Combination of Anti-Cancer Salan Ti(IV) Complexes with Cisplatin: Synergistic Effects

Nitzan Ganot, The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel
Edit Y. Tshuva, The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel

The significant drawbacks of cisplatin, namely its high toxicity and development of drug-resistance, initiated an extensive search for other metals that can lead to anti-cancer activity. Ti^IV complexes showed promising cytotoxic activity, and two Ti^IV based complexes reached clinical trials. Nevertheless, these complexes have failed clinical trials due to instability in aqueous environment. Our group designed a new family of anti-cancer Ti^IV complexes based on salan ligands, which showed high cytotoxic activity toward numerous cancer cell lines and enhanced stability in aqueous environment.

Combination therapy is a very common method in clinical treatment of cancer. By combining two drugs or more, the doses that are required to reach the desired effect are reduced, and consequently their side effects and toxicity are reduced as well.

Herein, combination of salan Ti^IV complexes with cisplatin are presented. Non-covalent combination of salan Ti^IV complexes and cisplatin often showed a synergistic behavior, depending on the substitution on the salan ligand, the ratio of the combined drugs, the type of the treated cancer cell lines, and the schedule of administration. Additionally, attempts are made to covalently combine salan Ti^IV complexes with cisplatin and with steroids.  Such combined complexes may enhance the cytotoxicity as well as the selectivity of the complexes to particular cell types. Achievements in these directions will be discussed.