Summary
12-O-Tetradecanoylphorbol-13-acetate (TPA), the prototype polyfunctional diterpene ester tumor promoter of two-step carcinogenesis in mouse skin, induced differentiation of human promyelocytic leukemia cells (HL-60) in culture.
Differentiation of HL-60 cells was characterized by increased phagocytosis, increased lysozyme activity (EC 3.2.1.17) in the growth medium, and changes in morphology to those characteristics of more mature cells resembling macrophages. Many of the cells treated with TPA became aggregated, attaching firmly to culture flasks. The average intracellular myeloperoxidase activity (EC 1.11.1.7) per cell decreased during induction of differentiation by TPA. It was also found that TPA enhanced, rather than inhibited, differentiation of HL-60 cells induced by DMSO.
In addition to TPA, several polyfunctional diterpene esters of the tigliane, ingenane, and daphnane type have been tested for their ability to induce morphological and functional changes of HL-60 cells. The activities of the compounds to induce these changes correlated well with their activities as tumor promoters in two-step carcinogenesis in mouse skin. In particular, half the concentrations required for induction of adhesion of the cells to flasks were roughly correlated to the potency of these compounds as tumor promoters. Among the compounds tested, phorbol-12,13-didecanoate (PDD), ingenol-3-hexadecanoate, Pimelea factor P1 and Pimelea factor P2 were as active as TPA, while 4-O-methyl-TPA and 4α-PDD were much less active. Phorbol and ingenol were totally inactive up to a concentrations 10,000-fold higher than that of TPA.
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Abbreviations
- DMSO:
-
dimethyl sulfoxide
- TPA:
-
12-O-tetradecanoylphorbol-13-acetate
- PDD:
-
phorbol-12,13-didecanoate
References
Adolf W, Hecker E (1971) Further new diterpene ester from the irritant and cocarcinogenic seed oil and latex of the caper spurge (Euphorbia Lathyris L.). [Separatum] Experientia 27:1393–1394
Balmain A, Hecker E (1976) On the biochemical mechanism of tumorigenesis in mouse skin VII. The effects of tumor promoters on 3H-choline and 3H-glycerol incorporation into mouse epidermal phosphatidylcholine in relation to their effects on 3H-thymidine incorporation into DNA. Z Krebsforsch 86:251–261
Berenblum I (1978) Historical perspective. In: Slaga TJ, Sivak A, Boutwell RK (eds) Carcinogenesis-Mechanisms of tumor promotion and cocarcinogenesis, vol 2. Raven Press, New York, pp 1–10
Boutwell RK (1974) The function and mechanism of promoters of carcinogenesis. CRC Crit Rev Toxicol 2:419–443
Chance B, Maehly AC (1955) Assay of catalases and peroxidases. In: Colowick SP, Kaplan NO (eds) Methods in enzymology, vol 2, Academic Press, New York, pp 764–775
Cline MJ (1975) Morphology and morphogenesis of granulocytes. In: Cline MJ (ed) The white cell. Harvard Univ. Press, Cambridge, MA, pp 5–21
Collins SJ, Gallo RC, Gallagher RE (1977) Continuous growth and differentiation of human myeloid leukaemic cells in suspension culture. Nature 270:347–349
Collins SJ, Ruscetti FW, Gallagher RE, Gallo RC (1978) Ferminal differentiation of human promyelocytic leukemia cells induced by dimethyl sulfoxide and other polar compounds. Proc Natl Acad Sci USA 75:2458–2462
Fujiki H, Mori M, Nakayasu M, Terada M, Sugimura T (1979) A possible naturally occurring tumor promoter, teleocidin B from streptomyces. Biochem Biophys Res Commun 90:976–983
Gallo RC, Reitz MS, Saxinger WC, Jacquemin P, Ruscetti FW (1979) Studies in human hematopoietic cells: Cellular and virological aspect. In: Chendra P (ed) Antiviral mechanisms in the control of neoplasis. Plenum Press, New York, pp 153–175
Goldstein IM (1978) Effects of phorbol esters on polymorphonuclear leukocyte function in vitro. In: Slaga TJ, Sivak A, Boutwell RK (eds) Mechanisms of tumor promotion and cocarcinogenesis. Raven Press, New York, pp 389–400
