Oncolytic Activity and Mechanisms of Action by a small β2,2-amino acid derivative LTX-401

Abstract

Antimicrobial peptides are part of the innate immune defence of many organisms and represent a novel class of therapeutics due to their broad-spectrum activities, including cytotoxic activity against cancer cells. It has recently been reported that small antimicrobial β2,2-amino acid derivatives (Mw<500), such as LTX-401, possess potent anticancer activity against Ramos human Burkitt’s lymphoma cells. In the present thesis, the anticancer properties displayed by LTX-401 became subject for a continued investigation. In vitro cytotoxicity studies revealed that LTX-401 was highly active against a panel of malignant cells including murine and human cancer cell lines. Moreover, LTX-401 was found to induce known features of immunogenic cell death as shown by the release of Damage-Associated Molecular Pattern molecules such as High-Mobility Group Box-1 protein, adenosine triphosphate and cytochrome c in vitro. Intralesional administration of LTX-401 into intradermally established B16 melanomas in syngeneic mice resulted in complete regression of the tumor. Moreover, cured animals that were given a second tumor challenge with live B16F1 cells did not develop tumor and displayed immune protection against the cancer. Altogether, these results underscore the therapeutic potential of LTX-401 in conveying local tumor control and generation of protective immunity, presumably by the engagement of immunogenic cell death.