Knowledge production in experimental molecular medicine Primers for a reflexive life knowledge.

Experimental molecular medicine has developed into a major scientific discipline. It has during the last 60 years had significant impact on health, and disease, and on the understanding of life. The main aim of this study was to investigate how experimental molecular medicine produces knowledge. Trough a discussion of works of thinkers like Claude Bernard, Georges Canguilhem, Hans-Jörg Rheibnerger and Bruno Latours I develop an understanding of experimental molecular medicine as a hybrid activity. In the knowledge production social, technological and practical factors are intrinsically connected. The second question posed in this work was whether a philosophical reflection over the knowledge production in experimental molecular medicine could lead to self-reflection and a subsequent change of the theory-practice within experimental molecular medicine itself? I suggest that by using Georges Canguilhem's concept of biological normativity it is possible to develop an understanding of how biological systems are constructed to deal with world of dangers, unanticipated events, and environmental variations that make up the life of an organism

Intracellular glutathione determines bortezomib cytotoxicity in multiple myeloma cells

Multiple myeloma (myeloma in short) is an incurable cancer of antibody-producing plasma cells that comprise 13% of all hematological malignancies. The proteasome inhibitor bortezomib has improved treatment significantly, but inherent and acquired resistance to the drug remains a problem. We here show that bortezomib-induced cytotoxicity was completely dampened when cells were supplemented with cysteine or its derivative, glutathione (GSH) in ANBL-6 and INA-6 myeloma cell lines. GSH is a major component of the antioxidative defense in eukaryotic cells. Increasing intracellular GSH levels fully abolished bortezomib-induced cytotoxicity and transcriptional changes. Elevated intracellular GSH levels blocked bortezomib-induced nuclear factor erythroid 2-related factor 2 (NFE2L2, NRF2)-associated stress responses, including upregulation of the xCT subunit of the Xc- cystine-glutamate antiporter. INA-6 cells conditioned to increasing bortezomib doses displayed reduced bortezomib sensitivity and elevated xCT levels. Inhibiting Xc- activity potentiated bortezomib-induced cytotoxicity in myeloma cell lines and primary cells, and re-established sensitivity to bortezomib in bortezomib-conditioned cells. We propose that intracellular GSH level is the main determinant of bortezomib-induced cytotoxicity in a subset of myeloma cells, and that combined targeting of the proteasome and the Xc- cystine-glutamate antiporter can circumvent bortezomib resistance