INTRODUCTION: 1
How human milk provides relief for cancer patients? It is still unclear. But there are many people who believe that it is actually capable of killing cancer cells. This information is supported by a study published from Lund University in Sweden in 1995 that showed that human milk could cause cultured cancer cells to undergo apoptosis i.e. programmed cell death. A recently published qualitative study in the Journal of Human Lactation assessed whether cancer patients that had taken human milk as part of their therapy experienced any benefit. Men and women with various stages of cancer were asked to evaluate their cancer symptoms before and after commencing human milk therapy. Patients reported the improvements such as reduction of chemotherapy symptoms (nausea, diarrhea, and fatigue), drop in PSA levels after one month (prostate cancer), improved respiratory function, improved appearance, resistance to colds, etc. after beginning human milk treatment. 1
During the investigation of the effect of human milk on bacterial adherence to a human lung cancer cell line it is observed that the protein α-lactalbumin present in breast milk was killing human cancer cells in the lab. But the compound becomes lethal only when exposed to acid, as it is in a stomach and was in the lab. The acid unfolds the α-lactalbumin and that acidified form of the protein is called as HAMLET, for ‘human α-lactalbumin made lethal to tumors’. The huge quantities of unfolded proteins destroy the cancer cells. Cancer cells take up far more HAMLET than healthy cells do. Researchers are currently concluding human trials of HAMLET for bladder cancer and say that the results "look very good," and has no side effects. Since this specific protein seems to be effective against so many types of cancer many pharmaceutical companies are now developing the activated protein for clinical use.2
Human milk and its composition:
The World Health Organization recommends exclusive breastfeeding for the first six months of life, with solids gradually being introduced around this age when signs of readiness are shown. Breastfeeding continues to offer health benefits into and after toddlerhood. These benefits include; lowered risk of Sudden Infant Death Syndrome (SIDS), increased intelligence, decreased likelihood of contracting middle ear infections, cold, and flu bugs, decreased risk of some cancers such as childhood leukemia, lower risk of childhood onset diabetes, decreased risk of asthma and eczema, decreased dental problems, decreased risk of obesity later in life, and decreased risk of developing psychological disorders.3
Macronutrients3:
Fats- Fatty acids up to the length of 8 C are found in trace amounts along with the polyunsaturated fatty acid in human milk.
Carbohydrates- Carbohydrates like Lactose and oligosaccharides are present in breast milk.
Minerals- Calcium, Phosphorus, Sodium, Potassium, chlorine are the minerals shows presence in human breast milk.
Proteins- Human milk contains four main types of proteins: β-casein, κ-casein, α-lactalbumin and serum albumin. In addition, it contains other whey proteins of high molecular weight such as immunoglobulin’s IgA, IgG, IgM and IgD and lactoferrin. Goat and cow milk both contain some of these proteins, but have three additional protein types present in significant quantities: αs1-casein, αs2-casein and lactoglobulin. 4
Bioactive components- Breast milk contains a range of bioactive components in addition to the above main macronutrients. These bioactive components include: nucleotides, polyamines, free amino acids, growth factors, etc. Some of these elements have important physiological functions and are thought to have an effect on gastrointestinal maturation and the immune system.
Macrophages and neutrophils are amongst the most common leucocytes in human milk and they surround and destroy harmful bacteria by their phagocytic activity. Secretory IgA and interferon are important anti-infective agents produced in abundance by lymphocytes in human milk. IgA, is the most important Immunoglobulin which appears to be both synthesized and stored in the breast. It 'paints' the intestinal epithelium and protects the mucosal surfaces against entry of pathogenic bacteria and enteroviruses. 5
Cancer:
Cancer is a class of diseases in which a group of cells display uncontrolled growth (division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood). These three malignant properties of cancers differentiate them from benign tumors, which are self-limited, and do not invade or metastasize. Cancers are caused by abnormalities in the genetic material of the transformed cells. These abnormalities may be due to the effects of carcinogens, such as tobacco smoke, radiation, chemicals, or infectious agents. Other cancer-promoting genetic abnormalities may randomly occur through errors in DNA replication, or are inherited, and thus present in all cells from birth. The heritability of cancers is usually affected by complex interactions between carcinogens and the host's genome. 6
Cancer (fig.-1) is fundamentally a disease of regulation of tissue growth. In order for a normal cell to transform into a cancer cell, genes which regulate cell growth and differentiation must be altered. Genetic changes can occur at many levels, from gain or loss of entire chromosomes to a mutation affecting a single DNA nucleotide. There are two broad categories of genes which are affected by these changes. Oncogenes may be normal genes which are expressed at inappropriately high levels, or altered genes which have novel properties. In either case, expression of these genes promotes the malignant phenotype of cancer cells. Tumor suppressor genes are genes which inhibit cell division, survival, or other properties of cancer cells. Tumor suppressor genes are often disabled by cancer-promoting genetic changes. Typically, changes in many genes are required to transform a normal cell into a cancer cell. 7
Fig.1) Generation of cancer cells.
