α-Lactalbumin species variation, HAMLET formation, and tumor cell death

Pettersson, Jenny; Mossberg, Ann-Kristin; Svanborg, Catharina

doi:10.1016/j.bbrc.2006.04.081

Cited by 92 publications

(83 citation statements)

References 37 publications

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“…Whereas the purified bovine α-lactalbumin alone failed to induce any cytotoxicity, the BAMLET complex exhibited cytotoxic activity similar to that of HAMLET in L1210 mouse lymphoma cells as reported earlier (19), and in seven additional cancer cell lines tested with LC 50 values ranging from 0.05 to 0.34 mg/mL (Table 1 and Fig. 1).…”

Section: Bamlet Induces Caspase-independent Apoptosislike Cell Death supporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

“…Amino-acid sequences of human, bovine, equine, caprine, and porcine show 71% homology and 63% identity with the highest sequence conservation surrounding the high affinity Ca ++ -binding site (19). Accordingly, ion exchange chromatography on oleic acid-conditioned matrixes allows the formation of protein:lipid complexes of nonhuman α-lactalbumins with yields comparable with HAMLET (19). Importantly, all of these complexes have been reported to have tumoricidal activity as assessed by their ability to kill L1210 mouse lymphoma cells, indicating that α-lactalbumins from different species can be converted into active cytotoxic protein-lipid complexes.…”

Section: Introductionmentioning

confidence: 99%

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BAMLET Activates a Lysosomal Cell Death Program in Cancer Cells

Rammer

Groth‐Pedersen

Kirkegaard

et al. 2010

Molecular Cancer Therapeutics

119

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A complex of human α-lactalbumin and oleic acid (HAMLET) was originally isolated from human milk as a potent anticancer agent. It kills a wide range of transformed cells of various origins while leaving nontransformed healthy cells largely unaffected both in vitro and in vivo. Importantly, purified α-lactalbumins from other mammals form complexes with oleic acid that show biological activities similar to that of HAMLET. The mechanism by which these protein-lipid complexes kill tumor cells is, however, largely unknown. Here, we show that complex of bovine α-lactalbumin and oleic acid (BAMLET), the bovine counterpart of HAMLET, kills tumor cells via a mechanism involving lysosomal membrane permeabilization. BAMLET shows potent cytotoxic activity against eight cancer cell lines tested, whereas nontransformed NIH-3T3 murine embryonic fibroblasts are relatively resistant. BAMLET accumulates rapidly and specifically in the endolysosomal compartment of tumor cells and induces an early leakage of lysosomal cathepsins into the cytosol followed by the activation of the proapoptotic protein Bax. Ectopic expression of three proteins known to stabilize the lysosomal compartment, i.e. heat shock protein 70 (Hsp70), Hsp70-2, and lens epithelium-derived growth factor, confer significant protection against BAMLET-induced cell death, whereas the antiapoptotic protein Bcl-2, caspase inhibition, and autophagy inhibition fail to do so. These data indicate that BAMLET triggers lysosomal cell death pathway in cancer cells, thereby clarifying the ability of α-lactalbumin:oleate complexes to kill highly apoptosis-resistant tumor cells. Mol Cancer Ther; 9(1); 24-32. ©2010 AACR.

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Section: Bamlet Induces Caspase-independent Apoptosislike Cell Death supporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

BAMLET Activates a Lysosomal Cell Death Program in Cancer Cells

Rammer

Groth‐Pedersen

Kirkegaard

et al. 2010

Molecular Cancer Therapeutics

119

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“…In addition to human and bovine -LA, equine, caprine, and porcine -LA can also form cytotoxic complexes with OA [7]. Later investigations showed that the loss of tertiary structure in -LA denatured by heat-treatment or a recombinant variant of -LA in which all four cysteines have been exchanged with alanine did not prevent it from forming cytotoxic complexes using an OA conditioned column [8,9].…”

Section: Introductionmentioning

confidence: 99%

The cytotoxicity of fatty acid/α‐lactalbumin complexes depends on the amount and type of fatty acid

Brinkmann

Brodkorb

Thiel

et al. 2013

Euro J Lipid Sci & Tech

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Complexes of the milk protein, α‐lactalbumin, and the fatty acid, oleic acid, have previously been shown to be cytotoxic. Complexes of α‐lactalbumin and five different fatty acids (vaccenic, linoleic, palmitoleic, stearic, and elaidic acid) were prepared and compared to those formed with oleic acid. All complexes were cytotoxic to human promyelocytic leukemia‐derived (HL‐60) cells but to different degrees depending on the fatty acid. The amount of fatty acid per α‐lactalbumin molecule was found to correlate with the cytotoxicity; the higher the number of fatty acids per protein, the more cytotoxic the complex. Importantly, all the tested fatty acids were also found to be cytotoxic on their own in a concentration dependent manner. The cytotoxic effect of complexes between α‐lactalbumin and linoleic acid, vaccenic acid, or oleic acid was further investigated using flow cytometry and found to induce cell death resembling apoptosis on Jurkat cells.Practical applications: Cytotoxic complexes of α‐lactalbumin and several different fatty acids could be produced. The cytotoxicity of all the variants is similar to that previously determined for α‐lactalbumin/oleic acid complexes.

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“…Furthermore, lactoferrin and its peptides, for example, lactoferricin [212][213][214], both possess anticancer activity by inducing apoptosis; inhibit angiogenesis, modulating the carcinogen metabolizing enzymes, and so on. Casein and casein derived peptides have antimutagenic properties, and other whey protein components, such as -lactoglobulin, -lactalbumin and serum albumin, have also demonstrated anticancer potential [212,[215][216][217]. Moreover, a recombinant adenovirus containing the human lactoferrin cDNA has been constructed and its effects against tumor growth have been investigated in mice bearing EMT6 breast cancer.…”

Section: Commercial Potential Of Milk Derived Proteins and Peptidesmentioning

confidence: 99%