Signal Transduction and Drug Resistance in Leukaemia Cells
Group Leader: Dr Gitendra Wickramasinghe
Our group uses a biochemical approach to study signal transduction in leukaemia cells. The overall emphasis is to use insights provided by these studies to identify novel drugs and strategies which can be used to induce more effective apoptotic killing of chronic lymphocytic leukaemia (CLL) cells than is possible using conventional chemotherapy. Recent studies fall into two principle categories, as outlined below.
The first approach involves the p53 gene and its protein product which plays a key role in inducing apoptosis following treatment with conventional agents. Mutation of this gene frequently contributes to drug resistance in CLL and in other cancers, therefore drugs which kill cells independently of p53 are of potential value in the treatment of CLL patients who have become resistant to standards regimes. These studies have resulted in the identification of three novel drugs which induce CLL apoptosis regardless of the mutation status of the p53 gene, but which are relatively inactive against normal cells.
The second approach attempts to define biochemical signalling strategies used by CLL cells to avoid apoptosis induction following treatment with cytotoxic agents. Some of these strategies are cell-intrinsic and include constitutive activation of STAT3, MAP kinase and PI-3kinase signalling pathways, while others involve signalling to CLL cells from extrinsic cytoprotective cytokines including IL-4. Understanding of these mechanisms has resulted in the identification of highly selective small molecule inhibitors which antagonize the protective mechanisms and result in more efficient cell killing. An example of this type of strategy, directed against a cell-intrinsic mechanism of drug resistance, is shown in the figures below.
• Dr Andrew J. Steele BSc (Hons) PhD, Honorary Lecturer/Research Fellow
• Dr. Archibald G. Prentice MB, FRCP,FRCPath, Consultant Haematologist
• Dr. R.Gitendra Wickremasinghe BSc (Hons) PhD, Reader in Experimental Haematology
Phenylacetylenesulfonamide (PAS) induces p53-independent apoptotic killing of B-chronic lymphocytic leukemia (CLL) cells. Steele AJ, Prentice AG, Hoffbrand AV, Yogashangary BC, Hart SM, Lowdell MW, Samuel ER, North JM, Nacheva EP, Chanalaris A, Kottaridis P, Cwynarski K, Wickremasinghe RG. Blood. 2009 Aug 6;114(6):1217-25.
Baou M, Jewell A, Muthurania A, Wickremasinghe RG, Yong KL, Carr R, Marsh P, Murphy JJ. Leukemia. 2009 May;23(5):986-9.
Why is CLL refractory to bortezomib? Wickremasinghe RG. Blood. 2008 Nov 1;112(9):3540-187.
p53-mediated apoptosis of CLL cells: evidence for a transcription-independent mechanism. Steele AJ, Prentice AG, Hoffbrand AV, Yogashangary BC, Hart SM, Nacheva EP, Howard-Reeves JD, Duke VM, Kottaridis PD, Cwynarski K, Vassilev LT, Wickremasinghe RG. Blood. 2008 Nov 1;112(9):3827-34.
The sesquiterpene lactone parthenolide induces selective apoptosis of B-chronic lymphocytic leukemia cells in vitro. Steele AJ, Jones DT, Ganeshaguru K, Duke VM, Yogashangary BC, North JM, Lowdell MW, Kottaridis PD, Mehta AB, Prentice AG, Hoffbrand AV, Wickremasinghe RG. Leukemia. 2006 Jun;20(6):1073-9.
Selective apoptotic killing of malignant hemopoietic cells by antibody-targeted delivery of an amphipathic peptide. Marks AJ, Cooper MS, Anderson RJ, Orchard KH, Hale G, North JM, Ganeshaguru K, Steele AJ, Mehta AB, Lowdell MW, Wickremasinghe RG. Cancer Res. 2005 Mar 15;65(6):2373-7.