Anticancer activity of amphipathic barbiturates

Abstract

Cancer is one of the leading causes of death worldwide. Challenges related to drug resistance, side effects, and poor response rates makes cancer treatment complicated. However, different forms of immunotherapy have been effective for some cancer patients. Oncolytic therapies which can be administered directly intratumorally represent a promising form of immunotherapy. The aim of oncolytic therapies is to kill cancer cells by inducing immunogenic cell death, which can activate a natural anti-tumor immune response.

The current project focused on exploring the potential of amphipathic barbiturates, herein referred to as marine product mimics (MPMs), as novel oncolytic compounds for cancer treatment. The MPMs were developed with inspiration from antimicrobial peptides and the eusynstyelamides, which are a group of natural compounds that have previously been isolated from marine animals.

It was demonstrated that the compound MPM-1 could kill a range of different cell types and induced a necrosis like death in the head and neck squamous cell carcinoma cell line HSC-3. Nine additional MPMs were synthesized and included in further studies. In vitro experimentation indicated that the MPMs have an intracellular target and that they accumulate in lysosomes, which could be part of their mechanism of inducing cell death.

It was demonstrated that the MPMs could cause the release and exposure of damage-associated molecular patterns which are associated with immunogenic cell death, indicating that they could have the potential to be used in oncolytic cancer therapy. An in vivo study was performed where intratumoral injections of MPM-1 were administered to mice bearing B16F1 melanoma tumors. Complete tumor remission was achieved. However, significant protective effects against a rechallenge with the same cancer cells was not observed.

In summary, the MPMs demonstrate potent anticancer activity but whether they have the potential to be used in treatment of human cancer remains to be seen.