HAMLET - In vivo effects and mechanisms of tumor-cell death

Abstract: HAMLET (human alpha-lactalbumin made lethal to tumor cells), a molecular complex derived from human milk, is an interesting new tool in cancer research since it induces programmed cell death in tumor cells while leaving normal, differentiated cells unharmed. The in vivo effects of HAMLET were studied in a rat xenograft model of human glioblastoma. HAMLET reduced the tumor volume and delayed the onset of pressure symptoms. Programmed cell death was induced in the tumor, but not in the adjacent normal brain tissue. In non-grafted rats, HAMLET spread throughout the infused brain hemisphere and no significant toxic side-effects were recorded. The therapeutic effects of HAMLET were investigated further in a placebo-controlled study of patients with skin papillomas. Local application of HAMLET for a three-week period reduced the volume of the papillomas by >75% in all the patients and in 96% of the papillomas as compared with 21% in the placebo-control group. No adverse reactions were reported and there was no difference in outcome for immunosuppressed patients. A mechanism of tumor-cell death was suggested, one that relates to the partially unfolded state of HAMLET. Massive amounts of HAMLET gained entry into the tumor cells, it interacted with the proteasomes and caused a stress response due to the overload of partially unfolded protein. HAMLET activated the proteasomes in the cytoplasm, but degradation was delayed and fragmentation of the proteasomes was triggered instead. HAMLET and proteasomes translocated to the tumor cell nuclei, where chromatin homeostasis was disrupted. HAMLET-induced tumor-cell death was partially prevented by blocking proteasome activity, supporting the role of proteasomes in cell death. HAMLET represents a new approach to cancer therapy, having therapeutic effects in vivo and targeting cell death pathways that are susceptible for activation in tumor cells, thus circumventing the roadblocks that prevent cell death in many tumor cells.