1. Cepharanthine enhances in vitro and in vivo thermosensitivity of a mouse fibrosarcoma, FSa-II, based on increased apoptosis.
- Author
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Wang Y, Kuroda M, Gao XS, Akaki S, Asaumi J, Okumura Y, Shibuya K, Kawasaki S, Joja I, Kato H, Himei K, Dendo S, Kanazawa S, and Hiraki Y
- Subjects
- Animals, Apoptosis drug effects, Benzylisoquinolines, Caspase 3, Caspases metabolism, Cell Line, Tumor, Combined Modality Therapy, Fibrosarcoma drug therapy, Fibrosarcoma pathology, Fibrosarcoma therapy, In Vitro Techniques, Mice, Mice, Inbred C3H, Sarcoma, Experimental pathology, Temperature, Alkaloids pharmacology, Antineoplastic Agents, Phytogenic pharmacology, Hyperthermia, Induced, Sarcoma, Experimental drug therapy, Sarcoma, Experimental therapy
- Abstract
Cepharanthine (Ce) is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata. In our previous study, Ce significantly enhanced thermosensitivity and thereby reduced thermotolerance in vitro, and intra-peritoneal injection of Ce slightly enhanced thermosensitivity in vivo. In the present study, we investigated Ce's effect in vitro on the pattern of cell death after heating and the effect of intra-tumoral injection of Ce on in vivo thermosensitivity using a mouse fibrosarcoma, FSa-II, and C3H/He mice. Ce significantly enhanced the in vitro thermosensitivity of FSa-II cells with heating at 44 degrees C, with increased Ce concentration. Time-lapse microscopic observation of individual cells confirmed that Ce treatment hastened both apoptosis (specifically, apoptotic budding) and necrosis (as indicated by staining with propidium iodide). Staining with annexin V-enhanced green fluorescent protein indicated that Ce used concomitantly with heating significantly increased the proportion of cells in the early stage of apoptosis. Ce combined with heating also significantly increased the proportion of cells with high intracellular caspase-3 activity, as detected by a substrate of caspase-3, PhiPhiLux-G1D2. The intra-tumoral injection of Ce, followed by heating at 44 degrees C, significantly delayed in vivo tumor growth, and this delay increased in a Ce concentration-dependent manner. Ce injected 30 min before heating delayed tumor growth more than Ce injected immediately before heating. These findings suggest the potential of Ce as a thermosensitizer to increase apoptosis of tumor cells.
- Published
- 2004