HAMLET kills tumor cells by an apoptosis-like mechanism--cellular, molecular, and therapeutic aspects.

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HAMLET kills tumor cells by an apoptosis-like mechanism--cellular, molecular, and therapeutic aspects. / Svanborg, Catharina; Ågerstam, Helena; Aronson, Annika; Bjerkvig, Rolf; Düringer, Caroline; Fischer, Walter; Gustafsson, Lotta; Hallgren, Oskar; Leijonhuvud, Irene; Linse, Sara; Mossberg, Anki; Nilsson, Hanna; Pettersson, Jenny; Svensson, Malin.

In: Advances in Cancer Research, Vol. 88, 2003, p. 1-29.

Research output: Contribution to journalReview article

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Svanborg C, Ågerstam H, Aronson A, Bjerkvig R, Düringer C, Fischer W, Gustafsson L, Hallgren O, Leijonhuvud I, Linse S, Mossberg A, Nilsson H, Pettersson J, Svensson M. 2003. HAMLET kills tumor cells by an apoptosis-like mechanism--cellular, molecular, and therapeutic aspects. Advances in Cancer Research. 88:1-29.

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Svanborg, Catharina ; Ågerstam, Helena ; Aronson, Annika ; Bjerkvig, Rolf ; Düringer, Caroline ; Fischer, Walter ; Gustafsson, Lotta ; Hallgren, Oskar ; Leijonhuvud, Irene ; Linse, Sara ; Mossberg, Anki ; Nilsson, Hanna ; Pettersson, Jenny ; Svensson, Malin. / HAMLET kills tumor cells by an apoptosis-like mechanism--cellular, molecular, and therapeutic aspects. In: Advances in Cancer Research. 2003 ; Vol. 88. pp. 1-29.

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TY - JOUR

T1 - HAMLET kills tumor cells by an apoptosis-like mechanism--cellular, molecular, and therapeutic aspects.

AU - Svanborg, Catharina

AU - Ågerstam, Helena

AU - Aronson, Annika

AU - Bjerkvig, Rolf

AU - Düringer, Caroline

AU - Fischer, Walter

AU - Gustafsson, Lotta

AU - Hallgren, Oskar

AU - Leijonhuvud, Irene

AU - Linse, Sara

AU - Mossberg, Anki

AU - Nilsson, Hanna

AU - Pettersson, Jenny

AU - Svensson, Malin

PY - 2003

Y1 - 2003

N2 - HAMLET (human α-lactalbumin made lethal to tumor cells) is a protein-lipid complex that induces apoptosis-like death in tumor cells, but leaves fully differentiated cells unaffected. This review summarizes the information on the in vivo effects of HAMLET in patients and tumor models, on the tumor cell biology, and on the molecular characteristics of the complex. HAMLET limits the progression of human glioblastomas in a xenograft model and removes skin papillomas in patients. This broad anti-tumor activity includes >40 different lymphomas and carcinomas and apoptosis is independent of p53 or bcl-2. In tumor cells, HAMLET enters the cytoplasm, translocates to the perinuclear area, and enters the nuclei, where it accumulates. HAMLET binds strongly to histones and disrupts the chromatin organization. In the cytoplasm, HAMLET targets ribosomes and activates caspases. The formation of HAMLET relies on the propensity of α-lactalbumin to alter its conformation when the strongly bound Ca2+ ion is released and the protein adopts the apo-conformation that exposes a new fatty acid binding site. Oleic acid (C18:1,9 cis) fits this site with high specificity, and stabilizes the altered protein conformation. The results illustrate how protein folding variants may be beneficial, and how their formation in peripheral tissues may depend on the folding change and the availability of the lipid cofactor. One example is the acid pH in the stomach of the breast-fed child that promotes the formation of HAMLET This mechanism may contribute to the protective effect of breastfeeding against childhood tumors. We propose that HAMLET should be explored as a novel approach to tumor therapy.

AB - HAMLET (human α-lactalbumin made lethal to tumor cells) is a protein-lipid complex that induces apoptosis-like death in tumor cells, but leaves fully differentiated cells unaffected. This review summarizes the information on the in vivo effects of HAMLET in patients and tumor models, on the tumor cell biology, and on the molecular characteristics of the complex. HAMLET limits the progression of human glioblastomas in a xenograft model and removes skin papillomas in patients. This broad anti-tumor activity includes >40 different lymphomas and carcinomas and apoptosis is independent of p53 or bcl-2. In tumor cells, HAMLET enters the cytoplasm, translocates to the perinuclear area, and enters the nuclei, where it accumulates. HAMLET binds strongly to histones and disrupts the chromatin organization. In the cytoplasm, HAMLET targets ribosomes and activates caspases. The formation of HAMLET relies on the propensity of α-lactalbumin to alter its conformation when the strongly bound Ca2+ ion is released and the protein adopts the apo-conformation that exposes a new fatty acid binding site. Oleic acid (C18:1,9 cis) fits this site with high specificity, and stabilizes the altered protein conformation. The results illustrate how protein folding variants may be beneficial, and how their formation in peripheral tissues may depend on the folding change and the availability of the lipid cofactor. One example is the acid pH in the stomach of the breast-fed child that promotes the formation of HAMLET This mechanism may contribute to the protective effect of breastfeeding against childhood tumors. We propose that HAMLET should be explored as a novel approach to tumor therapy.

M3 - Review article

VL - 88

SP - 1

EP - 29

JO - Advances in Cancer Research

JF - Advances in Cancer Research

SN - 0065-230X

ER -