Potentiation of myeloid differentiation by anti-inflammatory agents, by steroids and by retinoic acid involves a single intracellular target, probably an enzyme of the aldoketoreductase family

Abstract

HL60 cells are human promyeloid cells that can be induced to differentiate by physiological stimuli (e.g. all-trans retinoic acid (ATRA), 1 alpha,25-dihydroxyvitamin D3 (D3), granulocyte colony-stimulating factor (G-CSF)) and by non-physiological agents such as dimethysulphoxide (DMSO) and protein kinase C-activating phorbol esters. The sensitivity of HL60 cells to physiological differentiating agents, but not to DMSO, is enhanced when cells are exposed to 'anti-inflammatory agents' (e.g. indomethacin) or are 'primed' (pretreated) with a small amount of ATRA: alone, neither treatment induces differentiation. We earlier suggested that indomethacin might act by inhibiting the endogenous formation of a differentiation-suppressing prostanoid (Bunce, C.M., et al. (1994) Leukemia 8, 595-604). Studies of the formation of prostanoids by HL60 cells and of the effects of prostanoids on these cells failed to identify any prostanoid that could be implicated in sensitization by indomethacin. 3 alpha-Hydroxysteroid dehydrogenase (3 alpha-HSD) is another target of such 'anti-inflammatory agents'. Steroid inhibitors of 3 alpha-HSD sensitized HL60 cells to inducers of differentiation in a manner similar to indomethacin. 3 alpha-HSD is a member of the aldoketoreductase enzyme family, which comprises many enzymes of similar size and primary sequence. A protein that was recognised by an antiserum to 3 alpha-HSD was found in HL60 cells, but the cells showed no detectable 3 alpha-HSD activity. The 3 alpha-HSD-like protein was strikingly down-regulated by 'priming' doses of ATRA. When treatment with a differentiation-sensitizing 'anti-inflammatory agent' or steroid was combined with ATRA "priming', the effects of the different treatments were not additive: the resulting increase in sensitivity equalled that achievable by either treatment alone. We conclude that interference with a single intracellular regulatory mechanism underlies the increases in sensitivity of cells to differentiating agents that are caused by anti-inflammatory agents, by certain steroids and by 'priming' with ATRA. Decreased activity of a yet-to-be-identified member of the aldoketoreductase family of dehydrogenases is likely to be a central feature of a previously unrecognised mechanism that controls the responsiveness of cells to environmental stimuli such as retinoids and D3.

Induction of differentiation of human leukemia cells by combinations of COX inhibitors and 1, 25-dihydroxyvitamin D3 involves Raf1 but not Erk 1/2 signaling

“…On the practical side, we asked if combination of low concentrations of 1,25D with COX inhibitors is likely to be useful in the prevention or treatment of human myeloid leukemia, and if so, would selective COX-1 or COX-2 inhibitors be more effective than the non-selective inhibitors previously reported to synergize with 1,25D in HL60 cells. 11,30 We found that leukemia cell lines other than HL60 also exhibit enhanced differentiation, …”

“…It was previously reported that in HL60 cells ASA and INDO also have this synergy with 1,25D, but it was not clear if the more specific COX inhibitors are more, or less, effective potentiators of 1,25D-induced differentiation. 11,30 We now show that ASA can be an effective potentiator of 1,25D-induced differentiation not only in HL60 but also in U937, THP-1 cells (Fig. 3) and in primary AML cells (Fig.…”

AKR1C Isoforms Represent a Novel Cellular Target for Jasmonates alongside Their Mitochondrial-Mediated Effects

“…Treatment of HL-60 cells with the AKR inhibitors indomethacin or medroxyprogesterone acetate enhances both neutrophil and monocyte differentiation (7,8), and reciprocally, overexpression of AKR1C3 suppresses HL-60 differentiation (8,9). More recently, we have shown that knockdown of AKR1C3 in K562 cells results in erythroid differentiation (10).…”

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

“…BEZ is a lipid-lowering agent that mediates its activity as a ligand of the nuclear receptor PPARa and MPA is an orally active contraceptive progestogen. The study was based on our previous experience in Burkitts lymphoma 9 and acute myeloid leukemia (AML) [10][11][12] (Khanim et al, 2008, unpublished data). We show that both BEZ and MPA induce apoptosis in primary CLL cells and that the combination BEZ þ MPA is significantly more proapoptotic than either agent alone.…”