Abstract
Vesnarinone, an oral cardiotonic, inhibited the growth of several human non-small cell lung carcinoma cell lines, and its anti-proliferative effects in vitro and in vivo were greatly enhanced by combination with glucocorticoids, but not other steroids. Simultaneous treatment with vesnarinone and dexamethasone is the most effective to evoke the synergistic effect in the growth inhibition of lung carcinoma EBC-1 cells. Dexamethasone and other glucocorticoids induced morphological changes in EBC-1 cells and these agents together with vesnarinone induced alkaline phosphatase activity, which is a typical marker of type II pneumocyte maturation. This treatment arrested the growth of the cells at the G1 phase, indicating that this treatment is cytostatic rather than cytotoxic. These results suggest that vesnarinone plus glucocorticoid might be useful in lung cancer therapy.
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References
Alberts, A. S., Thorburn, A. M., Shenolikar, S., Mumby, M. C. & Feramisco, J. R. (1993) Regulation of cell cycle progression and nuclear affinity of the retinoblastoma protein by protein phosphatases. Proc Natl Acad Sci USA 90: 388–392.
Beattie, C. W., Hansen, N. W. & Thomas, P. A. (1985) Steroid receptors in human lung cancer. Cancer Res 45: 4206–4214.
Chakrabarty, S., Fan, D. & Varani, J. (1990) Modulation of differentiation and proliferation in human colon carcinoma cells by transforming growth factor β1 and β2. Int J Cancer 46: 493–499.
Chaudhuri, P. K., Thomas, P. A., Walker, M. J., Briele, H. A., Gupta, T. K. D. & Beattie, C. W. (1982) Steroid receptors in human lung cancer cytosols. Cancer Lett 16: 327–332.
Christoffersen, J., Smeland, E. B., Stokke, T., Tasken, K., Anderson, K. B. & Blomhoff, H. K. (1994) Retinoblastoma protein is rapidly dephosphorylated by elevated cyclic adenosine monophosphate levels in human B-lymphoid cells. Cancer Res 54: 2245–2250.
DeLemos, R. A., Shermeta, D. W., Knelson, J. H., Kotas, R. & Avery, M. E. (1970) Acceleration of appearance of pulmonary surfactant in the fetal lamb by administration of corticosteroids. Am Rev Respir Dis 102: 459–461.
Donnadieu, N., Paesmans, M. & Sculier, J. P. (1991) Chemotherapy of non-small lung cancer according to disease extent: a meta-analysis of the literature. Lung Cancer 7: 243–252.
Dou, Q. P., An, B. & Will, P. L. (1995) Induction of a retinoblastoma phosphatase activity by anticancer drugs accompanies p53-independent G1 arrest and apoptosis. Proc Natl Acad Sci USA 92: 9019–9023.
Edelson, J. D., Shannon, J. M. & Mason, R. J. (1988) Alkaline phosphatase: a marker of alveolar type II cell differentiation. Am Rev Respir Dis 138: 1268–1275.
Goto, I., Hozumi, M. & Honma, Y. (1994) Selective effect of O-alkyl lysophospholipids on the growth of a human lung giant cell carcinoma cell line. Anticancer Res 14: 357–362.
Goto, I., Yamamoto-Yamaguchi, Y. & Honma, Y. (1996) Enhancement of sensitivity of human lung adenocarcinoma cells to growth-inhibitory activity of interferon-α by differentiation-inducing agents. Br J Cancer 74: 546–554.
Hartwell, L. H. & Kastan, M. B. (1994) Cell cycle control and cancer. Science 266: 1821–1828.
Hofmann, J., Kaiser, U., Maasberg, M. & Havemann, K. (1995) Glucocorticoid receptors and growth inhibitory effects of dexamethasone in human lung cancer cell lines. Eur J Cancer 31A: 2053–2058.
Jones, K. L., Anderson, N. S. & Addison, J. (1978) Glucocorticoid-induced growth inhibition of cells from a human lung alveolar cell carcinoma. Cancer Res 38: 1688–1693.
Kanatani, Y., Kasukabe, T., Hozumi, M., Motoyoshi, K., Nagata, N. & Honma, Y. (1993) Genistein exhibits preferential cytotoxicity to a leukemogenic variant but induces differentiation of a non-leukemogenic variant of the mouse monocytic leukemia Mm cell line. Leuk Res 17: 847–853.
Kanatani, Y., Kasukabe, T., Okabe-Kado, J., Hayashi, S., Yamamoto-Yamaguchi, Y., Motoyoshi, K., Nagata, N. & Honma, Y. (1996) Transforming growth factor β and dexamethasone cooperatively enhance c-jun gene expression and inhibit the growth of human monocytoid leukemia cells. Cell Growth Diff 7: 187–196.
