Myeloperoxidase: an enzyme involved in intrinsic vincristine resistance in human myeloblastic leukemia

Abstract

One of the differences between acute myeloblastic leukemia (AML) and acute lymphoblastic leukemia (ALL) is their sensitivity to vincristine. Although vincristine plays an important role in chemotherapeutic regimens for ALL, it does not possess clinically significant activity in AML. Horseradish peroxidase, a heme-centered peroxidase, oxidatively degrades Vinca derivatives and thereby abrogates their cytotoxic activity. This finding suggested that myeloperoxidase (MPO), a heme- centered peroxidase characteristically found in AML and not in ALL, might also degrade vincristine. We first examined the effects of MPO on vincristine in a cell-free system and demonstrated that this enzyme is capable of catalyzing vincristine's oxidative breakdown. We also observed that vincristine is more rapidly degraded in tissue culture by MPO-positive HL-60 cells than by a MPO-negative HL-60 subclone. The degree of MPO activity in these cell lines correlated in a positive manner with their degree of resistance to vincristine's cytotoxic activity. Moreover, the differential resistance to vincristine observed between these cell lines could be increased by increasing the concentration of H2O2 available to the enzyme. These data support the hypothesis that MPO-mediated oxidation of vincristine accounts in part for this drug's lack of activity in AML.

Overexpression of heme oxygenase‐1 in microenvironment mediates vincristine resistance of B‐cell acute lymphoblastic leukemia by promoting vascular endothelial growth factor secretion

“…As shown in Figure 3-1D and E, the IC 50 values of CCRF-SB and Super B15 cells are 3 nM and 4 nM, respectively, which are similar to those reported in previous studies using other leukemia cell lines. [28][29][30] The IC 50 values of Super B15 (5.458 ± 0.278 nM) and CCRF-SB cells (4.625 ± 0.294 nM) were higher after BMSCs treatments (P < 0.05) compared with those after control treatments. Compared with BMSCs treatments, the values were higher after L-HO-1-BMSCs treatments (Super B15: 6.425 ± 0.301 nm; CCRF-SB: 5.741 ± 0.329 nM) (P < 0.05), but lower after SiHO-1-BMSCs treatments (Super B15: 4.334 ± 0.309 nM; CCRF-SB: 3.291 ± 0.305 nM) (P < 0.01) ( Tables 1,2).…”

Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or “Immuno-Fairy Tales”?

“…Vasculitis (63) and almost all diseases for which no etiology has been identified may potentially be related to abnormal phagocyte functions. Other possible deleterious consequences of phagocyte activities include a potential effect of MPO-mediated oxidation of anticancer drugs such as vincristine (343). Material, such as defensin, released by biomaterialactivated PMNs may contribute to creating an environment hostile to host defenses at the biomaterial surface by cell deactivation.…”

Cellular drug resistance in acute myeloid leukemia: literature review and preliminary analysis of an ongoing collaborative study

“…Differences in resistance to 9 other drugs (cytarabine, anthracyclines, thiopurines, teniposide, asparaginase, vindesine) were not sig- cept that the former are resistant to glucocorticoid,. The increased sensitivity to vincristine may be explaim:d by the low activity of myeloperoxydase in AML M5 sampies, an enzyme that confers resistance to vincristine [32,33]. The increased sensitivity of AML M5 sampies to I-aspclraginase may be explained by the low asparagine synthetase activity in this particular type of AML sampies [6].…”