Promyelocytes

Imidazole antimycotics, ketoconazole, clotrimazole, and miconazole are potent inhibitors of various cytochrome P450-isoenzymes that also affect the metabolism of retinoids. They were fust shown to inhibit the metabolism of RA in F9 embryonal carcinoma cells. When tested in vitm liarazole, a potent CYP-inhibitor, suppressed neoplastic transformation and upregulated gap junctional communication in murine and human fibroblasts, which appeared to be due to the presence of retinoids in the serum component of the cell culture medium. Furthermore, liarazole magnified the cancer chemopreventive activity of RA and (3-carotene in these experiments by inhibiting RA-catabolism as demonstrated by absence of a decrease in RA-levels in the culture medium in the presence of liarazole over 48 h, whereas without liarazole 99% of RA was catabolized. In vivo, treatment with liarazole and ketoconazole reduced the accelerated catabolism of retinoids and increased the mean plasma all-irans-RA-concentration in patients with acute promyelocytic leukemia and other cancels. 

Included among other differentiating cell lines which have been established in culture, is the human promyelocytic cell line HL-60, which differentiates into more mature myeloid cells upon treatment with retinoic acid and prostaglandin E] (PGEi). Friend erythroleukemia cells differentiate into hemoglobin-producing cells when treated with either dimethyl sulfoxide, or hexamethylene bis-acetamide. 

Gambacorti-Passerini C., Mologni L, Bertazzoli C., le Coutre P., Marchesi E., Grignani F., Nielsen P.E. In vitro transcription and translation inhibition by anti-promyelocytic leukemia (PML)/re-tinoic acid receptor-alpha and anti-PML peptide nucleic acid. Blood 1996 88 1411-1417. 

Mologni L., Marches E., Nielsen P.E., Gai4BACOrti-Passerini C. Inhibition of promyelocytic leukemia (PML)/retinoic acid receptor-alpha and PML expression in acute promyelocytic leukemia cells by anti-PML peptide nucleic acid. Cancer Res. 2001 61 5468-5473. 

Tretinoin, also referred to ATRA, which stands for all-trans-retinoic acid, is a retinoic acid that is not cytotoxic but promotes the maturation of early promyelocytic cells and is specific to the t(15 17) cytogenetic marker. The time to peak concentrations is 1 to 2 hours after an oral dose. The elimination half-life is 21 to 51 minutes.32 These maroon-and-gold capsules are dosed at 45 mg/m2 per day divided into two doses. The most significant side effect is the retinoic acid syndrome, which may occur anywhere from the first couple of days of therapy until the end of therapy and consists of symptoms of... 

An extract from Lactuca indica showed significant free radical scavenging activity, and protected phixl74 supercoiled DNA against strand cleavage and reduced oxidative stress in human promyelocytic leukemia HL-60 cells. On account of protocatechulic acid, methyl p-hydroxybenzoate, caffeic acid, 3,5-dicaffeoylquinic acid, luteolin 7-O-fT glucopyranoside, and quercetin 3-0-(3-g 1 ucopyranoside are the major antioxidative constituents (111). 

Martelli AM, Bortul R, Bareggi R, et al. The pro-apoptotic drug camptothecin stimulates phospholipase D activity and diacylglycerol production in the nucleus of HL-60 human promyelocytic leukemia cells. Cancer Res 1999 59 3961-3967. 

Nakatani N, Ichimaru M, Moriyasu M, Kato A. Induction of apoptosis in human promyelocytic leukemia cell line HL-60 by C-benzylated dihydrochalcones, uvaretin, isouvaretin and diuvaretin. Biol Pharm Bull 2005 28 83-86. 

Nara, E., H. Hayashi, M. Kotake, K. Miyashita, and A. Nagao. 2001. Acyclic carotenoids and their oxidation mixtures inhibit the growth of HL-60 human promyelocytic leukemia cells. Nutr Cancer 39(2) 273-283. 

The induction of differentiation may be an effective mechanism for chemoprevention of chronic diseases. It has been reported that lycopene alone induced differentiation of HL-60 promyelocytic leukemia cells (Amir et al., 1999). A similar effect was also observed for other carotenoids, including P-carotene and lutein (Liu et al., 1997 Sokoloski et al.,1997). 