Karp, J. E. & Broder, S. (1995) Molecular foundations of cancer: new targets for intervention. Nature Med 1: 309–320.
Kikkawa, Y., Kaibara, M., Motoyama, E. K. & Cook, C. D. (1971) Morphologic development of fetal rabbit lung and its acceleration with cortisol. Am J Pathol 64: 423–442.
Laemmli, U. K. (1970) Cleavage of structure proteins during the assembly of the head of bacteriophage T4. Nature 227: 680–685.
Liggins, G. C. (1969) Premature delivery of fetal lambs infused with glucocorticoids. Endocrinology 45: 515–523.
Liggins, G. C. & Howie, R. N. A. (1972) Controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 50: 515–525.
Ludlow, J. W., Glendening, C. L., Livingston, D. M. & DeCaprio, J. A. (1993) Specific enzymatic dephosphorylation of the retinoblastoma protein. Mol Cell Biol 13: 367–372.
Marchetti, A., Doglion, C., Barbareschi, M., Buttitta, F., Pellegrini, S., Bertacca, G., Chella, A., Merlo, G., Angeletti, C. A., Palma, P. D. & Bevilacqua, G. (1996) p21 RNA and protein expression in non-small cell lung carcinomas: evidence of p53-independent expression and association with tumoral differentiation. Oncogene 12: 1319–1324.
Mattern, J., Klinga, K., Rummebaum, B. & Volm, M. (1985) Influence of hormone therapy on human lung tumors transplanted into nude mice. Oncology 42: 388–390.
McCormick, C., Freshney, R. I. & Speirs, V. (1995) Activity of interferonα, interleukin 6 and insulin in the regulation of differentiation in A549 alveolar carcinoma cells. Br J Cancer 71: 232–239.
McLean, J. S., Frame, M. C., Freshney, R. I., Vaughan, P. F. T., Mackie, A. E. & Singer, I. (1986) Phenotypic modification of human glioma and non-small cell lung carcinoma by glucocorticoids and other agents. Anticancer Res 6: 1101–1106.
Miyamoto, G. & Sasabe, H. (1984) Pharmacokinetics of a new positive inotropic agent, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone (OPC-8212), in the rat, rabbit, beagle dog and rhesus monkey. Arzneimittel-Forschung Drug Res 34: 394–402.
OPC-8212 Multicenter Research Group (1990) A placebo-controlled, randomized, double-blind study of OPC-8212 in patients with mild chronic heart failure. Cardiovasc Drug Ther 4: 419–426.
Sato, M., Harada, K., Bando, T., Shirakami, T., Nakashiro, K., Yoshida, H., Nakai, S., Kawai, K. & Adachi, M. (1995) Characteristics of antitumor activity of 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2 (1H)-quinolinone (Vesnarinone) against a human adenoid squamous carcinoma-forming cell line grown in athymic nude mice. Cancer Lett 91: 1–9.
Sato, S., Tomoyasu, S., Okabe-Kado, J., Hozumi, M., Tsuruoka, N., Nakai, S., Adachi, M. & Honma, Y. (1996) Induction of differentiation and enhancement of vincristine sensitivity of human erythroleukemia HEL cells by vesnarinone, a positive inotropic agent. Exp Hematol 24: 37–42.
Schroy, P., Rifkin, J., Coffey, R. J., Winawer, S. & Friedman, E. (1990) Role of transforming growth factor β in induction of colon carcinoma differentiation by hexamethylene bisacetamide. Cancer Res 50: 261–265.
Taira, N., Endoh, M., Iijima, T., Satoh, K., Yanagisawa, T., Yamashita, S., Maruyama, M., Kawada, M., Morita, T. & Wada, Y. (1984) Mode and mechanism of action of 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2-(1H)-quinolinone (OPC-8212), a novel positive inotropic drug, on the dog heart. Arzneimittel-Forschung Drug Res 34: 35–43.
Twardzik, D. R., Ranchalis, J. E., McPherson, J. M., Ogawa, Y., Gentry, L., Purchio, A., Plata, E. & Todaro, G. J. (1989) Inhibition and promotion of differentiated-like phenotype of a human lung carcinoma in athymic mice by natural and recombinant forms of transforming growth factor-β. J Natl Cancer Inst 81: 1182–1185.
Weinberg, R. A. (1995) The retinoblastoma protein and cell cycle control. Cell 81: 323–330.
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Honma, Y., Yamamoto-Yamaguchi, Y. & Kanatani, Y. Vesnarinone and glucocorticoids cooperatively induce G1 arrest and have an anti-tumour effect on human non-small cell lung carcinoma cells grown in nude mice. Br J Cancer 80, 96–103 (1999). https://doi.org/10.1038/sj.bjc.6690327
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DOI: https://doi.org/10.1038/sj.bjc.6690327