Hecker E (1968) Cocarcinogenic principles from the seed oil of croton tiglium and from other euphorbiaceae. Cancer Res 28:2338–2349
Hecker E (1978) Structure-activity relationships in diterpene esters irritant and cocarcinogenic to mouse skin. In: Slaga TJ, Sivak A, Boutwell RK (eds) Carcinogenesis-mechanisms of tumor promotion and cocarcinogenesis, vol 2 Raven Press, New York, pp 11–48
Hecker E, Schmidt R (1974) Phorbol esters — The irritants and cocarcinogens of croton tiglium L. Progr Chem Org Natur Prod 31:377–467
Huberman E, Callaham HF (1979) Induction of terminal differentiation in human promyelocytic leukemia cells by tumor promoting agents. Proc Natl. Acad Sci USA 76:1293–1297
Lotem J, Sachs L (1979) Regulation of normal differentiation in mouse and human leukemic cells by phorbol esters and the mechanism of tumor promotion. Proc Natl Acad Sci USA 76:5158–5162
Miao RM, Fieldsteel AH, Fodge DW (1978) Opposing effects of tumor promoters on erythroid differentiation. Nature 274:271–272
Nakayasu M, Shoji M, Aoki N, Sato S, Miwa M, Sugimura T (1979) Enhancing effect of phorbol esters on induction of differentiation of mouse myeloid leukemia cells by human urinary protein and lipopolysaccharide. Cancer Res 39:4668–4672
Nakayasu M, Fujiki H, Mori M, Sugimura T and Moore RE (1981) Teleocidin, Lyngbyatoxin A and their hydrogenated derivatives, possible tumor promoters, induce terminal differentiation in HL-60 cells. Cancer Lett 12:271–277
Opferkuch HJ, Hecker E (1982) On the active principles of the spurge family (Euphorbiaceae) IV Skin irritant and tumor-promoting diterpene esters from Euphorbia ingens E. Mey. J Cancer Res Clin Oncol (in press)
Osserman EF, Lawlor DP (1966) Serum and urinary lysozyme (Muramidase) in monocytic and monomyelocytic leukemia. J Exp Med 124:921–952
Rovera G, O'Brien TG, Diamond L (1979a) Induction of differentiation in human promyelocytic leukemia cells by tumor promoters. Science 204:868–870
Rovera G, Santoli D, Damsky C (1979b) Human promyelocytic leukemia cells in culture differentiate into macrophage-like cells when treated with a phorbol diester. Proc Natl Acad Sci USA 76:2779–2783
Sivak A (1978) Mechanisms of tumor promotion and cocarcinogenesis. In: Slaga TJ, Sivak A, Boutwell RK (eds) Carcinogenesis — Mechanisms of tumor promotion and cocarcinogenesis, vol 2. Raven Press, New York, pp 554–564
Van Duuren BL (1969) Tumor-promoting agents in two-stage carcinogenesis. Progr Exp Tumor Res 11:31–68
Weinstein IB, Yamasaki H, Wigler M, Lee LS, Fisher PB, Jeffrey A, Grunberger D (1979) Molecular and cellular events associated with the action initiating carcinogens and tumor promoters. In: Griffin AC, Shaw CR (eds) Carcinogens: Identification and mechanisms of action. Raven Press, New York, pp 399–418
Yamada M, Shimada T, Nakayasu M, Okada H, Sugimura T (1978) Induction of differentiation of mouse myeloid leukemia cells by poly(ADP-ribose). Biochem Biophys Res Commun 83:1325–1332
Zayed S, Adolf W, Hafez A, Hecker E (1977) New highly irritant 1-alkyldaphnane derivatives from several species of thymelaeaceae. Tetrahedron Lett 3481–3482
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Partially supported by a grant-in-aid for cancer research from the Ministry of Education, Science and Culture and a grant-in-aid for cancer research from the Ministry of Health and Welfare of Japan
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Nakayasu, M., Terada, M., Adolf, W. et al. Induction of differentiation in human promyelocytic leukemia cells by tumor promoters. J Cancer Res Clin Oncol 103, 17–29 (1982). https://doi.org/10.1007/BF00410302
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DOI: https://doi.org/10.1007/BF00410302