HEALTH NEWS

Study Title:

HAMLET Kills Bladder Cancer Cells in Humans

Study Abstract

Background
Cell membrane interactions rely on lipid bilayer constituents and molecules inserted within the membrane, including specific receptors. HAMLET (human α-lactalbumin made lethal to tumor cells) is a tumoricidal complex of partially unfolded α-lactalbumin (HLA) and oleic acid that is internalized by tumor cells, suggesting that interactions with the phospholipid bilayer and/or specific receptors may be essential for the tumoricidal effect. This study examined whether HAMLET interacts with artificial membranes and alters membrane structure.

Methodology/Principal Findings
We show by surface plasmon resonance that HAMLET binds with high affinity to surface adherent, unilamellar vesicles of lipids with varying acyl chain composition and net charge. Fluorescence imaging revealed that HAMLET accumulates in membranes of vesicles and perturbs their structure, resulting in increased membrane fluidity. Furthermore, HAMLET disrupted membrane integrity at neutral pH and physiological conditions, as shown by fluorophore leakage experiments. These effects did not occur with either native HLA or a constitutively unfolded Cys-Ala HLA mutant (rHLAall-Ala). HAMLET also bound to plasma membrane vesicles formed from intact tumor cells, with accumulation in certain membrane areas, but the complex was not internalized by these vesicles or by the synthetic membrane vesicles.

Conclusions/Significance
The results illustrate the difference in membrane affinity between the fatty acid bound and fatty acid free forms of partially unfolded HLA and suggest that HAMLET engages membranes by a mechanism requiring both the protein and the fatty acid. Furthermore, HAMLET binding alters the morphology of the membrane and compromises its integrity, suggesting that membrane perturbation could be an initial step in inducing cell death.

From press release:

A substance found in breast milk can kill cancer cells, reveal studies carried out by researchers at Lund University and the University of Gothenburg, Sweden.

Although the special substance, known as HAMLET (Human Alpha-lactalbumin Made LEthal to Tumour cells), was discovered in breast milk several years ago, it is only now that it has been possible to test it on humans. Patients with cancer of the bladder who were treated with the substance excreted dead cancer cells in their urine after each treatment, which has given rise to hopes that it can be developed into medication for cancer care in the future.

Discovered by chance

HAMLET was discovered by chance when researchers were studying the antibacterial properties of breast milk. Further studies showed that HAMLET comprises a protein and a fatty acid that are both found naturally in breast milk. So far, however, it has not been proven that the HAMLET complex is spontaneously formed in the milk. It is speculated, however, that HAMLET can form in the acidic environment of the babies´ stomachs. Laboratory experiments have shown that HAMLET kills 40 different types of cancer, and the researchers are now going on to study its effect on skin cancer, tumours in the mucous membranes and brain tumours. Importantly, HAMLET kills only cancer cells and does not affect healthy cells.

Studying the integration of the substance

Researchers at the University of Gothenburg are focusing on how HAMLET can be taken up into tumour cells. The researchers, Roger Karlsson, Maja Puchades and Ingela Lanekoff, are attempting to gain an in-depth understanding of how the substance interacts with cell membranes, and their findings were recently published in the journal PLoS One.

Study Information

1.Mossberg et al.
HAMLET Interacts with Lipid Membranes and Perturbs Their Structure and Integrity
PLoS ONE,
2010 February
Lund University and the University of Gothenburg, Sweden.