Synergistic effects induced by cycloprodigiosin hydrochloride and epirubicin on human breast cancer cells.
The effects of cPrG x HCl and epirubicin on the suppression of cell growth were examined on human breast cancer cell line (MDA-MB-231). Either cPrG x HCl or epirubicin alone showed a tumor growth inhibition in a time- and dose-dependent manner, however, the combinatory use of cPrG x HCl together with epirubicin resulted in prominent synergistic effects on the breast cancer cells. In the in vitro studies, the combinatory use of these two drugs accelerated apoptotic cell death as revealed by morphological changes as well as by the appearance of subG1 population by flow cytometry. In addition, confocal microscopy revealed that the accumulation of epirubicin in nucleus increased apparently when cPrG x HCl were present. In the in vivo assay, nude mice bearing xenografted tumor cells received 4 weeks of intraperitoneal administration of cPrG-HCl and epirubicin. After 12 days, the combinatory treatment significantly suppressed the tumor growth compared to the controls. The TUNEL staining revealed that tumor cells in cPrG x HCl plus epirubicin-treated mice exhibited a higher apoptotic rate. In addition, 31P-NMR studies on the xenografted tumor revealed that cPrG x HCl lowered tumor pHi (below pH 6.9). while it did not affected muscle pHi. No pathological changes were observed in any intrinsic organs and the serum alanine aminotransferase levels remained within normal limits among the groups. These results suggest that the combinatory use of cPrG x HCl and epirubicin may be useful for breast cancer therapy.
Yamamoto
Daigo
D
Department of Surgery II, Kansai Medical University, Moriguchi, Osaka, Japan. yamamotd@takii.kmu.ac.jp
Tanaka
Kanji
K
Nakai
Koji
K
Baden
Tetsuya
T
Inoue
Kentaro
K
Yamamoto
Chizuko
C
Takemoto
Hirota
H
Kamato
Keiko
K
Hirata
Hajime
H
Morikawa
Shigehiro
S
Inubushi
Toshiro
T
Hioki
Koshiro
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015251:Epirubicin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D010761:Phosphorus Radioisotopes; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D007211:Indoles; D010761:Phosphorus Radioisotopes; D011758:Pyrroles; D015251:Epirubicin; C108328:cycloprodigiosin