Arturo Araujo-Conejo¹* and Gloria G Guerrero M²*

¹Hospital General Zacatecas "Luz González Cosió" de la Secretaria de Salud de Zacatecas, Zacatecas, Zac, Mexico
²Unidad Académica de Ciencias Biológicas, Universidad Autónoma de Zacatecas, Campus II, Zac, Mexico

*Corresponding Author: Arturo Araujo-Conejo and Gloria G Guerrero M, Hospital General Zacatecas "Luz González Cosió" de la Secretaria de Salud de Zacatecas, Zacateca and Unidad Académica de Ciencias Biológicas, Universidad Autónoma de Zacatecas, Campus II, Zac, Mexico.

Received: May 03, 2024; Published: June 04, 2024

Abstract

Cancer is the second cause of death worldwide, characterized by high and unregulated cell proliferation. The causes are multifactorial, including damage or mutation of proto-oncogenes, genetic predisposition and environmental factors. Various treatments have been used, such as surgery, radiation, chemotherapy and immunotherapy, with the aim of attacking mutated and highly proliferating tumor cells. Human Alpha-Lactalbumine (ALA) of molecular weight 14 kDa, is a small protein present in the human milk at a concentration of 2.0 mg/ml with lethal effects on cells of different types of cancer. It is commonly known as Human Alpha-Lactalbumine made lethal to tumor cells or HAMLET. The therapeutic efficacy of HAMLET has been demonstrated in animal models, with human glioblastoma xenograft, bladder cancer and bowel cancer in vivo. In clinical settings, HAMLET has been shown to act on skin tags. Cellular targets are found in the cytoplasmic membrane, cytoskeleton, mitochondria, proteasomes, lysosomes, and nuclei. In the mode of action of HAMLET it has been proposed that the protein insert in the cellular membrane and then internalize targeting the cytoplasmic membrane, cytoskeleton, mitochondria, proteasomes, lysosomes, and lastly nuclei. Inducing DNA fragmentation. By other hand, long term effect of Chemotherapy include symptoms such as fatigue, peripheral neuropathy, and cognitive impairment, whereas, late effects, including osteoporosis, heart failure, and secondary leukemia, occur after treatment ends, but are causally related to cancer and treatment exposures. Herein, we pinpointed the clinical use of HAMLET as palliative after chemotherapy treatment.

 Keywords: Cancer; Human Maternal Milk; HAMLET; Chemotherapy; Radiotherapy; Surgery; Pharmacological Drugs

