Abstract
In the treatment of malignant glioma, chemotherapy plays a critical role as do surgical resection and irradiation. Cepharanthine (CEP), a biscoclaurine-derived alkaloid, reportedly potentiates the effects of antitumor agents and induces apoptosis in some cancer cells. Here, we examined the effects of CEP, alone and in combination with nimustine hydrochloride (ACNU), on the in vitro proliferation of malignant glioma cells. The cell lines used were U87MG, U251MG, and T98G. At concentrations from 1 to 10 μg/ml, CEP-promoted cell proliferation somewhat; growth inhibition was noted at concentrations of 15 μg/ml and higher. Phase-contrast microscopy showed that cells tended to detach from the culture dishes and that cell density became sparse at the higher concentrations. DAPI fluorescence nuclear staining revealed condensation and fragmentation of nuclei, indicating the induction of apoptosis. To examine the cascade of apoptosis, the caspase inhibitors YVAD and DEVD were added. They inhibited CEP-induced apoptosis in U251MG cells (a p53-mutant cell line), but not in U87MG cells (a p53 wild-type cell line), suggesting that in CEP-induced apoptosis two possible cascades are in play. In combination with ACNU, the effects of the higher concentrations of CEP were enhanced.
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References
Report of brain tumor registry of Japan (1969-1993) 10th edition, Neurologia medico-chirurgica Suppl 40: 42-43, 2000
Takakura K, Abe H, Tanaka R, Kitamura K, Miwa T, Takeuchi K, Yamamoto S, Kageyama N, Handa H, Mogami H: Effects ofACNUand radiotherapy on malignant glioma. J Neurosurg 64: 53-57, 1986
Miyagami M, Tsubokawa T, Tazoe M, Kagawa Y: Intraarterial ACNU chemotherapy employing 20% mannitol osmotic blood-brain barrier disruption for malignant brain tumors. Neurol Med Chir (Tokyo) 30(8): 582-590, 1990
Kuratsu J, Ushio Y: Chemotherapy of brain tumors. Gan To Kagaku Ryoho Suppl 3: 377-383, 1994
Hori T, Muraoka K, Saito Y, Sasahara K, Inagaki H, Inoue Y, Adachi S, Anno Y: Influence of modes of ACNU administration on tissue and blood drug concentration in malignant brain tumors. J Neurosurg 66: 372-378, 1987.
Bigner DD, Schold C, Bigner SH, Bullard DE, Wikstrand C: How heterogeneous are gliomas? Cancer Treat Rep 65: 45-49, 1981
Nagatsuka S, Nakazawa T: Effect of membrane-stabilizing agents, cholesterol and cepharanthine, on radiation-induced lipid peroxidation and permeability in liposomes. Biochim Biophys Acta 691: 171-177, 1982
Sugiyama K: Inhibition of histamine release from rat peritoneal mast cells. Allergy 25: 685-690, 1976
Kasajima T, Yamakawa M, Maeda K, Matsuda M, Dobashi M, Imai Y: Effect of cepharanthine on peripheral leukocytopenia caused by antineoplastic agents. Gan To Kagaku Ryoho 10: 1188-1196, 1983
Ono M, Tanaka N: Positive interaction of bisbenzylisoquinoline alkaloid, cepharanthine, with vinca alkaloid agents against human tumors. In Vivo 11: 233-241, 1997
Asaumi J, Nishikawa K, Matsuoka H, Iwata M, Kawasaki S, Hiraki Y, Nishijima K: Direct antitumor effect of cepharanthine and combined effect with adriamycin against Ehrlich ascites tumor in mice. Anticancer Res 15: 67-70, 1995
Ida M, Tetsumura A, Kurabayashi T, Sasaki T: Antitumor effect of simultaneous use of cepharanthine and 5Fu on oral cancer cell line (KM-1). J Jpn Soc Oral Tumor 9: 7-12, 1997
Kato T, Suzumura Y: Potentiation of antitumor activity of vincristine by the biscoclaurine alkaloid cepharanthine. JNCI 79: 527-532, 1987
Aogi K, Nishiyama M, Kim R, Hirabayashi N, Toge T, Mizutani A, Okada K, Sumiyoshi H, Fujiwara Y, Yamakido M, Kusano T, Andoh T: Overcoming COT-11 resistance by using a biscoclaurine alkaloid, cepharanthine, to modulate plasma trans-membrane potential. Int J Cancer 72(2): 295-300, 1997
Murai N, Ueba T, Takahashi JA, Yang HQ, Kikuchi H, Hiai H, Hatanaka M, Fukumoto M: Apoptosis of human glioma cells in vitro and in vivo induced by a neutralizing antibody against human basic fibroblast growth factor. J Neurosurg 85(6): 1072-1077, 1996
Tomita M, Fujita K, Aoyagi Y: Synthesis of dicepharanthine. Tetrahedron Lett 13: 1201-1206, 1967
Abe T, Koike K, Ohga T, Kubo T, Wada M, Kohno K, Mori T, Hidaka K, Kuwano M: Chemosensitisation of spontaneous multidrug resistance by a 1,4-dihydropyridine analogue and verapamil in human glioma cell lines overexpressing MRP or MDR1. Br J Cancer 72(2): 418-423, 1995
Nakaoji K, Nayeshiro H, Tanahashi T, Su Y, Nagakura N: Bisbenzylisoquinoline alkaloids from Stephania cepharantha and their effects on proliferation of cultured cells from the murine hair apparatus. Planta Med 63(5): 425-428, 1997
Ono M: Direct action of cepharanthin on tumor cell growth and cell cycle in vitro. Igaku no Ayumi 143: 777-778, 1987
Ohuchi Y: A case of carcinoma of the maxillary sinus kept on intra-arterial infusion therapy for 162 days: a case of long-term intra-arterial infusion therapy. Ji Bi Rinsho Suppl 31: 112-116, 1989
Kitajima K, Yoshida T, Okada K, Kishimoto T, Takahashi K: PS (peplomycin-silicone) bullet cancer therapy for bladder tumor: combination of hyperthermic treatment and cepharanthine. Jpn J Cancer Chemother 11(Part 1): 2520-2525, 1984
Yokoshima T: Studies on metabolic fate of cepharanthine absorption, distribution, metabolism and excretion in rats. Iyakuhin Kenkyu 17: 458-479, 1986
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Kono, K., Takahashi, J.A., Ueba, T. et al. Effects of Combination Chemotherapy with Biscoclaurine-derived Alkaloid (Cepharanthine) and Nimustine Hydrochloride on Malignant Glioma Cell Lines. J Neurooncol 56, 101–108 (2002). https://doi.org/10.1023/A:1014548618440
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DOI: https://doi.org/10.1023/A:1014548618440