HAMLET: Functional Properties and Therapeutic Potential

Abstract

Human α-lactalbumin made lethal to tumor cells (HAMLET) is the first member in a new family of protein-lipid complexes that kills tumor cells with high selectivity. The protein component of HAMLET is α-lactalbumin, which in its native state acts as a substrate specifier in the lactose synthase complex, thereby defining a function essential for the survival of lactating mammals. In addition, α-lactalbumin acquires tumoricidal activity after partial unfolding and binding to oleic acid. The lipid cofactor serves the dual role as a stabilizer of the altered fold of the protein and a coactivator of specific steps in tumor cell death. HAMLET is broadly tumoricidal, suggesting that the complex identifies conserved death pathways suitable for targeting by novel therapies. Sensitivity to HAMLET is defined by oncogene expression including Ras and c-Myc and by glycolytic enzymes. Cellular targets are located in the cytoplasmic membrane, cytoskeleton, mitochondria, proteasomes, lysosomes and nuclei, and specific signaling pathways are rapidly activated, first by interactions of HAMLET with the cell membrane and subsequently after HAMLET internalization. Therapeutic effects of HAMLET have been demonstrated in human skin papillomas and bladder cancers, and HAMLET limits the progression of human glioblastomas, with no evidence of toxicity for normal brain or bladder tissue. These findings open up new avenues for cancer therapy and the understanding of conserved death responses in tumor cells.

Oleic Acid May Be the Key Contributor in the BAMLET-Induced Erythrocyte Hemolysis and Tumoricidal Action

“…The exact mechanism by which HAMLET-like complexes exert tumoricidal action continues to remain elusive despite concerted global efforts. Available data however suggest that the OA complex of α-LA selectively enters tumor cells and induces apoptosis-like events, stimulates macroautophagy and inhibits proteasomes [9,10]. Storm et al [11,12] using small-hairpin RNA inhibition, proteomic and metabolomics technologies showed that c-Myc oncogene is an important determinant of HAMLET sensitivity; cells expressing high levels of c-Myc were more sensitive, while knock down of the gene lowered HAMLET sensitivity.…”

Protein–lipid complexes: molecular structure, current scenarios and mechanisms of cytotoxicity

“…Therefore, internalization of protein-lipid complexes to tumor cells, interference with proteasomes and perturbations of proteasome structure can combine with the cytotoxic activity of oxidized and misfolded protein complexes that attack the host cells. 95 f. Autophagic action Autophagy (autophagocytosis) is a natural pathway of orderly lysosomal degradation and recycling that has been used by eukaryotic cells to regulate large protein aggregates, intracellular organelles and dysfunctional components that cannot be degraded by proteasome cores. 96,97 In most eukaryotic cells, autophagy takes place at basal stages as an adaptive response in extreme cases such as starvation, which stimulates survival, but in other cases it appears to stimulate morbidity and cell death.…”

Clinical Experience of Cancer Immunotherapy Integrated With Oleic Acid Complexed With De-Glycosylated Vitamin D Binding Protein

“…Since OA-protein complexes and GcMAF show no evidence of toxicity (Ho et al, 2012;Bradstreet et al, 2012), these complexes were selected as part of an integrative immunotherapeutic approach to advanced cancers in the context of the so-called compassionate approach. In this study we describe the preliminary experiences of treating patients with advanced cancers, some of them considered as "incurable", with an integrative immunotherapy centred on OA-GcMAF.…”