Treatment of Skin Papillomas with Topical α-Lactalbumin–Oleic Acid

Gustafsson, Lotta; Leijonhufvud, Irene; Aronsson, Annika; Mossberg, Ann-Kristin; Svanborg, Catharina

doi:10.1056/nejmoa032454

Cited by 179 publications

(150 citation statements)

References 21 publications

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“…The MG state is characterized by the absence of long-lived tertiary structure, but it still contains a high degree of secondary structure (20,21), with a radius of gyration only Ϸ10% larger than the native state (22,23). The MG state of ␣-lactalbumin has recently attracted considerable interest when it was realized that it may act as an important component causing apoptosis of tumor cells (24).…”

Section: Conformational Transition Kinetics Of ␣-Lactalbumin From An mentioning

confidence: 99%

Protein folding and unfolding studied at atomic resolution by fast two-dimensional NMR spectroscopy

Schanda

Forge

Brutscher

2007

Proc. Natl. Acad. Sci. U.S.A.

152

151

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Atom-resolved real-time studies of kinetic processes in proteins have been hampered in the past by the lack of experimental techniques that yield sufficient temporal and atomic resolution. Here we present band-selective optimized flip-angle short transient (SOFAST) real-time 2D NMR spectroscopy, a method that allows simultaneous observation of reaction kinetics for a large number of nuclear sites along the polypeptide chain of a protein with an unprecedented time resolution of a few seconds. SOFAST real-time 2D NMR spectroscopy combines fast NMR data acquisition techniques with rapid sample mixing inside the NMR magnet to initiate the kinetic event. We demonstrate the use of SOFAST real-time 2D NMR to monitor the conformational transition of ␣-lactalbumin from a molten globular to the native state for a large number of amide sites along the polypeptide chain. The kinetic behavior observed for the disappearance of the molten globule and the appearance of the native state is monoexponential and uniform along the polypeptide chain. This observation confirms previous findings that a single transition state ensemble controls folding of ␣-lactalbumin from the molten globule to the native state. In a second application, the spontaneous unfolding of native ubiquitin under nondenaturing conditions is characterized by amide hydrogen exchange rate constants measured at high pH by using SOFAST real-time 2D NMR. Our data reveal that ubiquitin unfolds in a gradual manner with distinct unfolding regimes.hydrogen/deuterium exchange ͉ molecular kinetics ͉ ␣-lactalbumin ͉ ubiquitin A detailed description of the structural changes occurring during the folding and unfolding of proteins still remains a challenging objective in biophysics. The understanding of the fundamental mechanisms of the folding process will also shed light on the factors leading to protein misfolding responsible for neurodegenerative diseases such as Alzheimer's and Parkinson's diseases (1). The ideal method to study protein folding/unfolding provides structural information at atomic resolution and is sensitive to changes occurring on time scales ranging from microseconds to minutes, a task that no single technique is able to fulfill. NMR spectroscopy is especially well adapted to obtain detailed atomistic information about the mechanisms, kinetics, and energetics of the folding/unfolding process for virtually every nuclear site in the protein. NMR methods are sensitive to molecular dynamics occurring over a wide range of time scales (Fig. 1a). Although steady-state NMR methods are well suited to characterize equilibrium molecular dynamics occurring on a subsecond time scale (2, 3), unidirectional processes are best studied by real-time NMR (4, 5), where a series of NMR spectra is recorded during the reaction (Fig. 1b). Two difficulties have so far hampered the widespread application of real-time NMR to the study of protein folding. The first problem is the low intrinsic sensitivity of NMR at ambient temperature, a consequence of the small transition energies ...

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Section: Conformational Transition Kinetics Of ␣-Lactalbumin From An mentioning

confidence: 99%

Protein folding and unfolding studied at atomic resolution by fast two-dimensional NMR spectroscopy

Schanda

Forge

Brutscher

2007

Proc. Natl. Acad. Sci. U.S.A.

152

151

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“…We have shown that the partially unfolded form of the human protein attains a new function when bound to oleic acid [1]. HAMLET kills tumor cells in vitro and the anti-tumor activity is retained in vivo, in a brain tumor model and in patients with skin papillomas [24,25]. This study examined if α -lactalbumins from different species can form HAMLET-like with similar biological activity as HAMLET.…”

Section: Can Hamlet-like Complexes Be Formed From Casein If Oleic Acimentioning

confidence: 99%

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

Pettersson

Mossberg

Svanborg

2006

Biochemical and Biophysical Research Communications

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HAMLET (human α-lactalbumin made lethal to tumor cells) is a tumoricidal complex of apo α-lactalbumin and oleic acid, formed in casein after low pH treatment of human milk. This study examined if HAMLET-like complexes are present in casein from different species and if isolated α-lactalbumin from those species can form such complexes with oleic acid. Casein from human, bovine, equine and porcine milk were separated by ion exchange chromatography and active complexes were only found in human casein. This was not explained by α-lactalbumin sequence variation, as purified bovine, equine, porcine and caprine α-lactalbumins formed complexes with oleic acid with biological activity similar to HAMLET. We conclude that structural variation of α-lactalbumins does not preclude the formation of HAMLET-like complexes and that natural HAMLET formation in casein was unique to human milk, which also showed the highest oleic acid content.

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“…HAMLET showed promising healing results in vivo when tested as topical application on human skin papillomas [3], on human glioblastoma xenografts in a rat model [4] and by intravesical HAMLET instillations in both mice and humans with bladder cancer [5,6].…”

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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Treatment of Skin Papillomas with Topical α-Lactalbumin–Oleic Acid

Abstract: Treatment with topical alpha-lactalbumin-oleic acid has a beneficial and lasting effect on skin papillomas.

Cited by 179 publications

References 21 publications

Protein folding and unfolding studied at atomic resolution by fast two-dimensional NMR spectroscopy

Protein folding and unfolding studied at atomic resolution by fast two-dimensional NMR spectroscopy

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

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

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