HAMLET: Functional Properties and Therapeutic Potential

James Ho CS; Anna Rydström; Maria Trulsson; Johannes Bålfors; Petter Storm; Manoj Puthia; Aftab Nadeem; Catharina Svanborg


Future Oncol. 2012;8(10):1301-1313. 

In This Article

Effects of HAMLET on Bacteria

The tumoricidal activity of HAMLET was discovered as a result of attempts to define the antiadhesive effect of human milk casein. The authors had previously observed that casein reduced the attachment of Streptococcus pneumoniae to human respiratory tract cells and therefore used different casein fractions as a tool to further understand the molecular specificity involved in host cell recognition by pneumococci.[91] In addition to the lethal effects on tumor cells, HAMLET was shown to also kill the bacteria. Analysis of the antibacterial spectrum showed sensitivity mainly of streptococci; most Gram-negative and other Gram-positive bacteria were resistant. Thus, in addition to its tumoricidal effect, HAMLET shows significant antimicrobial activity.

Further studies showed that an apoptosis-like response is also activated by HAMLET in bacterial cells. Striking similarities were observed, including DNA fragmentation and a change in morphology.[92] HAMLET induced a calcium-dependent membrane depolarization in both host cells[9] and bacteria,[92] possibly reflecting the shared evolutionary origin of mitochondria and bacteria. In addition, a bovine α-lactalbumin-OA complex prepared under alkaline conditions (bLA-OA-45) was shown to depolarize and damage the plasma membrane in S. pneumonia D39.[42] Downstream degradation pathways involved protease and endonuclease activity. These findings suggest that pathways associated with apoptosis are present in prokaryotes and that mechanisms of bacterial cell death may be explored to further our understanding of key activation mechanisms leading to cell death in eukaryote cells. Furthermore, the bacterial responses may prove essential to identify novel targets for future antimicrobial therapy. The similarities between mitochondrial and bacterial responses to HAMLET may be essential in this context.