Abstract
Induction of differentiation is a new and promising approach to leukemia therapy, well illustrated by the treatment of acute promyelocytic leukemia with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] or all-trans retinoic acid (ATRA). Using combination of either 1,25-(OH)2D3 or ATRA and chemotherapy, adverse effects 1,25-(OH)2D3 or ATRA such as hypercalcemic effects have decreased, and long-term survival has improved. In a previous study, we demonstrated that santonin could be chemically modified into a diacetoxy acetal derivative of santonin with strong differentiation-inducing activity. In this study, we further synthesized C6-epimer derivatives of diacetoxy acetal derivative of santonin and tested their effects on HL-60 cell differentiation. Some of the C6-epimer derivatives themselves induced increases in cell differentiation. Especially, (11S)-3,3-(ethylenedioxy) eudesmano-13-ol-6β-acetate (7) was demonstrated to induce differentiation with larger than 80% of the cells attaining a differentiated phenotype. Importantly, 7 strongly enhanced differentiation of HL-60 cells in a dose-dependent manner when combined with either low doses of 1,25-(OH)2D3 or ATRA. The ability to enhance the differentiation potential of 1,25-(OH)2D3 or ATRA by 7 may improve outcomes in the therapy of acute promyelocytic leukemia.
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Beere, H. M. and Hickman, J. A., Differentiation: a suitable strategy for cancer chemotherapy. Anticancer Drug Des., 8, 299–322 (1993).
Breitman, T. R., Selonick, S. E., and Collins, S. J., Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc. Natl. Acad. Sci. U. S. A., 77, 2936–2940 (1980).
Chomienne, C., Balitrand, N., Cost, H., Degos, L., and Abita, J. P., Structure-activity relationships of aromatic retinoids on the differentiation of the human histiocytic lymphoma cell line U-937. Leuk. Res., 10, 1301–1305 (1986).
Degos, L. and Wang, Z. Y., All trans retinoic acid in acute promyelocytic leukemia. Oncogene, 20, 7140–7145 (2001).
Frankel, S. R., Eardley, A., Lauwers, G., Weiss, M., and Warrell, R. P. Jr., The “retinoic acid syndrome” in acute promyelocytic leukemia. Ann. Intern. Med., 17, 292–296 (1992).
Hershberger, P. A., Yu, W. D., Modzelewski, R. A., Rueger, R. M., Johnson, C. S., and Trump, D. L., Calcitriol (1,25-dihydroxycholecalciferol) enhances paclitaxel antitumor activity in vitro and in vivo and accelerates paclitaxelinduced apoptosis. Clin. Cancer Res., 7, 1043–1051 (2001).
Hughes, P. J., Lee, J. S., Reiner, N. E., and Brown, G., The vitamin D receptor-mediated activation of phosphatidylinositol 3-kinase (PI3Kalpha) plays a role in the 1alpha, 25-dihydroxyvitamin D3-stimulated increase in steroid sulphatase activity in myeloid leukaemic cell lines. J. Cell. Biochem., 103, 1551–1572 (2008).
Ishida, S., Shigemoto-Mogami, Y., Shinozaki, Y., Kagechika, H., Shudo, K., Ozawa, S., Sawada, J., Ohno, Y., and Inoue, K., Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem. Pharmacol., 68, 2177–2186 (2004).
Jamshidi, F., Zhang, J., Harrison, J. S., Wang, X., and Studzinski, G. P., 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. Cell Cycle, 7, 917–924 (2008).
Kang, S. N., Lee, M. H., Kim, K. M., Cho, D., and Kim, T. S., Induction of human promyelocytic leukemia HL-60 cell differentiation into monocytes by silibinin: involvement of protein kinase C. Biochem. Pharmacol., 61, 1487–1495 (2001).
Kansas, G. S., Muirhead, M. J., and Dailey, M. O., Expression of the CD11/CD18, leukocyte adhesion molecule 1, and CD44 adhesion molecules during normal myeloid and erythroid differentiation in humans. Blood, 76, 2483–2492 (1990).
Kato, K., Hirata, Y., and Yamamura, S., Syntheses of shyobunone and related sesquiterpenes. Tetrahedron, 27, 5987–5992 (1971).