There is a diverse classification scheme for the various genomic changes which may contribute to the generation of cancer cells. Most of these changes are mutations, or changes in the nucleotide sequence of genomic DNA.
Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and such an event may also result in the expression of viral oncogenes in the affected cell and its descendants. 8
Development of apoptosis:
The term apoptosis had been coined in order to describe the morphological processes leading to controlled cellular self-destruction. Apoptosis is of Greek origin, having the meaning "falling off or dropping off", in analogy to leaves falling off trees or petals dropping off flowers. This analogy emphasizes that the death of living matter is an integral and necessary part of the life cycle of organisms. The apoptotic mode of cell death is an active and defined process which plays an important role in the development of multicellular organisms and in the regulation and maintenance of the cell populations in tissues upon physiological and pathological conditions. 9, 10 Apoptotic cells can be recognized by stereotypical morphological changes: the cell shrinks, shows deformation and looses contact to its neighboring cells. Its chromatin condenses and marginates at the nuclear membrane, the plasma membrane is blebbing or budding, and finally the cell is fragmented into compact membrane-enclosed structures, called 'apoptotic bodies' which contain cytosol, the condensed chromatin, and organelles. The apoptotic bodies are engulfed by macrophages and thus are removed from the tissue without causing an inflammatory response. Those morphological changes are a consequence of characteristic molecular and biochemical events occurring in an apoptotic cell, most notably the activation of proteolytic enzymes which eventually mediate the cleavage of DNA into oligonucleosomal fragments as well as the cleavage of a multitude of specific protein substrates which usually determine the integrity and shape of the cytoplasm or organelles. Apoptosis is in contrast to the necrotic mode of cell-death in which case the cells suffer a major insult, resulting in a loss of membrane integrity, swelling and disrupture of the cells. During necrosis, the cellular contents are released uncontrolled into the cell's environment which results in damage of surrounding cells and a strong inflammatory response in the corresponding tissue. 11, 12
How Human milk act as anticancer alternative?
Multimeric α-lactalbumin:
However, it has rarely been considered that human milk may also contain substances bioactive toward host cells. While investigating the effect of human milk on bacterial adherence to a human lung cancer cell line, researchers were surprised to discover that the milk killed the cells. Analysis of this effect revealed that a component of milk in a particular physical state- multimeric α-lactalbumin is a potent Ca2+-elevating and apoptosis-inducing agent with broad, yet selective, cytotoxic activity. 13 Human milk from several donors induced apoptosis in transformed and nontransformed immature cell lines and lymphoid cells but not in mature cells. This effect was first observed in studies with A549 cells, a human lung carcinoma cell line used to investigate bacterial adherence and antimicrobial properties of human milk. Cell viability was reduced by 98%, and the cells displayed morphological changes compatible with apoptosis (nuclear condensation, appearance of apoptotic bodies, and cell shrinkage). Associated with this was the formation of high molecular weight DNA fragments in A549 cells. The factors that regulate the aggregation state of α-lactalbumin in whole human milk are not understood. Both the bioactivity of whole milk and the size fractionation profile of the α-lactalbumin component indicate that multimers of α-lactalbumin occur naturally. Moreover, we could induce multimerization of monomeric α-lactalbumin by anion exchange chromatography in the presence of high concentrations of NaCl and recover the apoptosis-inducing activity of whole milk. Several peptides and proteins, including cytokines, bacterial toxins, and viral envelope proteins, induce apoptosis in mammalian cells by receptor-mediated signaling or by formation of transmembrane pores. Whether the induction of apoptosis by MAL reflects cross-linking of receptors to which monomeric α-lactalbumin normally binds without any cytotoxic consequence remains to be determined. Unlike normal cells, tumor cells may fail to activate the apoptotic pathway. Indeed, a characteristic of most tumor cells is the resistance to agents that induce apoptosis in non malignant cells. In contrast, MAL induced apoptosis in tumor cells but left other cells intact. Since tumor cells are often resistant to the normal apoptosis-inducing signals, our finding may be important in further elucidation of the pathways that lead to apoptosis in tumor cells. 14
