הרספטין ורפואה טבעית

1) סרטן השד, כמו גידולים רבים אחרים, הוא תוצאה של שיבוש בפעולתם של מספר גנים בתא ולא בגן אחד. קישור גורם הצמיחה לקולטן HER 2/NEU אינו גורם לתא לעבור ממצב נורמלי לסרטני אלא מאפשר לתא לעבור חלוקות מהירות ורבות יותר. 2) הקולטן הנ"ל, הנחסם ע"י תרופת ההרספטין, מצוי גם על פני הקרום של תאים נורמלים אך בכמות קטנה. בכ 25% מגידולי השד יש ביטוי יתר של הקולטן, מה שגורם לצמיחה מהירה של הגידול ולפרוגנוזה גרועה יותר. מאידך זה מאפשר טיפול יעיל בהרספטין (בד"כ בשילוב עם כימותרפיה). 3) האפקט המשולב של שמן זית והרספטין בהורדת מספר הקולטנים ובמות התא הסרטני הודגם עד כה רק בתרביות תאים. אין עדיין ניסויים קליניים (אולי צריך לשתות חצי ליטר שמן זית ביום כדי שזה יעבוד בחולים?). אילו כל טיפול שנמצא יעיל על תאי סרטן במעבדה או כנגד גידולים בעכברים היה פועל גם בחולים מזמן לא היה סרטן. במעבדות מכון וייצמן והדסה כבר ריפאו את הסרטן לפני 10 שנים! 4) באופן כללי שמן זית מומלץ לבריאים ולחולים כאחד. קצת ספרות רקע: European Journal of Cancer Volume 43, Issue 3, February 2007, Pages 481-489 1. The ErbB receptor family The ErbB OR epidermal growth factor (EGF) receptors are members of subclass 1 of the receptor tyrosine kinase (RTK) superfamily. There are four ErbB receptor family members: ErbB1 (EGFR, HER1), ErbB2 (HER2/neu), ErbB3 (HER3) AND ErbB4 (HER4).1, 2 AND 3 The receptors are situated at the cell membrane AND have an extracellular ligand-binding region, a transmembrane region AND a cytoplasmic tyrosine-kinase domain. Ligand binding to the receptors results in receptor homo- AND heterodimers, activation of the intrinsic kinase domain AND phosphorylation of specific tyrosine residues within the cytoplasmic tail. Proteins dock on these phosphorylated residues, leading to the activation of a variety of intracellular signalling pathways that promote cell growth, proliferation, differentiation, AND migration.1, 2 AND 3 Interactions between ErbB receptors allow ErbB2, which has no identified ligand, AND ErbB3, which has no kinase activity, to participate in effective signalling.1, 3 AND 4 ErbB2 is the preferred dimerisation partner for all the other ErbB receptors. 2. ErbB receptors AND carcinogenesis These receptors are profoundly important in human cancer. In particular, EGFR AND ErbB2 have been implicated in the development of human cancers.2 Patients whose tumours have an alteration in ErbB receptors are associated with more aggressive disease AND poorer clinical outcome.5 ErbB receptors undergo various types of alteration in human tumours including gene amplification, receptor overexpression, activating mutations, overexpression of receptor ligands and/ OR loss of negative regulatory controls.2 The most robust example is that of amplification of HER2/neu in breast cancer. Amplification of HER2/neu is seen in 25–30% of breast cancers AND is associated with a statistically significant shortening in disease-free AND overall survival.6, 7 AND 8 Other examples include the discovery of activating mutations in the tyrosine-kinase domain of EGFR in non-small-cell lung cancer,9 AND 10 AND gene amplification AND overexpression of wild-type EGFR in head AND neck cancer.11 A number of agents directed against individual ErbB receptors have been approved for clinical use in human cancer AND can broadly be separated into two main groups. Humanised monoclonal antibodies are directed against the extracellular domain of the receptor, e.g. trastuzumab (Herceptin™); AND small molecule tyrosine kinase inhibitors, e.g. gefitinib (Iressa™), bind to the ATP binding site of the intrinsic tyrosine-kinase domain of the receptor.2 1: BMC Cancer. 2007 May 9;7:80. Olive oil's bitter principle reverses acquired autoresistance to trastuzumab (Herceptin) in HER2-overexpressing breast cancer cells. Menendez JA, Vazquez-Martin A, Colomer R, Brunet J, Carrasco-Pancorbo A, Garcia-Villalba R, Fernandez-Gutierrez A, Segura-Carretero A. Catalan Institute of Oncology (ICO)-Health Services Division of Catalonia, Spain. [email protected] BACKGROUND: A low incidence of breast cancer in the Mediterranean basin suggests that a high consumption of Extra Virgin Olive Oil (EVOO) might confer this benefit. While the anti-HER2 oncogene effects of the main omega-9 fatty acid present in EVOO triacylglycerols (i.e., oleic acid) have been recently described, the anti-breast cancer activities of EVOO non-glyceridic constituents--which consist of at least 30 phenolic compounds--remained to be evaluated. METHODS: Semi-preparative HPLC was used to isolate EVOO polyphenols (i.e., tyrosol, hydroxytyrosol, oleuropein). Both the anti-proliferative AND the pro-apoptotic effects of EVOO phenolics were evaluated by using MTT-based quantification of metabolically viable cells AND ELISA-based detection of histone-associated DNA fragments, respectively. The nature of the interaction between oleuropein aglycone AND the anti-HER2 monoclonal antibody trastuzumab (Herceptin) was mathematically evaluated by the dose-oriented isobologram technique. HER2-specific ELISAs were employed to quantitatively assess both the basal cleavage of the HER2 extracellular domain (ECD) AND the expression level of total HER2. The activation status of HER2 was evaluated by immunoblotting procedures using a monoclonal antibody specifically recognizing the tyrosine phosphorylated (Phosphor-Tyr1248) form of HER2. RESULTS: Among EVOO polyphenols tested, oleuropein aglycone was the most potent EVOO phenolic in decreasing breast cancer cell viability. HER2 gene-amplified SKBR3 cells were ~5-times more sensitive to oleuropein aglycone than HER2-negative MCF-7 cells. Retroviral infection of the HER2 oncogene in MCF-7 cells resulted in a "SKBR3-assimilated" phenotype of hypersensitivity to oleuropein aglycone. An up to 50-fold increase in the efficacy of trastuzumab occurred in the presence of oleuropein aglycone. A preclinical model of acquired autoresistance to trastuzumab (SKBR3/Tzb100 cells) completely recovered trastuzumab sensitivity (> 1,000-fold sensitization) when co-cultured in the presence of oleuropein aglycone. Indeed, the nature of the interaction between oleuropein aglycone AND trastuzumab was found to be strongly synergistic in Tzb-resistant SKBR3/Tzb100 cells. Mechanistically, oleuropein aglycone treatment significantly reduced HER2 ECD cleavage AND subsequent HER2 auto-phosphorylation, while it dramatically enhanced Tzb-induced down-regulation of HER2 expression. CONCLUSION: Olive oil's bitter principle (i.e., oleuropein aglycone) is among the first examples of how selected nutrients from an EVOO-rich "Mediterranean diet" directly regulate HER2-driven breast cancer disease.