Title: HAMLET (protein complex) Content: HAMLET (from Human Alpha-lactalbumin Made LEthal to Thumor cells) is a complex between alpha-lactoalbumin and oleic acid that has been shown to be effective to induce apoptosis in tumor cells. HAMLET is a potential chemotherapeutic agent. == History == Catharina Svanborg, immunologist at Lund University, and her student Anders Håkansson began experimenting in 1992 with human milk, microbes and cells in routine research. By chance, they observed how isolated cancer cells decreased in contact with milk. They formed a team of thesis students to investigate the finding and to search for the mechanism and the component that causes it. In 1995, Håkansson found an isolated compound in a fraction of human milk that induced what appeared to be apoptosis in human lung carcinoma, pneumococcal bacteria and other pathogens, leaving healthy cells unaffected. It was the perfect cure in that case. The Vice President of the American Cancer Society traveled to Sweden and awarded them a grant to continue researching cancer. The company HAMLET Pharma was created to explore the compound. The active component responsible for the tumoricidal activity, a complex of alpha-lactoalbumin and oleic acid, was found in 2000. == Composition == Endogenous human alpha-lactoalbumin serves as a cofactor in lactose synthesis, but has no tumoricidal properties. Alpha-lactoalbumin must be partially deployed to allow the release of the calcium ion and its replacement by an oleic acid molecule. Partially folded conformation is essential for HAMLET cytotoxicity. Oleic acid is needed to stabilize this molecule in the partially unfolded state. In recent years, HAMLET's structure, function and clinical applications are under investigation. == Mechanism of action == HAMLET performs attacks on many different cell organelles, including mitochondria, proteasomes, and histones, and interferes with cellular processes such as macroautophagy. HAMLET has been shown to bind to the cell surface and rapidly invade cells, and tumor cells absorb much more protein than healthy, differentiated cells. One of HAMLET's most prominent targets once inside the cell is mitochondria. Electron microscopy revealed physical damage to mitochondrial membranes. Another target of HAMLET is the proteasome. 26S are activated in response to large amounts of HAMLET protein deployed in the cytoplasm, but degradation of HAMLET by the proteasome is unusually slow. However, proteasome inhibition alone does not appear to be responsible for HAMLET-induced cell death, as proteasome inhibitors have been shown to reduce HAMLET cytotoxicity. HAMLET also targets the nucleus, where it interacts with histones to interfere with transcription processes. HAMLET cells have shown the physiological characteristics of macroautophagy, a process in which cellular components are sequestered into double-membrane-bound vesicles that fuse with lysosomes for degradation. HAMLET and cells under amino acid starvation conditions (an initiator of macroautophagy) showed similar expression patterns of autophagocytotic proteins and responded equally well to the addition of inhibitors of macroautophagy. == Research == === Antibiotic adjuvant === Although HAMLET alone is not active against most bacteria, when it is present along with antibiotics, HAMLET can help. Specifically, HAMLET can cause MRSA bacteria to be sensitive to methicillin, vancomycin, gentamicin, and erythromycin. === Tumors === Research is underway to determine if this could be a possible treatment for cancer. Animal models of glioblastoma have been successfully studied. The first human trial of the therapy was on benign skin growths (warts) and showed positive results with no side effects. It is being studied in carcinomas of the lung, throat, kidney, colon, bladder, prostate, and ovaries, as well as in melanomas, glioblastomas, and leukemias. A study of bladder cancer in a mouse found that it caused the elimination of TUNEL-positive cancer cells in the urine, with no adverse side effects on healthy cells. == Audiovisuals == BBC presents Howard Cohen as an American physicist-theorist with prostate cancer diagnosed in 1999 who decided to start a diet with human breast milk intake after reading works on HAMLET. Anders Håkansson mentioned that, since it is a protein complex, most of it is digested in the stomach, and it is not known how much of the compound can reach a tumor. Cohen has appeared in several US TV-news and in 2020 he participated in Netflix's (Un)Well program on human milk. The program addresses the various practices of consuming human milk in adults, including unregulated online shopping and its use by bodybuilders for alleged unproven benefits. HAMLET Pharma has also made various audiovisuals such as 'This is HAMLET' .