title: Cepharanthine enhances in vitro and in vivo thermosensitivity of a mouse fibrosarcoma, FSa-II, based on increased apoptosis.
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.
authors.affiliation: Department of Radiology, Okayama University Medical School, Okayama 700-8558, Japan.
authors.forename: Yadi
authors.initials: Y
authors.lastname: Wang
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kuroda
authors.forename: Xian-Shu
authors.initials: XS
authors.lastname: Gao
authors.forename: Shiro
authors.initials: S
authors.lastname: Akaki
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Asaumi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Okumura
authors.forename: Kohichi
authors.initials: K
authors.lastname: Shibuya
authors.forename: Shoji
authors.initials: S
authors.lastname: Kawasaki
authors.forename: Ikuo
authors.initials: I
authors.lastname: Joja
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kato
authors.forename: Kengo
authors.initials: K
authors.lastname: Himei
authors.forename: Shu-Ichi
authors.initials: S
authors.lastname: Dendo
authors.forename: Susumu
authors.initials: S
authors.lastname: Kanazawa
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hiraki
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D044182:Benzylisoquinolines; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005354:Fibrosarcoma / Q000188:drug therapy / Q000473:pathology / Q000628:therapy; D006979:Hyperthermia, Induced; D066298:In Vitro Techniques; D051379:Mice; D008809:Mice, Inbred C3H; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000628:therapy*; D013696:Temperature; D052117:Benzodioxoles
chemical_list: D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D044182:Benzylisoquinolines; D053148:Caspase 3; D020169:Caspases; C006947:cepharanthine; D052117:Benzodioxoles; C505409:Casp3 protein, mouse