The proteasome inhibitor PS-341 inhibits growth and induces apoptosis in Bcr/Abl-positive cell lines sensitive and resistant to imatinib mesylate
Gatto, S.; Scappini, B.; Pham, L.; Onida, F.; Milella, M.; Ball, G.; Ricci, C.; Divoky, V.; Verstovsek, S.; Kantarjian, H.M.; Keating, M.J.; Cortes-Franco, J.E.; Beran, M.
Haematologica 88(8): 853-863
2003
ISSN/ISBN: 0390-6078 PMID: 12935973 Document Number: 555418
Background and Objectives: Imatinib mesylate (IM) is the choice treatment for Bcr/Abl-positive malignancies. Emergence of resistance to IM warrants the exploration of novel well-tolerated anticancer agents. We intended to evaluate the effect of PS-341 on proliferation, survival, and cellular events in Bcr/Abl-positive cells sensitive and resistant to IM, and to investigate the effect of PS-341 and IM in conjunction. Design and Methods: Bcr/Abl-positive cell lines sensitive (p210Bcr/Abl KBM5, p210Bcr/Abl KBM7, and p190Bcr/Abl Z-119) or resistant (KBM5-R) to IM were treated with PS-341 alone or in combination with IM. The effect on cell growth was determined using the MTT assay. Cell-cycle analysis was performed by propidium iodide staining. Apoptosis was evaluated by measurement of sub-G1 DNA content, annexin V binding, and caspase 3 activity assays. Levels of apoptotic proteins, P-IkBalpha, Bcr/Abl, and phosphorylated Bcr/Abl were determined by western blotting. NF-kB activity was evaluated by electromobility gel shift assays. Results: PS-341 exerted growth inhibition effects in IM-sensitive and -resistant cells. This phenomenon correlated with accumulation of cells in the G2/M phase of cell cycle; transient downregulation of NFkappaB DNA binding activity; downregulation of Bcl-xL; activation of caspase 3, induction of apoptosis; inhibition of expression and phosphorylation of Bcr/Abl. Seqential combination of PS-341 followed by IM demonstrated a synergistic pro-apoptotic effect in IM-sensitive cells; concomitant exposure was antagonistic. Interpretation and Conclusions: PS-341 suppresses growth and induces apoptosis in Bcr/Abl-positive cells sensitive and resistant to IM. The use of PS-341 should be explored in patients with chronic myelogenous leukemia resistant to IM. Trials of combinations of PS-341 and IM require cautious design.