Kurzfassung

Multiple myeloma is the second most prevalent hematological cancer. The disease is due to malignant expansion of antibody-secreting plasma cells, is characterised by a high degree of morbidity (e.g. anemia, bone fractures and pain, kidney failure, infections) and is still largely incurable. Due their high immunoglobulin synthesis and secretion, myeloma cells are especially dependent on a proper protein metabolism with degradation and disposal of misfolded proteins. To cope with misfolded...Multiple myeloma is the second most prevalent hematological cancer. The disease is due to malignant expansion of antibody-secreting plasma cells, is characterised by a high degree of morbidity (e.g. anemia, bone fractures and pain, kidney failure, infections) and is still largely incurable. Due their high immunoglobulin synthesis and secretion, myeloma cells are especially dependent on a proper protein metabolism with degradation and disposal of misfolded proteins. To cope with misfolded proteins, myeloma cells rely on a cellular stress response program (Unfolded Protein Response, UPR), which preserves cellular viability under physiological conditions but induces cell death upon prolonged or exaggerated induction via misfolded intracellular proteins. Since availability of arginine is necessary for unimpaired protein synthesis, we are currently analysing the role of therapeutic arginine deprivation as potential UPR inducer. This strategy is also tested in combination with (i) the anti-myeloma drug class of proteasome inhibitors, which interfere with proper protein degradation and (ii) the arginine analogue canavanine, which by itself can induce massive protein misfolding due to incorporation into nascent protein chains instead of arginine. We also characterize the arginine transporters in myeloma cells as potential novel target structures for pharmacological interference with arginine supply for these cancer cells.» weiterlesen» einklappen