The mechanism of apoptosis induction and the molecular basis for the difference in susceptibility between tumor cells and healthy cells have not been defined. By studying the interaction of MAL with different cellular compartments, using confocal microscopy and sub cellular fractionation it observed that MAL was shown to accumulate in the nuclei of sensitive cells rather than in the cytosol, the vesicular fraction, or the ER–Golgi complex. Nuclear uptake occurred rapidly in cells that were susceptible to the apoptosis inducing effect, but not in nuclei of resistant cells. Nuclear uptake was through the nuclear pore complex and was critical for the induction of DNA fragmentation. Ca21 was required for MAL-induced DNA fragmentation but nuclear uptake of MAL was independent of Ca21. This way MAL differs from most previously described agents in that it crosses the plasma membrane and cytosol, and enters cell nuclei where it induces DNA fragmentation through a direct effect at the nuclear level. Apoptotic cell death is characterized by loss of cytoplasmic material, nuclear changes with marginalization of chromatin, and the formation of apoptotic bodies. The reduction in cell viability is accompanied by stepwise chromatin fragmentation with initial formation of high-molecular-weight (HMW) DNA fragments(50–300 kbp) followed by oligonucleosome length DNA fragments consisting of oligomers of approximately 200bp. Apoptosis inducing agonists often bind to specific cell surface receptors and activate transmembrane signaling events that trigger a cascade of cytoplasmic and nuclear changes. There are also agents that bypass this sequential activation and instead trigger the apoptosis cascade through targeting of molecules directly in the cytoplasm and/or at the nuclear level. The transport of macromolecules from the cytoplasm into the nucleus is highly regulated. Nuclear pore complexes (NPCs) are the sites of exchange of macromolecules between the cytoplasm and nucleoplasm. The NPCs allow passive diffusion of molecules smaller than 20–40 kDa but larger proteins are delayed. Entry of large molecules or complexes into the nucleus requires active transport to be efficient and is commonly carrier-mediated. The specificity for the carrier may be determined by nuclear targeting or nuclear localization sequences (NLS) that characterize proteins with the ability to enter the nucleus. 13, 14
Molecular characterization of α-lactalbumin folding variants:
The active fraction was purified from casein by anion exchange chromatography. The active fraction showed N-terminal amino acid sequence identity with human milk α-lactalbumin. Size exclusion chromatography resolved monomers and oligomers of α-lactalbumin that were characterized using UV absorbance, fluorescence, and circular dichroism spectroscopy. The high molecular weight oligomers were kinetically stable against dissociation into monomers and were found to have an essentially retained secondary structure but a less well organized tertiary structure. Comparison with native monomeric and molten globule α-lactalbumin showed that the active fraction contains oligomers of α-lactalbumin that have undergone a conformational switch toward a molten globule-like state. Oligomerization appears to conserve α-lactalbumin in a state with molten globule-like properties at physiological conditions.. The crystal structure of α-lactalbumin has been solved. It is a metalloprotein with high affinity for Ca21 and other divalent cations and Ca21 is essential for the folding and structural stability of α-lactalbumin. At low pH, α-lactalbumin forms a relatively stable protein folding variant. This form, the molten globule, has native-like secondary structure but less well defined tertiary structure. Unlike monomeric α-lactalbumin from whey, the apoptosis inducing component was purified from the casein fraction (precipitated at pH 4.3), and behaved as a multimeric protein rather than a monomer. Furthermore, native monomeric α-lactalbumin from human milk whey was inactive in the apoptosis assay. These observations suggested that the active fraction contains an alternative molecular form of α-lactalbumin. It is shown that, using mass spectrometry, gel filtration, UV absorption, fluorescence, and CD spectroscopy that the apoptosis-inducing form of α-lactalbumin is a mixture of monomeric and multimeric forms with molten globule-like properties and suggest that folding variants of α-lactalbumin differ in biologic activity. 15
HAMLET (Human α-lactalbumin made lethal to tumor cells) 16
Lactalbumin can be converted to an apoptosis-inducing complex only in the presence of a lipid cofactor. The complex is formed from pure components i.e α-lactalbumin and oleic acid, each of which is inactive in the apoptosis assays. The folding change and the lipid cofactor were both necessary to attain this new function. The specificity of the lipid cofactor was investigated using fatty acids differing in carbon-chain length, saturation, or cis/trans conformation. They identified unsaturated C18 fatty acids in the cis conformation as the cofactors that interact with partially unfolded α-lactalbumin and form HAMLET. The interaction between protein and fatty acid was specific, because saturated C18 fatty acids or unsaturated C18:1 trans conformers were unable to form complexes with partially unfolded α-lactalbumin as were fatty acids with shorter or longer carbon chains. Partially unfolded α-lactalbumin does not induce apoptosis in the absence of the lipid cofactor. In conclusion, the α-lactalbumin structure can be adjusted by shifting environments and functional diversity can be created by changes in tertiary structure. Also, lipid cofactors enable proteins to adopt stable novel conformations and thus to act as partners in protein folding. In this way, a single polypeptide chain can vary its structure and function, thereby participating in different biological processes in distinct environments.
