Mechanisms of action of anti-cancer drugs
The aim of our research is to reveal the mechanisms of programmed cell death induced by the drugs commonly used in medical oncology, and to define the signalling pathways involved in the induction of cell death. Our ultimate goal is to reveal the reasons for the primary and secondary resistance of tumors to these drugs and to develop new combination protocols to improve treatment modalities in cancer therapy
IFN-alpha (IFN) is used for treatment of cancer mainly in combination with other drugs or as adjuvant therapy. IFN-induced cell death of tumor cells has been a focus of research in our group for several years (Cell Growth Differ. 1997; Oncogene. 2002, Oncogene. 2003, J Biol Chem. 2004, Mol. Biol. Cell, 2007, Exp Cell Res, 2007, Exp Cell Res, 2011). Interestingly, IFN is able to block survival signalling delivered by growth factors such as IL-6 in myeloma cell lines leading to the inhibition of STAT3 activity (Exp Cell Res, 2007). We are engaged in retrospective studies on melanoma patients involved in the Nordic IFN trial aiming to understand the mechanisms of IFN-sensitivity. We are also involved in a clinical study aiming at studying the effect of IFN in the combination treatment with Rituximab in follicular lymphoma.
Chemotherapy is an established treatment modality against cancer. Cytotoxic drugs induce cancer cell death. We have delineated the molecular mechanisms behind the DNA damaging anthracyclin doxorubicin (DXR)-induced apoptosis (J Biol Chem. 2002 Nov 15; Mol Biol Cell. 2005 May25). Many of the established drugs used in the treatment of cancer, both DNA-damaging compounds and the tyrosine kinase and proteosome inhibitors, induce autophagy. Autophagy is a cellular response to starvation and stress, which might either promote cell death or protect from the cytotoxic effects of the drug in question. Thus, the relative impact of autophagy on cell death is controversial and depends both on cell type and on the drug being used. Therefore it is important to understand the role and mechanism of action of autophagy and to develop tools to manipulate this process. Our studies are focused on: screening of drugs approved for anticancer treatment for the induction of autophagy; developing and validating drugs-inhibitors of autophagy; analyzing the pro- or anti-apoptotic role of autophagy in drug-induced cell death and the molecular mechanisms behind.
GLUCOCORTICOID-INDUCED CELL DEATH IN ALL
Glucocorticoid hormones (GC), such as dexamethasone (Dex) are major anti-cancer compounds used in the treatment of lymphoid malignancies. They induce programmed cell death in normal and neoplastic lymphocytes. We have previously characterized Dex-induced apoptosis in acute lymphoblastic leukemia (ALL) cells and found that differential regulation of the Bcl-2-family members by Dex correlated with the sensitivity to dexamethasone treatment of the ex vivo ALL cells (Haematologica. 2007 Nov;92(11).
We also discovered that Dex treatment initiates autophagy that further leads to the apoptotic cell death (Cell Death Differ. 2009 Jul;16(7). GCs are known to modulate glucose metabolism in several tissues such as skeletal muscle and pancreatic beta-cells through reduction of glucose uptake. It has been also shown in the 60-s by F. Rosen and A. Munck labs that GCs affect glucose uptake in malignant lymphocytes. Indeed, we also found that Dex potently inhibited GLUT1 glucose transporter expression and glucose uptake and metabolism in ALL cell lines and in primary ALL cells. Moreover, block of glucose uptake correlated with the sensitivity to Dex in primary ALL cells suggesting that Dex kills leukemia cells through inhibition of glucose metabolism (Blood Cancer J. 2011 Jul;1(7). We aim now at establishing the molecular mechanisms of the block of glucose uptake, its role in induction of autophagy by Dex and at modulating the sensitivity of ALL cells by manipulating the levels of glucose and/or other metabolites. The important step would be to identify the consequences of the impaired glucose uptake for other cellular metabolic pathways, such as glutaminolysis and ROS production. This project is done in collaboration with the Childhood Cancer Research Unit, Department of Women and Child Health, Astrid Lindgren Children s Hospital.
METABOLISM AND CANCER
Normal and tumor cells differ markedly in their energy metabolism. Otto Warburg initially drew attention to the distinct metabolic state of tumors compared to normal tissues over 75 years ago, where tumor cells commonly favour glycolysis over oxidative phosphorylation even in the presence of oxygen (Warburg effect or aerobic glycolysis). Insight into the role and mechanism of this metabolic switch in tumorigenesis, and the utility of and means to therapeutically exploit altered metabolism in cancer was not clear, other than for utilization for FDG-PET imaging. Recently the metabolic requirements of tumor cells and the links to common pathway alterations in human cancers have been gradually emerging. It is now apparent that metabolic demand in tumor cells is high due to deregulation of cell growth, and that this constitutive activation of growth signaling pathways can disconnect cellular metabolism from nutrient and growth factor availability. Subversion of cellular metabolism for biosynthetic purposes is required to sustain deregulated tumor cell growth but can also restrict energy production that can limit tumor cell adaptation to metabolic stress. Hypoxic and acidic conditions in the tumor microenvironment are byproducts of these events and are common features of the tumor microenvironment that can activate stress responses, influence tumor growth, and impair treatment. Many of the oncogenic pathways altered in tumor cells modulate cell metabolism while enabling growth in these adverse conditions. Adaptation of tumor cells to stress through activation of the catabolic pathway of autophagy and its role in damage mitigation and promoting tumor cell survival to metabolic stress is also now emerging. From: Keystone symposia Metabolism and cancer progression , March 2010