The cytotoxicity of BAMLET complexes is due to oleic acid and independent of the α‐lactalbumin component

Delgado, Yamixa; Morales‐Cruz, Moraima; Figueroa, Cindy; Hernández-Román, José; Hernández, Glinda; Griebenow, Kai

doi:10.1016/j.fob.2015.04.010

Cited by 40 publications

(33 citation statements)

References 56 publications

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“…However, opposing views on specificity and cytotoxicity of HAMLET/BAMLET (the bovine counterpart) can be found in the literature. For example, while even recent papers still suggest that HAMLET/BAMLET are specifically cytotoxic to cancer cells [13,14], our results demonstrated that BAMLET could kill cancer cells (HeLa and A-549 lines) and normal cells (ChoK-1 and NIH-3T3 lines) almost with the same strength [15] and confirmed the results of Brinkmann on BAMLET cytotoxicity to non-cancer derived primary cells [16]. Similarly, several works established that HAMLET/BAMLET components (α-LA and OA) alone were unable to kill cancer cells [17,18] highlighting the importance of the synergy of the components in the tumor toxicity.…”

Section: Introductioncontrasting

confidence: 43%

“…However, other articles pointed out that OA prepared without the protein is sufficient for the potent cytotoxicity [20,21]. We demonstrated that the isolated FA OA and the polyunsaturated linoleic acid induced caspase-independent cell death at the same concentration at which BAMLET does [15]. It has also been shown that mono-and polyunsaturated FAs could be internalized by receptor-mediated endocytosis or by diffusion across the cell membranes [22,23] and influenced inflammation, apoptosis, and growth inhibition processes [24,25].…”

Section: Introductionmentioning

confidence: 66%

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Development of HAMLET-like Cytochrome c-Oleic Acid Nanoparticles for Cancer Therapy

Morales¹

2015

J Nanomed Nanotechnol

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In the literature, HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) is described as a tumoricidal complex composed of oleic acid (OA) non-covalently bound to α-lactalbumin. We recently demonstrated that OA is the real drug in this complex and that the protein solely serves as the drug carrier. We hypothesized that by replacing α-lactalbumin with a bioactive protein it should be possible to synergistically increase the efficiency of the complex. Consequently, we developed a HAMLET-like complex composed of OA coupled to the apoptosis-inducing protein cytochrome c (Cyt c). As control we coupled OA to the non-toxic protein bovine serum albumin (BSA). The syntheses of HAMLET-like Cyt c-OA and BSA-OA complexes were performed at pH 8 and 45°C and we loaded 10 and 53 molecules of OA per molecule of Cyt c and BSA, respectively. We found that OA binding promotes protein structural changes characteristic of the protein-OA interactions in HAMLET. Cyt c-OA and BSA-OA complexes had a circular shape and a diameter of 123 and 169 nm, respectively. Cell viability tests showed less than 10% of viability after cancer cell (HeLa and A-549) incubation for 6 h with Cyt c-OA, while normal cells (Cho-K1 and NIH/3T3) showed more than 20% of viability. BSA-OA killed both cell types with less efficiency and no selectivity. The Cyt c-OA complex showed 50% of caspase-3 and caspase-9 activation in a cell-free assay while BSA-OA lacked any caspase activation. Confocal micrographs showed morphological changes indicative of late-and early-apoptosis by the action of Cyt-OA and BSA-OA, respectively. This study demonstrates that using Cyt c increases the potency of OA in HAMLET-like complexes.

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Section: Introductioncontrasting

confidence: 43%

Section: Introductionmentioning

confidence: 66%

Development of HAMLET-like Cytochrome c-Oleic Acid Nanoparticles for Cancer Therapy

Morales¹

2015

J Nanomed Nanotechnol

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“…However, although HAMLET-like compounds have been assayed on 50 different cancer cell lines, the literature contains only 11 types of primary cell cultures, and thus it remains to be seen whether these trends will hold when more types of primary cells are investigated. The 6 immortalised non-cancer cells lines investigated have sensitivities to HAMLET that are in the same range as the cancer cell lines (7,14,16,22). It is not yet clear whether this is due to a general toxicity of HAMLET to healthy cells, or whether HAMLET is targeting a fundamental cancer-like characteristic that is possessed by immortalised non-cancer cell lines.…”

Section: Cytotoxicity To Cancer and Non-cancer Cellsmentioning

confidence: 99%

“…Modelling of SAXS data at pH 9.0 and RP-HPLC measurements give diameters of 1.8 to 3.6 nm depending on the BAMLET preparation method and diameters of 1.8 to 2.8 nm for HAMLET-like compounds made from β-lactoglobulin, lysozyme, parvalbumin, ovalbumin, albumin or immunoglobulin G (5). In filtered water, BAMLET has diameters ranging from 227 to 292 nm, as measured by DLS, depending on the BAMLET preparation method (22). Figure 3 shows a plausible model for a BAMLET oligomer at physiological pH.…”

Section: Partially Unfoldedmentioning

confidence: 99%

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

et al. 2015

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-The HAMLET family of compounds (Human Alpha-lactalbumin Made Lethal to Tumours) was discovered during studies on the properties of human milk, and is a class of protein-lipid complexes having broad spectrum anti-cancer, and some specific anti-bacterial properties. The structure of HAMLETlike compounds consists of an aggregation of partially unfolded protein making up the majority of the compound's mass, with fatty acid molecules bound in the hydrophobic core. This is a novel protein-lipid structure and has only recently been derived by small-angle X-ray scattering analysis. The structure is the basis of a novel cytotoxicity mechanism responsible for anti-cancer activity to all of the around 50 different cancer cell types for which the HAMLET family has been trialled. Multiple cytotoxic mechanisms have been hypothesised for the HAMLET-like compounds, but it is not yet clear which of those are the initiating cytotoxic mechanism(s) and which are subsequent activities triggered by the initiating mechanism(s). In addition to the studies into the structure of these compounds, this review presents the state of knowledge of the anti-cancer aspects of HAMLET-like compounds, the HAMLET-induced cytotoxic activities to cancer and non-cancer cells, and the several prospective cell membrane and intracellular targets of the HAMLET family. The emerging picture is that HAMLET-like compounds initiate their cytotoxic effects on what may be a cancer-specific target in the cell membrane that has yet to be identified.

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Bioactive Compounds

Visentini¹,

Pérez²,

Ferrado³

et al. 2022

Biomolecules From Natural Sources

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The cytotoxicity of BAMLET complexes is due to oleic acid and independent of the α‐lactalbumin component

Abstract: Graphical abstract

Cited by 40 publications

References 56 publications

Development of HAMLET-like Cytochrome c-Oleic Acid Nanoparticles for Cancer Therapy

Development of HAMLET-like Cytochrome c-Oleic Acid Nanoparticles for Cancer Therapy

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

Bioactive Compounds

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