Hamlet and Bamlet

Abstract

HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) is a compound that allows the cancer cell to die by forming a complex of oleic acid with lactoalbumin derived from human milk. BAMLET (Bovine Alpha-lactalbumin Made LEthal to Tumor cells) is a compound that causes the cancer cell to form oleic acid with lactoalbumin, which is obtained from the milk of bovine animals. Both compounds can form in the stomach as well as in vitro conditions. Tumor cells may undergo cell death in a variety of ways, including apoptosis, necrosis, and autophagic. The eff ects of both compounds on cancer cells are similar to apoptosis. Despite the fact that both animal and human studies are conducted with both compounds in the literature, they are a treatment method which is still in research stage.

Keywords

• Hamlet,Bamlet,Apoptosis

Hamlet and Bamlet

Abstract

HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) insan sütünden elde edilen laktoalbumin ile oleik asidin kompleks oluşturarak kanser hücresinin ölmesini sağlayan bileşiktir. BAMLET (Bovine Alpha-lactalbumin Made LEthal to Tumor cells) ise büyükbaş hayvanların sütünden elde edilen laktoalbumin ile oleik asidin bileşik oluşturması ile kanser hücresine sebep olan bileşiktir. Her iki bileşik de in vitro koşullarda oluşabildiği gibi, mide de oluşabilmektedir. Tümör hücreleri apoptoz, nekroz, otofajik gibi çeşitli yollarla hücre ölümlerine uğrayabilir. Her iki bileşiğin de kanser hücreleri üzerine etkileri apoptoza benzetilmektedir. Literatürde her iki bileşikle yapılmış hayvan ve insan çalışmaları olmakla birlikte henüz araştırma aşamasında olan bir tedavi yöntemidir.

Keywords

• Hamlet,Bamlet,Apoptoz

References

1. 1. Svensson M, Hakansson A, Mossberg AK, Linse SSvanborg C. Conversion of alpha-lactalbumin to a protein inducing apoptosis. Proc Natl Acad Sci U S A, 2000;97:(8): 4221-6.
2. 2. Hakansson A, Zhivotovsky B, Orrenius S, Sabharwal HSvanborg C. Apoptosis induced by a human milk protein. Proc Natl Acad Sci U S A, 1995;92:(17): 8064-8.
3. 3. Fang B, Zhang M, Tian M, Jiang L, Guo HYRen FZ. Bovine lactoferrin binds oleic acid to form an anti-tumor complex similar to HAMLET. Biochim Biophys Acta, 2014;1841:(4): 535-43.
4. 4. Rath EM, Duff AP, Hakansson AP, Vacher CS, Liu GJ, Knott RBChurch WB. Structure and Potential Cellular Targets of HAMLET-like Anti-Cancer Compounds made from Milk Components. J Pharm Pharm Sci, 2015;18:(4): 773-824.
5. 5. Mok KH, Pettersson J, Orrenius SSvanborg C. HAMLET, protein folding, and tumor cell death. Biochem Biophys Res Commun, 2007;354:(1): 1-7.
6. 6. Permyakov EABerliner LJ. alpha-Lactalbumin: structure and function. FEBS Lett, 2000;473:(3): 269-74.
7. 7. Ho JC, Nadeem ASvanborg C. HAMLET - A protein-lipid complex with broad tumoricidal activity. Biochem Biophys Res Commun, 2017;482:(3): 454-458.
8. 8. Kaufman RJ. Orchestrating the unfolded protein response in health and disease. J Clin Invest, 2002;110:(10): 1389-98.

9. 9. Hallgren O, Gustafsson L, Irjala H, Selivanova G, Orrenius SSvanborg C. HAMLET triggers apoptosis but tumor cell death is independent of caspases, Bcl-2 and p53. Apoptosis, 2006;11:(2): 221-33.
10. 10. Ciechanover A. Intracellular protein degradation: From a vague idea thru the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Best Pract Res Clin Haematol, 2017;30:(4): 341- 355.
11. 11. Goldberg AL. Protein degradation and protection against misfolded or damaged proteins. Nature, 2003;426:(6968): 895-9.
12. 12. Duringer C, Hamiche A, Gustafsson L, Kimura HSvanborg C. HAMLET interacts with histones and chromatin in tumor cell nuclei. J Biol Chem, 2003;278:(43): 42131-5.
13. 13. Yorimitsu TKlionsky DJ. Autophagy: molecular machinery for self-eating. Cell Death Differ, 2005;12 Suppl 2: 1542-52.
14. 14. Mizushima N, Ohsumi YYoshimori T. Autophagosome formation in mammalian cells. Cell Struct Funct, 2002;27:(6): 421-9.
15. 15. Codogno PMeijer AJ. Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ, 2005;12 Suppl 2: 1509-18.
16. 16. Deretic V. Autophagy as an immune defense mechanism. Curr Opin Immunol, 2006;18:(4): 375-82.
17. 17. Baehrecke EH. Autophagy: dual roles in life and death? Nat Rev Mol Cell Biol, 2005;6:(6): 505-10.
18. 18. Debnath J, Baehrecke EHKroemer G. Does autophagy contribute to cell death? Autophagy, 2005;1:(2): 66-74.
19. 19. Ho J, Sielaff H, Nadeem A, Svanborg CGruber G. The molecular motor F-ATP synthase is targeted by the tumoricidal protein HAMLET. J Mol Biol, 2015;427:(10): 1866-74.
20. 20. Gustafsson L, Aits S, Onnerfjord P, Trulsson M, Storm PSvanborg C. Changes in proteasome structure and function caused by HAMLET in tumor cells. PLoS One, 2009;4:(4): e5229.
21. 21. Mossberg AK, Hou Y, Svensson M, Holmqvist BSvanborg C. HAMLET treatment delays bladder cancer development. J Urol, 2010;183:(4): 1590-7.
22. 22. Fischer W, Gustafsson L, Mossberg AK, Gronli J, Mork S, Bjerkvig RSvanborg C. Human alpha-lactalbumin made lethal to tumor cells (HAMLET) kills human glioblastoma cells in brain xenografts by an apoptosis-like mechanism and prolongs survival. Cancer Res, 2004;64:(6): 2105-12.
23. 23. Puthia M, Storm P, Nadeem A, Hsiung SSvanborg C. Prevention and treatment of colon cancer by peroral administration of HAMLET (human alpha-lactalbumin made lethal to tumour cells). Gut, 2014;63:(1): 131-42.
24. 24. Mossberg AK, Wullt B, Gustafsson L, Mansson W, Ljunggren ESvanborg C. Bladder cancers respond to intravesical instillation of HAMLET (human alpha-lactalbumin made lethal to tumor cells). Int J Cancer, 2007;121:(6): 1352-9.
25. 25. Gustafsson L, Leijonhufvud I, Aronsson A, Mossberg AKSvanborg C. Treatment of skin papillomas with topical alpha-lactalbumin-oleic acid. N Engl J Med, 2004;350:(26): 2663-72.
26. 26. Artym JZimecki M. Milk-derived proteins and peptides in clinical trials. Postepy Hig Med Dosw (Online), 2013;67: 800-16.
27. 27. Rammer P, Groth-Pedersen L, Kirkegaard T, Daugaard M, Rytter A, Szyniarowski P, Hoyer-Hansen M, Povlsen LK, Nylandsted J, Larsen JEJaattela M. BAMLET activates a lysosomal cell death program in cancer cells. Mol Cancer Ther, 2010;9:(1): 24-32.