Kim, S. H., Song, J. H., Choi, B. G., Kim, H. J., and Kim, T. S., Chemical modification of santonin into a diacetoxy acetal form confers the ability to induce differentiation of human promyelocytic leukemia cells via the down-regulation of NF-kB DNA binding activity. J. Biol. Chem., 281, 13117–13125 (2006a).
Kim, S. H., Chung, S. Y., Kim, T. S., and Choi, B. G., Synthesis of diacetoxy acetal derivatives of santonin and their enhancing effects on HL-60 leukemia cell differentiation. Arch. Pharm. Res., 29, 40–45 (2006b).
Kim, S. H., Chung, S. Y., Kim, Y. W., Kim, T. S., and Choi, B. G., Synthesis of DAAS derivatives and their enhancement of HL-60 leukemia cell differentiation. Arch. Pharm. Res., 31, 300–304 (2008a).
Kim, S. H., Danilenko, M., and Kim, T. S., Differential enhancement of leukaemia cell differentiation without elevation of intracellular calcium by plant-derived sesquiterpene lactone compounds. Br. J. Pharmacol., 155, 814–825 (2008b).
Marcinkowska, E., Garay, E., Gocek, E., Chrobak, A., Wang, X., and Studzinski, G. P., Regulation of C/EBPbeta isoforms by MAPK pathways in HL60 cells induced to differentiate by 1,25-dihydroxyvitamin D3. Exp. Cell Res., 312, 2054–2065 (2006).
Mathieu, C. and Jafari, M., Immunomodulation by 1,25-dihydroxyvitamin D3: therapeutic implications in hemodialysis and renal transplantation. Clin. Nephrol., 66, 275–283 (2006).
Norman, A. W., Bishop, J. E., Bula, C. M., Olivera, C. J., Mizwicki, M. T., Zanello, L. P., Ishida, H., and Okamura, W. H., Molecular tools for study of genomic and rapid signal transduction responses initiated by 1 alpha,25 (OH)2-vitamin D3. Steroids, 67, 457–466 (2002).
Pan, Q., Granger, J., O’Connell, T. D., Somerman, M. J., and Simpson, R. U., Promotion of HL-60 cell differentiation by 1,25-dihydroxyvitamin D3 regulation of protein kinase C levels and activity. Biochem. Pharmacol., 54, 909–915 (1997).
Savickiene, J., Treigyte, G., Borutinskaite, V., Navakauskiene, R., and Magnusson, K. E., The histone deacetylase inhibitor FK228 distinctly sensitizes the human leukemia cells to retinoic acid-induced differentiation. Ann. N. Y. Acad. Sci., 1091, 368–384 (2006).
Si, J., Mueller, L., Schuler, A., Simon, J., and Collins, S. J., The retinoic acid receptor/CaMKII interaction: pharmacologic inhibition of CaMKII enhances the differentiation of myeloid leukemia cells. Blood Cells Mol. Dis., 39, 307–315 (2007).
Sokoloski, J. A., Shyam, K., and Sartorelli, A. C., Induction of the differentiation of HL-60 promyelocytic leukemia cells by curcumin in combination with low levels of vitamin D3. Oncol. Res., 9, 31–39 (1997).
Tanaka, H., Abe, E., Miyaura, C., Shiina, Y., and Suda, T., 1(a),25-dihydroxyvitamin D3 induces differentiation of human promyelocytic leukemia cells (HL-60) into monocytic macrophages, but not into granulocytes. Biochem. Biophy. Res. Commun., 117, 86–92 (1983).
Van der Schoot, C. E., von dem Borne, A. E., and Tetteroo, P. A., Characterization of myeloid leukemia by monoclonal antibodies, with an emphasis on antibodies against myeloperoxidase. Acta Haematol., 78, 32–40 (1987).
Wang, Z. Y. and Chen, Z., Acute promyelocytic leukemia: from highly fatal to highly curable. Blood, 111, 2505–2515 (2008).
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Kweon, S.H., Kim, K.T., Hee Hong, J. et al. Synthesis of C 6-epimer derivatives of diacetoxy acetal derivative of santonin and their inducing effects on HL-60 leukemia cell differentiation. Arch. Pharm. Res. 34, 191–198 (2011). https://doi.org/10.1007/s12272-011-0202-4
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DOI: https://doi.org/10.1007/s12272-011-0202-4