Reveromycin A Inhibits Osteolytic Bone Metastasis of Small-Cell Lung Cancer Cells, SBC-5, through an Antiosteoclastic Activity

Abstract

Purpose: 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.Lung cancer is the major cause of malignancy-related death worldwide and its incidence is increasing in many countries. More than 50,000 new cases of lung cancer are detected annually in Japan, and the mortality rate of nearly 90% makes it the leading cause of cancer-related deaths (1). The high mortality of this disease is predominantly due to the difficulty of early diagnosis and the highly metastatic potential of lung cancer. In many cases, metastases to multiple organs have already developed by the time of the diagnosis. Over one third of patients with advanced lung cancer develop osteolytic bone metastasis, which cause pain, pathologic fractures, spinal cord compression, and hypercalcemia (2). It leads to a considerable reduction in quality of life in lung cancer patients. Currently, no curative therapy exists for bone metastasis, and clinical management is generally palliative. Therefore, the prevention and treatment of osteolytic bone metastasis are clinically important.Bone metastasis is a multistep event regulated not only by cancer cells but also by host microenvironments. Of the host microenvironmental cells, osteoclasts are suggested to play the critical role. Osteoclasts cause bone resorption, which supplies the space for cancer cells to grow and leak out various growth factors from bone matrix (3, 4). Therefore, osteoclasts are the ideal therapeutic target of osteolytic bone metastasis.Reveromycin A is an antibiotic that was discovered in the culture medium of Actinomycetes because of its inhibitory activity on epidermal growth factor -dependent responses of mouse epidermal cells (5). Then, reveromycin A was shown to have an antitumor effect against a human ovarian carcinoma BG-1, which is a transformin...

Intensification therapy with anti-parathyroid hormone-related protein antibody plus zoledronic acid for bone metastases of small cell lung cancer cells in severe combined immunodeficient mice

“…This finding is consistent with our previous reports on PTHrP antibody alone (14) and reveromycin A (28). Using a breast cancer model, however, we found that zoledronic acid suppressed lung and liver metastases and prolonged overall survival (31), and a recent clinical trial showed that zoledronic acid inhibited visceral metastases and prolonged survival of patients with breast cancer (32).…”

“…This is supported by our findings, showing that PTHrP antibody and/or zoledronic acid did not directly inhibit the proliferation of SBC-5 cells in vitro and in vivo and that treatment with PTHrP antibody and/or zoledronic acid decreased the number of osteoclasts and increased the number of apoptotic tumor cells in bone lesions. Similar results have been observed by treatment of bone metastatic lesions with reveromycin A, an inhibitor of isoleucyl-tRNA synthesis that efficiently induces the apoptosis of osteoclasts (28). The mechanism by which these agents induce tumor cell apoptosis without affecting the number of proliferating tumor cells is unknown at present.…”

E7080 Suppresses Hematogenous Multiple Organ Metastases of Lung Cancer Cells with Nonmutated Epidermal Growth Factor Receptor

“…One of the advantages of our metastasis models is that therapeutic efficacy can be evaluated in multiple organs simultaneously (22)(23)(24). We found that E7080 showed therapeutic effects in almost all organs evaluated.…”

“…Intravenous inoculation of the SCLC cell line, SBC-5, into NK cell-depleted SCID mice has been shown to produce experimental metastases within 35 days (22)(23)(24). These metastatic lesions were located primarily in the liver where some were greater than 2 mm in diameter.…”

The identification of an osteoclastogenesis inhibitor through the inhibition of glyoxalase I

“…Elucidation of the mechanisms underlying bisphosphonate activity, especially the identification of target proteins, has led to a deep understanding of osteoclast function (4). In addition, many naturally occurring small molecules have been reported to inhibit the differentiation and function of osteoclasts (5)(6)(7)(8)(9)(10)(11)(12).…”