References

1. World Health Organization (WHO). World health statistics 2022: monitoring health for the SDGs, sustainable development goals (2022).
2. Hanahan D and Weinberg RA. “Hallmarks of cancer: the next generation”. Cell 144 (2011): 646-674.
3. Barbari C., et al. “Immunotherapies and Combination Strategies for Immuno-Oncology”. International Journal of Molecular Sciences 21 (2020): 5009.
4. Lerksuthirat T., et al. “ALA-A2 Is a Novel Anticancer Peptide Inspired by Alpha-Lactalbumin: A Discovery from a Computational Peptide Library, In Silico Anticancer Peptide Screening and In Vitro Experimental Validation”. Global Chall 7 (2023): 2200213.
5. Allegra A., et al. “The cancer stem cell hypothesis: A guide to potential molecular targets”. Cancer Investigation 32 (2014): 470-495.
6. Lippitz BE. “Cytokine patterns in patients with cancer: A systematic review”. Lancet Oncology 14 (2013): e218-e228.
7. Bent EH., et al. “Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy”. Nature Communication 12 (2021): 6218.
8. Taefehshokr N., et al. “Promising approaches in cancer immunotherapy”. Immunobiology 225 (2020): 151875.
9. Dagher OK., et al. “Advances in cancer immunotherapies”. Cell 186 (2023): 1814-1814.e1.
10. Wei G., et al. “Emerging immune checkpoints in the tumor microenvironment: Implications for cancer immunotherapy”. Cancer Letter 511 (2021): 68-76.
11. Saxena M., et al. “Therapeutic cancer vaccines”. Nature Reviews Cancer 2 (2021): 360-378.
12. Marshall HT and Djamgoz MBA. “Immuno-Oncology: Emerging Targets and Combination Therapies”. Frontiers in Oncology 8 (2018): 315.
13. Zhou Y., et al. Breastfeeding Medicine 10 (2015): 175-182.
14. Svensson M., et al. “Hamlet — A Complex from Human Milk that Induces Apoptosis in Tumor Cells but Spares Healthy Cells”. Advances in Experimental Medicine and Biology 503 (2002): 125-132.
15. Svensson M., et al. “Lipids as cofactors in protein folding: Stereo-specific lipid-protein interactions are required to form HAMLET (human α-lactalbumin made lethal to tumor cells)”. Protein Science 12 (2003): 2805-2814.
16. Svensson M., et al. “α-Lactalbumin unfolding is not sufficient to cause apoptosis, but is required for the conversion to HAMLET (human α-lactalbumin made lethal to tumor cells)”. Protein Science 12 (2003): 2794-2804.
17. Zherolova OM., et al. “Interaction of antitumor alpha-lactalbumin-oleic acid complexes qith artificial and natural membranes”. Journal of Bioenergetics and Biomembranes 41 (2009): 229-237.
18. Fang B., et al. “Internalization properties of the antitumor alpha-lactalbumin-oleci acid complex”. International Journal of Biological Macromolecules 96 (2017): 44-51.
19. Chaudhuri A., et al. “Protein-dependent membrane interactio of a partially disordered protein complex with oleic acid: Implications for cancer lipidomics”. Scientific Report 6 (2016): 35015.
20. Storm P., et al. “A unifying mechanism for cancer cell death through ion channel activation by HAMLET”. PLoS ONE 8 (2013): e58578.
21. Dobson CM. “The structural basis of protein folding and its links with human disease”. Philosophical Transactions of the Royal Society B 356 (2001): 133-145.
22. Uversky VN and Fink AL. “Conformational constraints for amyloid fibrillation: The importance of being unfolded”. Biochimica et Biophysica Acta 1698 (2004): 131-153.
23. Uversky VN. “Nanoimaging in protein-misfolding and -conformational diseases”. Nanomedicine 2 (2007): 615-643.
24. Chiti F and Dobson CM. “Protein misfolding, functional amyloid, and human disease”. Annual Review of Biochemistry 75 (2006): 333-366.
25. Stefani M and Dobson CM. “Protein aggregation and aggregate toxicity: New insights into protein folding, misfolding diseases and biological evolution”. Journal of Molecular Medicine 81 (2003): 678-699.
26. Baumann A., et al. “HAMLET forms annular oligomers when deposited with phospholipid monolayers”. Journal of Molecular Biology 418 (2012): 90-102.
27. Nadeem A., et al. “Protein receptor-independent plasma membrane remodeling by HAMLET: A tumoricidal protein-lipid complex”. Scientific Report 5 (2015): 16432.
