Reveromycin A inhibits osteolytic bone metastasis of small-cell lung cancer cells, SBC-5, through an antiosteoclastic activity.
OBJECTIVE
The purpose of this study was to determine therapeutic effect of a novel antibiotic, reveromycin A, against osteolytic bone metastasis of human small cell lung cancer (SBC-5) cells.


RESULTS
Reveromycin A induced apoptosis specifically in osteoclasts in vitro. Although reveromycin A did not inhibit SBC-5 cell proliferation, it suppressed the expression of parathyroid hormone-related peptide. Intravenous inoculation of SBC-5 cells in natural killer cell-depleted severe combined immunodeficient mice produced experimental metastases in multiple organs, including the bone. Daily administration of reveromycin A inhibited the bone metastasis, but not visceral metastasis, in a dose-dependent manner. Histologic analyses revealed that although treatment with reveromycin A did not affect the number of proliferating tumor cells, it decreased the number of osteoclasts and increased apoptotic cells in bone lesions.


CONCLUSIONS
These findings suggest that reveromycin A may inhibit osteolytic bone metastasis through suppression of osteoclast activity by directly inducing apoptosis and indirectly inhibiting tumor cell-derived parathyroid hormone-related peptide production. Therefore, reveromycin A may be a novel, potent therapeutic agent against osteolytic bone metastasis of lung cancer in humans.
Muguruma
Hiroaki
H
Department of Internal Medicine and Molecular Therapeutics, University of Tokushima Graduate School, Tokushima, and Antibiotics Laboratory, Discovery Research Institute, RIKEN, Saitama, Japan.
Yano
Seiji
S
Kakiuchi
Soji
S
Uehara
Hisanori
H
Kawatani
Makoto
M
Osada
Hiroyuki
H
Sone
Saburo
S
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism; D011714:Pyrans / Q000494:pharmacology / Q000627:therapeutic use*; D013141:Spiro Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D044162:Parathyroid Hormone-Related Protein; D011714:Pyrans; D013141:Spiro Compounds; D042461:Vascular Endothelial Growth Factor A; C068098:reveromycin A