A [Pt(cis-1,3-diaminocycloalkane)Cl2] analog exhibits hallmarks typical of immunogenic cell death inducers in model cancer cells.

Abstract

The platinum drugs belong to prevailing chemotherapeutics used in the treatment of cancer. At present, however, the search for new anticancer metal-based drugs that operate by the mechanisms distinct from those of the conventional chemotherapeutics is very active. Furthermore, it has been demonstrated that cytotoxic chemotherapy and immunotherapy may exert a highly synergistic anticancer activity. Thus, the development of antitumor platinum and other metal-based drugs that exhibit cytostatic effects and concurrently elicit immunogenic cell death (ICD) has shown promise for cancer treatment. Notably, conventional platinum drug oxaliplatin ([Pt(1R,2R-DACH)(oxalate)], DACH = diaminocyclohexane) is a well-known agent that displays both cytostatic and immune responses. Moreover, it was also demonstrated that even minor derivatization of the unleaving cycloalkyl moiety in oxaliplatin might have a pronounced effect on its immunomodulatory activity. Here, we investigated how replacing the 1R,2R- diaminocyclohexane ring by 1,3-diaminocycloalkane (alkane = butane, pentane, or hexane) affects the ability to evoke secretion of damage-associated molecular patterns characteristic of ICD in model murine colorectal carcinoma cell line CT26. The results indicate that among the investigated [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes, the complex containing the cyclobutyl moiety exhibits the hallmarks typical of ICD inducers. Thus, [Pt(cis-1,3-diaminocyclobutane)Cl2] may expand the spectrum of anticancer chemotherapeutics capable of inducing ICD in cancer cells and might be of interest for further (pre)clinical development.