Structure and Potential Cellular Targets of HAMLET-like Anti-Cancer Compounds made from Milk Components

Rath, Emma M.; Duff, Anthony P.; Håkansson, Anders; Vacher, Catherine; Liu, Guo Jun; Knott, Robert; Church, W. Bret

doi:10.18433/j3g60c

Cited by 22 publications

(16 citation statements)

References 229 publications

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“…HAMLET is a potent anticancer agent, killing tumor cells of approximately 50 cancer cell types with high selectivity 165 , 166 while leaving healthy cells largely unaffected both in vitro and in vivo. 167 The structure of HAMLET compounds consists of an aggregation of partially unfolded proteins with fatty acid molecules bound in the hydrophobic core.…”

Section: Application Of α-Lactalbumin In Cancer Treatmentsmentioning

confidence: 99%

Applications for α-lactalbumin in human nutrition

2018

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Abstractα-Lactalbumin is a whey protein that constitutes approximately 22% of the proteins in human milk and approximately 3.5% of those in bovine milk. Within the mammary gland, α-lactalbumin plays a central role in milk production as part of the lactose synthase complex required for lactose formation, which drives milk volume. It is an important source of bioactive peptides and essential amino acids, including tryptophan, lysine, branched-chain amino acids, and sulfur-containing amino acids, all of which are crucial for infant nutrition. α-Lactalbumin contributes to infant development, and the commercial availability of α-lactalbumin allows infant formulas to be reformulated to have a reduced protein content. Likewise, because of its physical characteristics, which include water solubility and heat stability, α-lactalbumin has the potential to be added to food products as a supplemental protein. It also has potential as a nutritional supplement to support neurological function and sleep in adults, owing to its unique tryptophan content. Other components of α-lactalbumin that may have usefulness in nutritional supplements include the branched-chain amino acid leucine, which promotes protein accretion in skeletal muscle, and bioactive peptides, which possess prebiotic and antibacterial properties. This review describes the characteristics of α-lactalbumin and examines the potential applications of α-lactalbumin for human health.

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Section: Application Of α-Lactalbumin In Cancer Treatmentsmentioning

confidence: 99%

Applications for α-lactalbumin in human nutrition

2018

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“…Over 20 years of BAMLET research has resulted in many investigations into the BAMLET mechanism of anti-cancer activity and has thrown up many possible cellular targets, but as yet there is no full understanding. The BAMLET mechanism of anti-cancer activity is in some way or another related to the BAMLET structure releasing oleic acid to perturb cancer cell membranes (reviewed in [ 22 ]) and thus is not the same mechanism employed by currently used anti-cancer drugs. ATP synthase is a membrane protein involved in energy production previously shown to be a HAMLET target, with HAMLET treatment resulting in a dose-dependent reduction in levels of the ATP energy molecule [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

“…Complexes of oleic acid with bovine α-lactalbumin protein (BAMLET/HAMLET–Bovine/Human Alpha-lactalbumin Made LEthal to Tumours [ 10 – 11 ]) and with bovine β-lactoglobulin (BLAGLET–Beta-LActoGlobulin made LEthal to Tumours) have demonstrated broad-spectrum anti-cancer activity in vitro to over 50 cancer cell lines [ 12 – 21 ] inventoried in [ 22 ], and have shown efficacy in reducing tumours and non-toxicity to healthy tissue in a few in vivo experiments of cancer tumours in humans, mice, and rats [ 13 , 15 , 23 – 25 ]. HAMLET and BAMLET are also cytotoxic towards some bacteria in vitro and in vivo in mice [ 26 – 29 ].…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown that the fatty acid, most commonly oleic acid, is the main active component of BAMLET and HAMLET-like complexes [ 14 , 18 ]. However, the protein component also plays an important role in BAMLET activity, as not only are a range of anti-cancer and anti-bacterial activities observed for BAMLETs prepared by different methods, but also in BAMLETs constituted with different proteins (reviewed in [ 22 ]). A striking example is albumin which binds oleic acid in blood without reports of associated anti-cancer activity [ 32 ], yet forms a cytotoxic BAMLET complex with oleic acid when prepared using a BAMLET heating protocol [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

“…What the specific cellular targets of BAMLET are is an open question and is an active area of investigation (reviewed in [ 22 ]). The many proposed cellular targets include membrane ion channels [ 29 , 47 – 50 ], histones [ 51 – 53 ], mitochondria [ 54 – 56 ], proteasomes [ 19 ], α-actinin [ 57 ], annexin [ 30 ], and ATP synthase [ 58 ].…”

