MPA increases idarubicin‐induced apoptosis in chronic lymphatic leukaemia cells via caspase‐3

Abstract

The caspase family of protease is speculated to have a crucial role in apoptosis. The effect of treatment with Idarubicin (IDA) and Medroxyprogesterone acetate (MPA), used alone or in combination, on the activation of Caspase-3 in canine Chronic Lymphatic Leukaemia (CLL) cells was investigated, in order to clarify the mechanism of chemo- and hormone-therapy mediated apoptosis. Caspase activity was determined by a quantitative fluorimetric assay. Apoptosis was monitored by propidium iodide (PI) and nucleosomes assay. Treatment of CLL cells for 24 h with MPA 5 microM did not significantly activate caspase-3 but its activity was increased almost 5-fold more with IDA 1 microM (P < 0.05) than control. Treatment of CLL cells with IDA 1 microM in equimolecular association with MPA was able to increase the activation of caspase-3 induced by IDA of the 61.2% (P < 0.05) in comparison with IDA alone. The activation of caspase-3 was confirmed evaluating apoptosis by PI and nucleosomes assay. Furthermore, both caspase-3 activation and apoptosis triggered by IDA alone or in combination with MPA were significantly inhibited by specific caspase-3 inhibitor AC-DEVD-CMK. These findings provide an explanation for IDA and MPA induced-apoptosis mechanism.

Treatment of primary CLL cells with bezafibrate and medroxyprogesterone acetate induces apoptosis and represses the pro-proliferative signal of CD40-ligand, in part through increased 15dΔ12,14,PGJ2

“…Others have identified that MPA enhances anthracyclin uptake by CLL cells and increases apoptosis of cultured CLL cells exposed to the anthracyclin idarubicin. 43,44 These observations are possibly explained by the chemosensitizing actions of MPA acting as an inhibitor of the ATP-binding cassette drug resistance transporter p-glycoprotein (MDR1). 45 Future studies will address whether the role of MPA in enhancing the effect of BEZ on CLL cells is similarly mediated by inhibition of p-glycoprotein or other ATP-binding cassette drug resistance transporters.…”

Medroxyprogesterone and tamoxifen augment anti‐proliferative efficacy and reduce mitochondria‐toxicity of epirubicin in FM3A tumor cells in vitro

“…Following our first report on epirubicin-MPA synergism in FM3A cells in vitro another study confirmed the same synergism to suppress FM3A growth in female mice in vivo (Yuyama et al, 2003). The same year MPA was found to increase leukemia sensitivity to idarubicine via caspase-3 (Florio et al, 2003). An experimental study revealed a MPA-mechanism of metastasis prevention.…”

“…A breast cancer with metastases to both the lungs and liver was also reported to undergo complete regression with a MPA combination of UFT and cyclophosphamide chemotherapy (Ishikawa et al, 2005). The same year MPA was found to increase leukemia sensitivity to idarubicine via caspase-3 (Florio et al, 2003). The study revealed that MPA induced highly significant increases in metastases-free and overall survival in women >60 years of age (Hupperets et al, 2001), and there have been no other published serial studies to date that prove the opposite.…”

Comparison of Dasatinib, Nilotinib, and Imatinib in the Treatment of Chronic Myeloid Leukemia

“…Intracellular Ca 2+ concentrations [Ca 2+ ] i were measured by using the radiometric fluorescent indicator dye FURA‐2/AM, the membrane‐permeant form of FURA‐2/AM as previously described and opportunely modified (Florio et al, ). Briefly, CS‐PBM or CML‐PBM cells were washed twice in PBS in 15 ml polypropylene tubes (Falcon/Becton Dickinson Labware, Lincoln Park, NJ) resuspended in Krebs Ringer (KRH) medium (1 × 10 6 cells/ml) with 3.0 mM Ca 2+ ‐sensitive dye FURA‐2/AM for 60 min at 30°C.…”