28. Pedersen JN., et al. “Structures and mechanisms of formation of liprotides”. Biochimica et Biophysica Acta 1868 (2020): 140505.
29. Permyakov SE., et al. “Oleic acid is a key cytotoxic component of HAMLET-like complexes”. Biological Chemistry 393 (2012): 85-92.
30. Mossberg AK., et al. “HAMLET interacts with lipid membranes and perturbs their structure and integrity”. PLoS ONE 5 (2010): e9384.
31. Ho JC., et al. “Targeting of nucleotide-binding proteins by HAMLET—a conserved tumor cell death mechanism”. Oncogene 35 (2016): 897-907.
32. Fang B., et al. “Alpha-Lactalbumin-oleic acid complex kills tumor cells by inducing excess energy metabolism but inhibiting mRNA expression of the related enzymes”. Journal of Dairy Science 101 (2018): 4853-4863.
33. Duringer C., et al. “HAMLET interacts with histones and chromatin in tumor cell nuclei”. Journal of Biological Chemistry 278 (2003): 42131-42135.
34. Brest P., et al. “Histone deacetylase inhibitors promote the tumoricidal effect of HAMLET”. Cancer Research 67 (2007): 11327-11334.
35. Nadeem A., et al. “Beta-sheet-specific interactions with heat shock proteins define a mechanism of delayed tumor cell death in response to HAMLET”. Journal of Molecular Biology 431 (2019): 2612-2627.
36. Hallgren O., et al. “HAMLET triggers apoptosis but tumor cell death is independent of caspases, Bcl-2 and p53”. Apoptosis 11 (2006): 221-233.
37. Pettersson J., et al. “Alpha-lactalbumin species variation, Hamlet formation, and tumor cell death”. Biochemical and Biophysical Research Communications 345 (2006): 260-270.
38. Gustafsson L., et al. “HAMLET kills tumor cells by apoptosis: Structure, cellular mechanisms, and therapy”. Journal of Nutrition 135 (2005): 1299-1303.
39. Fakharany-EI EM and Redwan EM. “Protein-lipid complexes; molecular structure, current scenarios and mechanisms of cytotoxicity”. RSC Advances 9 (2019): 36890-36907.
40. Permyakov EA. “-Lactalbumin, Amazing Calcium-Binding Protein”. Biomolecules 10 (2022): 1210-1240.
41. Lin IC., et al. “Induciton of cell death in RAW 2647 cells by alpha-lactalbumin”. Food and Chemical Toxicology 46 (2008): 842-853.
42. Bounous G., et al. “Differential effect of dietary protein type on the B-cell and T-cell immune responses in mice”. Journal of Nutrition 115 (1985): 1403-1408.
43. Hakansson A., et al. “A folding variant of α-lactalbumin with bactericidal activity against Streptococcus pneumoniae”. Molecular Microbiology 35 (2000): 589-600.
44. Clare DA., et al. “Biodefense properties of milk: The role of antimicrobial proteins and peptides”. Current Pharmaceutical Design 9 (2003): 1239-1255.
45. Svensson M., et al. “Conversion of α-lactalbumin to a protein inducing apoptosis”. PNAS 97 (2000): 4221-4226.
46. Nakamura T., et al. “Molecular Mechanisms of Lethal Human α-Lactalbumin Cytotoxicity to Tumor Cells (HAMLET) and Other Protein and Oleic Acid Complexes”. Journal of Biological Chemistry 288 (2013): 14408-14416.
47. Arai M and Kuwajima K. “Role of the molten globule state in protein folding”. Advances in Protein Chemistry 53 (2000): 209-282.
48. PROYECTO de Norma Oficial Mexicana PROY-NOM-050-SSA2-2018, Para el fomento, protección y apoyo a la lactancia materna.
49. Chetta KE. “Cytotoxic Lactalbumin-Oleic Acid Complexes in the Human Milk Diet of Preterm Infants”. Nutrients 13 (2021): 4336.
50. Mossberg AK., et al. “HAMLET treatment delays bladder cancer development”. Journal of Urology 183 (2010): 1590-1597.
51. Guerrero GG., et al. “Prophylactic Effect in the Gut Microbiota After Oral Administration of HAMLET Results of Case Control Study”. Acta Scientific Microbiology 7 (2024): 1-16.

Citation

Citation: Arturo Araujo-Conejo and Gloria G Guerrero M. “Perspective of the Use of Hamlet as Palliative in Patients Undergoing Chemotherapy”.Acta Scientific Medical Sciences 8.7 (2024): 23-29.

Copyright

Copyright: © 2024 Arturo Araujo-Conejo and Gloria G Guerrero M. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.