht, Lukas, Efanova, Elizaveta, Heinen‐Weiler, Jacqueline, Karges, Johannes
• Format: Article
• Language: English
• Subjects: Anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic drugs; Apoptosis; Bioinorganic Chemistry; Cancer; Cell death; Cell Line, Tumor; Cell Proliferation - drug effects; Chemical synthesis; Cobalt - chemistry; Cobalt - pharmacology; Colon cancer; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Drug Screening Assays, Antitumor; Ferroptosis; Ferroptosis - drug effects; Humans; Lipids; Medicinal Inorganic Chemistry; Metals in Medicine; Multicellular tumor spheroids; Peroxides; Pyridines - chemistry; Pyridines - pharmacology; Spheroids; Sulfasalazine; Sulfasalazine - chemistry; Sulfasalazine - pharmacology; Tumors
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202412585

Despite significant improvements in the treatment of cancerous tumors in the last decades, cancer remains one of the deadliest diseases worldwide. To overcome the shortcomings of currently applied chemotherapeutic treatments, much research efforts have been devoted towards the development of ferroptosis inducing anticancer agents. Ferroptosis is a newly described form of regulated, non‐apoptotic cell death that is associated with high potential inside the clinics. Herein, the chemical synthesis and biological evaluation of a Co(III) polypyridine sulfasalazine complex as a ferroptosis inducer is reported. Upon entering the cancerous cells, the metal complex primarily accumulated in the mitochondria, triggering the production of hydroxy radicals and lipid peroxides, ultimately causing cell death by ferroptosis. The compound demonstrated to eradicate various monolayer cancer cells as well as colon carcinoma multicellular tumor spheroids. To the best of our knowledge this study reports on the first example of a Co(III) complex that is capable of inducing ferroptosis. Targeting ferroptosis provides a novel avenue to overcome the limitations of apoptotic anticancer treatments. The Co(III) polypyridine sulfasalazine complex described here acts as a potent ferroptosis inducer for anticancer therapy. This complex selectively accumulates in mitochondria, generating reactive oxygen species, initiating lipid peroxidation, depleting glutathione, inhibiting glutathione peroxidase 4, and ultimately driving ferroptosis.