Cellular targets of HAMLET in tumor cells- The subcellular localization of HAMLET is a potential key to distinguish the cellular responses of sensitive tumor cells from responses by the resistant normal cells. The trafficking of HAMLET in tumor cells and normal differentiated cells was compared by confocal microscopy. The availability of surface receptors is not the limiting step, nor the critical factor determining sensitivity, because both cell types showed rapid surface binding of HAMLET. Translocation of HAMLET to the cytoplasm was detected in both cell types but with different efficiency. Large amounts of HAMLET reached the cytoplasm of the tumor cells and formed cytoplasmic aggregates. There was some cytoplasmic accumulation of HAMLET in normal cells.
The subsequent redistribution of HAMLET from the cytoplasm to the perinuclear region occurred only in the tumor cells. Despite the entry of HAMLET into the cytoplasm of normal cells, no trafficking to the perinuclear region was observed. The translocation to the perinuclear region was accompanied by the movement of mitochondria, as shown by co-staining with mitochondria-specific markers.
Mechanisms of cancer cell death17
Like non-malignant cells, tumor cells can undergo
various types of cell death, including apoptosis, necrosis, autophagic cell
death, and mitotic catastrophe. However, ionizing radiation and most
chemotherapeutic agents kill
tumor
cells by apoptosis, which most often is triggered by activation of the
mitochondrial signaling pathway, leading to caspase activation, cleavage of
cellular proteins, cell death, and phagocytosis. To avoid death, tumor cells
have developed various mechanisms of resistance, including gene amplification,
deletions and mutations. Hence, evasion of apoptosis is regarded as one of the
major characteristics of malignant growth. HAMLET represents a new type of tumoricidal
molecule. It can activate cell death pathways in tumor cells, which might be
resistant to both chemotherapy and ionizing radiation. In addition, HAMLET
appears to trigger a similar death response in tumor cells of very different
origins, while healthy, differentiated cells are resistant. Hence, it is
important to identify the mechanism(s) responsible for HAMLET-induced cell
death, as such information may help design more specific tumor therapies in the
future.
Membrane interactions- HAMLET starts the attack on tumor cells by binding to the cell surface, and thereafter rapidly invades the tumor cell. The mechanism is not fully understood, but invasion requires both the unfolding of α-lactalbumin and the presence of the fatty acid. The uptake of HAMLET by tumor cells is activated by the fatty acid and unfolded protein in combination. Invasion by HAMLET is likely to be an important determinant of cell sensitivity, as large amounts of the complex invade tumor cells whereas differentiated cells take up only small amounts of the complex. Furthermore, the protection patterns were found to differ depending on the lipids, suggesting that membrane fluidity may be important for the interaction of α-lactalbumin with membranes. Within the context of HAMLET’s putative interaction with cancer cells, it hypothesized that the role of the bound oleic acid is to stabilize the protein in a conformation suitable for interacting with membranes.
Apoptosis induction- Mitochondrial damage and cytochrome c release were detected in both intact tumor cells and isolated mitochondria, and there was a weak caspase response, including activation of effector caspases-3 and -9, and of the DNA damage-related, nuclear caspase-2. The apoptotic response was not the cause of cell death; however, as caspase inhibitors did not rescue the cells from dying. The mitochondria are only one of several targets for HAMLET in tumor cells.
HAMLET also interacts with tumor cell nuclei. Upon exposure of tumor cells to the LD50 concentration of HAMLET, the bulk of the complex is found within the nuclei after about one hour. This suggests a rapid translocation process and passage of HAMLET across the nuclear membrane. In the nuclei, HAMLET binds with high affinity to histones H3 and H4, and with lower affinity to histones H2a and H2b. HAMLET is also able to bind intact nucleosomes with very high affinity, causing the formation of virtually insoluble chromatin complexes in the nuclei of tumor cells. As a consequence, transcription is impaired and cell death becomes irreversible. HAMLET induces macroautophagy in tumor cells, and this appears to be partly responsible for HAMLET-induced cell death. Autophagy is a cellular process used for the degradation of long-lived cytosolic proteins and organelles. During macroautophagy, portions of the cytoplasm and organelles are enwrapped in membrane sacs, forming double-membrane-enclosed vesicles, termed autophagosomes, which are detectable by electron microscopy. Autophagosomes subsequently fuse with lysosomes, and lysosomal enzymes degrade their contents for reutilization. In addition, it has been proposed that macroautophagy is involved in a non-apoptotic form of programmed cell death, called autophagic cell death or type II cell death.
