J Pharm Pharmacogn Res 3(suppl. 1): S65, 2015
Proceedings of the 4th International Symposium on Pharmacology of Natural Products FAPRONATURA 2015 September 21st-25th, 2015; Cuban Society of Pharmacology. Topes de Collantes, Sancti Spiritus, Cuba.
OC-47: CHARACTERIZATION OF THE PROTEIN KINASE CYSTEINOME TARGETED BY WITHAFERIN A TO OVERCOME GC THERAPY RESISTANCE IN MULTIPLE MYELOMA
Chirumamilla CS1, Heyninck K2, Dom M1, Van Ostade X1, Vanden Berghe W1,2.
Introduction: Multiple myeloma is a clonal B-Cell malignancy characterized by the uncontrolled proliferation of malignant plasma cells in the bone marrow. Myeloma patients are widely treated based on the risk with different combinations of novel agents such as bortezomib (proteasome inhibitors), thalidomide (immuno-modulatory drugs) and prednisone (glucocorticoids). Despite the progress in therapy, MM remains largely incurable, due to low remission rates of conventional therapies and the development of drug resistance. It is now widely accepted that B-Cell receptor (BCR) signaling pathways and genetic aberrations are important factors for initiation and progression of cancer in MM patients. As such there is an urgent need to (1) develop GC analogues with improved therapeutic profile (increased efficacy, reduced side effects) (2) Investigate signaling pathways, which are associated with GC therapy response. Previously, we and others observed that the natural steroid and kinase inhibitor withaferin A (WFA), (isolated from Withania somnifera, also referenced as Ashwagandha in Ayurveda Medicine) chemosensitizes drug resistant cancer cells for induction of cell death. In this respect, withaferin A holds promise as a novel class of therapy sensitizing drugs. Methods: The in vitro effect of WFA on kinase activity profiles of multiple myeloma cell line models MM1.S and MM1.R were analyzed by means of innovative peptide array based kinase activity profiling by PamChip® peptide microarrays. This chip contains peptide sequences from known human phosphorylation sites of both Serine/threonine kinases (STK’s) and Phospho tyrosine kinases (PTK’s). Results: A comparison of the tyrosine kinase activity profile between the Dexamethasone sensitive (MM1.S) and resistant (MM1.R) myeloma cell types revealed a significant difference (p-value <0.05, student t test) in basal phosphorylation of 34 out of 144 peptide substrates tested. Of special note, treatment of cells with 1.5uM WFA reduced peptide tyrosine phosphorylation of non-receptor tyrosine kinases. Conclusions: We observed that glucocorticoid therapy resistance in multiple myeloma cells is associated with hyperactived non-receptor tyrosine kinases Moreover, the natural kinase inhibitor withaferin A can chemosensitize GC resistant multiple myeloma cells in part by inhibiting non-receptor tyrosine kinase activities.
Citation Format: Chirumamilla CS, Heyninck K, Dom M, Van Ostade X, Vanden Berghe W (2015) Characterization of the protein kinase cysteinome targeted by withaferin a to overcome GC therapy resistance in multiple myeloma. [Abstract]. In: Proceedings of the FAPRONATURA 2015; 2015 Sep 21-25; Topes de Collantes, Sancti Spiritus: CSF. J Pharm Pharmacogn Res 3(Suppl. 1): S65. Abstract nr OC-47.