Structural characterisation of BAMLET-like anti-cancer complexes and investigation of their potential for treating mesothelioma

Abstract

BAMLET and related compounds are a family of protein-oleic acid complexes that are cytotoxic towards a range of cancer cells and some bacteria, and for which no evidence of similar toxicity towards healthy tissue has yet been presented. This thesis determines the structure of BAMLET-like complexes, revealing that they belong to a new type of lipid-binding protein structure family consisting of the distinctive features of protein located on the periphery encapsulating a drop of oleic acid in the centre. This work is the first to reveal these distinctive structural features of what is now called the liprotide family. The oleic acid component of the BAMLET family member is shown to form a 36 Å diameter spheroid with the partially unfolded bovine α-lactalbumin polypeptide component expanded to a diameter of 79 Å. Small angle X-ray and neutron scattering were the principal techniques used and comprehensively elucidate the structure. The anti-cancer mechanism of BAMLET compounds appears to be novel and the novel structure revealed in this thesis provides part of the explanation for how they achieve broad spectrum activity. In an aqueous environment, the BAMLET complex is stable and its oleic acid cargo is thus solubilised, until a cell membrane is encountered, for which the oleic acid could have higher affinity resulting in activity against the cell. This thesis also demonstrates a possible application to the treatment of mesothelioma for BAMLET-like compounds, that negates the disadvantage that blood components disable BAMLET’s anti-cancer activity. Tissue culture and cell death assay techniques were used to show that BAMLET is equally cytotoxic towards mesothelioma cells that have developed increased resistance to the cisplatin or pemetrexed chemotherapy drugs, as towards mesothelioma cells that do not have heightened resistance. These results position BAMLET as a potentially valuable treatment option for this ultimately treatment-resistant cancer.