Liu, Y., Chang, R.L., Cui, X.X., Newmark, H.L. and Conney, A.H. 1997. Synergistic effects of curcumin on all-trans retinoic acid- and 1 alpha,25-dihydroxyvitamin D3-induced differentiation in human promyelocytic leukemia HL-60 cells. Oncol Res 9 19-29. 

Sokoloski, J.A., Hodnick, W.F., Mayne, S.T., Cinquina, C., Kim, C.S., and Sartorelli, A.C. 1997. Induction of the differentiation of HL-60 promyelocytic leukemia cells by vitamin E and other antioxidants in combination with low levels of vitamin D3 Possible relationship to NF-kappaB. Leukemia 11 1546-1553. 

Dunphy CH, Polski JM, Johns G, et al. Acute promyelocytic leukemia, hypo-granular variant, with uncharacteristic staining with chloroacetate esterase. Leak. Lymphoma 2001 42 215-219. 

HETE, 12-hydroxyeicosatetraenoic acid HL60, human promyelocytic leukemia cells... 

Classic antioxidants, vitamin E, vitamin C, and others can suppress the activation of apoptosis. For example, ascorbic acid prevented cytochrome c release and caspase activation in human leukemia cells exposed to hydrogen peroxide [128], Pretreatment with A -acctylcystcinc, ascorbate, and vitamin E decreased homocysteine thiolactone-induced apoptosis in human promyelocytic leukemia HL-60 cells [129]. Resveratrol protected rat brain mitochondria from anoxia-reoxygenation damage by the inhibition of cytochrome c release and the reduction of superoxide production [130]. However, it should be mentioned that the proapoptotic effect of ascorbate, gallic acid, or epigallocatechin gallate has been shown in the same human promyelocytic leukemia cells [131]. 

Granulocyte differentiation acute promyelocytic leukemia PBMCs (in vivo) Cultured bone marrow mononuclear cells (in vitro) All-trans retinoic acid (ATRA) Promoter analysis of ATRA response genes suggest molecular mechanism underlying ATRA-induced granulocytic differentiation [30]... 

Arsenic is highly toxic, and indeed much speculation has surrounded arsenic poisoning as the cause of death of Napoleon Bonaparte, on account of the levels of As in the Emperor s hair (perhaps derived from fungal activity on a green pigment present in the wallpaper of his apartments in St. Helena). Arsenic trioxide has been approved by the Food and Drug Administration (FDA) of the USA for the treatment of acute promyelocytic anaemia in adult patients who fail to respond to other chemotherapy, or have relapsed disease. 

Identification of these cell types is based on the morphological analysis of cells, staining for peroxidase and analysis by light and electron microscopy. Of every 100 nucleated cells in the marrow, 2 are myeloblasts, 5 are promyelocytes, 12 are myelocytes, 22 are metamyelocytes and band cells and 20 are mature neutrophils. These values are somewhat variable and may differ between individuals. Thus, about 60% of all marrow cells are of the neutrophil lineage. 

Histochemical studies of bone marrow samples show that peroxidase-containing granules are detectable in promyelocytes. The human promyelo-cytic leukaemia cell line HL-60 grows easily in culture, and the cells resemble promyelocytes both structurally and functionally. Furthermore, they can be induced to differentiate in vitro upon addition of various agents, such as retinoic acid and phorbol esters, and these differentiated cells resemble more mature forms of neutrophils. HL-60 cells possess almost the same amount of myeloperoxidase (4.4 fig per 106 cells) as mature neutrophils, and the enzyme purified from these cells has the same subunit structure. The cells thus actively synthesise the enzyme only until they are induced to differentiate. This cell line has been extensively used to study the molecular events controlling the expression of enzymes such as myeloperoxidase, and also to investigate the molecular controls that lead to a cessation of their expression. 

Nauseef, W. M. (1986). Myeloperoxidase biosynthesis by a human promyelocytic leukemia cell line Insight into myeloperoxidase deficiency. Blood 67,865-72. 

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