HAMLET interacts with histones and chromatin in tumor-cell nuclei. 18 The accumulation of HAMLET in tumor-cell nuclei encouraged us to identify molecular targets for HAMLET. The initial studies, using crude cellular fractions, showed that HAMLET binds to histone H3 in nuclear fractions from tumor cells. Mixing histones with HAMLET in solution resulted in precipitation of the proteins, further illustrating the high affinity of the interaction. Both denatured and native histones were precipitated by HAMLET, with a preference for H3 and H4. HAMLET colocalized with histones in cell nuclei and induced changes in the global chromatin structure. The chromatin was condensed to the nuclear periphery or to large, spherical structures. HAMLET was present in both of these chromatin patterns.
In the nucleus, HAMLET could bind histones in chromatin and either removes them from DNA or directly binds nucleosomes and impairs their function. Alternatively, the binding of HAMLET to chromatin could induce DNA damage. It has been observed that defects in chromatin assembly can lead to double-strand DNA breaks and activation of the S-phase checkpoint. However, it is not clear how HAMLET damages the DNA.
In conclusion, HAMLET binds to histones in the nuclei of tumor cells dying after HAMLET treatment. This interaction may disturb the structure and function of the chromatin and could be an important feature of HAMLET-induced cell death.
HAMLET interacts with mitochondria, as shown by co localization in living cells and by studies of isolated mitochondria. Furthermore, HAMLET triggers membrane depolarization, release of cytochrome C and activates pro-apoptotic caspases. HAMLET-induced cell death differs from most classical apoptotic systems in that caspase inhibitors do not rescue cells.
We conclude from these and other studies that HAMLET induces apoptosis-like death by a novel mechanism involving trafficking to the perinuclear region and translocation to the cell nuclei. The nuclear accumulation of HAMLET disrupts the chromatin and marks the irreversible stage of tumor cell apoptosis. 19
In vivo effects of HAMLET in tumor cell models:
Three types of in vivo models have been employed
to investigate if HAMLET can be used to treat tumors in vivo: (a) Human
glioblastoma xenografts in nude rats- (b) Topical treatment of skin papillomas
in patients, and (c) Intravesical inoculation of HAMLET in patients with
bladder cancer.
The results obtained by all the models identify HAMLET
as a potential new tool in cancertherapy
as it did not show any toxic side effects. And suggest that HAMLET should be
further explored as a novel approach to controlling glioblastoma progression
and skin papillomas reduction. Also, Local HAMLET administration might be of
value in the future treatment of bladder cancers 20, 21
CONCLUSION:
Human milk is an ideal food for infants because it contains a unique blend of carbohydrates, protein and fat that is perfect for a baby’s development. Additionally, breast milk contains digestive proteins, minerals, vitamins, hormones, antibodies, and stem cells that allow children to thrive and resist infection. These immune-building properties also make human milk a promising alternative medicine for adults with chronic diseases like cancer.
HAMLET
(Human α-lactalbumin made lethal to tumor cells) was discovered by
serendipity. α-lactalbumin is the most abundant protein in human
milk,
and oleic acid is the most abundant fatty acid. HAMLET is not present in newly
expressed milk,
however, as α-lactalbumin is in the native state and the fatty acids are
bound in triglycerides. The components needed to form HAMLET are thus present
in the stomach of breast-fed babies, and it is tempting to speculate that the
complex may be formed there. The gastrointestinal tract of the newborn
individual undergoes very rapid maturation, and it is possible that there is a
risk for cells to re-differentiate and form tumor progenitor cells. The
presence of a substance like HAMLET might help by removing these cells, and
such a mechanism would be of obvious benefit to the organism. Case control
studies show that breast-fed children have a reduced frequency of lymphoid
malignancies, suggesting that substances in milkmay
aid to protect against tumor development. A fraction of human
milkwas
able to kill
tumor cells by a mechanism resembling apoptosis, and many different types of
tumor cells were susceptible to this effect while healthy differentiated cells
were resistant. Since then, the HAMLET complex has been characterized in detail
in order to determine the structural basis and mechanisms of the tumoricidal
activity.
Thus, the use of human breast milk as an alternative therapy for cancer patients can reduce symptoms of disease and improve patient’s quality of life.
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Received on 12.09.2011 Modified on 24.09.2011
Accepted on 05.10.2011 © RJPT All right reserved
Research J. Pharm. and Tech. 5(1): Jan. 2012; Page 14-19