Section: Introductionmentioning

confidence: 99%

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BAMLET kills chemotherapy-resistant mesothelioma cells, holding oleic acid in an activated cytotoxic state

et al. 2018

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Malignant pleural mesothelioma is an aggressive cancer with poor prognosis. Here we have investigated in vitro efficacy of BAMLET and BLAGLET complexes (anti-cancer complexes consisting of oleic acid and bovine α-lactalbumin or β-lactoglobulin respectively) in killing mesothelioma cells, determined BAMLET and BLAGLET structures, and investigated possible biological mechanisms. We performed cell viability assays on 16 mesothelioma cell lines. BAMLET and BLAGLET having increasing oleic acid content inhibited human and rat mesothelioma cell line proliferation at decreasing doses. Most of the non-cancer primary human fibroblasts were more resistant to BAMLET than were human mesothelioma cells. BAMLET showed similar cytotoxicity to cisplatin-resistant, pemetrexed-resistant, vinorelbine-resistant, and parental rat mesothelioma cells, indicating the BAMLET anti-cancer mechanism may be different to drugs currently used to treat mesothelioma. Cisplatin, pemetrexed, gemcitabine, vinorelbine, and BAMLET, did not demonstrate a therapeutic window for mesothelioma compared with immortalised non-cancer mesothelial cells. We demonstrated by quantitative PCR that ATP synthase is downregulated in mesothelioma cells in response to regular dosing with BAMLET. We sought structural insight for BAMLET and BLAGLET activity by performing small angle X-ray scattering, circular dichroism, and scanning electron microscopy. Our results indicate the structural mechanism by which BAMLET and BLAGLET achieve increased cytotoxicity by holding increasing amounts of oleic acid in an active cytotoxic state encapsulated in increasingly unfolded protein. Our structural studies revealed similarity in the molecular structure of the protein components of these two complexes and in their encapsulation of the fatty acid, and differences in the microscopic structure and structural stability. BAMLET forms rounded aggregates and BLAGLET forms long fibre-like aggregates whose aggregation is more stable than that of BAMLET due to intermolecular disulphide bonds. The results reported here indicate that BAMLET and BLAGLET may be effective second-line treatment options for mesothelioma.

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Neutron scattering shows a droplet of oleic acid at the center of the BAMLET complex

et al. 2017

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The anti-cancer complex, Bovine Alpha-lactalbumin Made LEthal to Tumors (BAMLET), has intriguing broad-spectrum anti-cancer activity. Although aspects of BAMLET's anti-cancer mechanism are still not known, it is understood that it involves the oleic acid or oleate component of BAMLET being preferentially released into cancer cell membranes leading to increased membrane permeability and lysis. The structure of the protein component of BAMLET has previously been elucidated by small angle X-ray scattering (SAXS) to be partially unfolded and dramatically enlarged. However, the structure of the oleic acid component of BAMLET and its disposition with respect to the protein component was not revealed as oleic acid has the same X-ray scattering length density (SLD) as water. Employing the difference in the neutron SLDs of hydrogen and deuterium, we carried out solvent contrast variation small angle neutron scattering (SANS) experiments of hydrogenated BAMLET in deuterated water buffers, to reveal the size, shape, and disposition of the oleic acid component of BAMLET. Our resulting analysis and models generated from SANS and SAXS data indicate that oleic acid forms a spherical droplet of oil incompletely encapsulated by the partially unfolded protein component. This model provides insight into the anti-cancer mechanism of this cache of lipid. The model also reveals a protein component "tail" not associated with the oleic acid component that is able to interact with the tail of other BAMLET molecules, providing a plausible explanation of how BAMLET readily forms aggregates. Proteins 2017; 85:1371-1378. © 2017 Wiley Periodicals, Inc.

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Structure and Potential Cellular Targets of HAMLET-like Anti-Cancer Compounds made from Milk Components

Cited by 22 publications

References 229 publications

Applications for α-lactalbumin in human nutrition

Applications for α-lactalbumin in human nutrition

BAMLET kills chemotherapy-resistant mesothelioma cells, holding oleic acid in an activated cytotoxic state

Neutron scattering shows a droplet of oleic acid at the center of the BAMLET complex

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