title: Organ-specific efficacy of HSP90 inhibitor in multiple-organ metastasis model of chemorefractory small cell lung cancer.
abstract: Small-cell lung cancer (SCLC) accounts for nearly 15% of lung cancer cases and exhibits aggressive clinical behavior characterized by rapid growth and metastatic spread to multiple organs. About 70% of patients with SCLC present with extensive disease and distant metastases at diagnosis. HSP90 is a 90-kDa molecular chaperone whose association is required for the stability and function of its numerous "client proteins." Here, we assessed the therapeutic potential of the HSP90 inhibitor 17-DMAG in SCLC. Notably, 17-DMAG hindered the viability of human SCLC cell lines-regardless of their chemosensitivity-via the decreased expression of client proteins, including the proto-oncogene c-Raf (also known as RAF1). In an in vivo imaging model of SCLC multiple-organ metastasis with the human SCLC cell line SBC-5, treatment with 17-DMAG remarkably inhibited the formation of metastatic sites in the liver, but was ineffective in hindering the progression of bone lesions. The latter was likely the result of activation of osteoclasts. IGF-1, which is supposed to be rich in bone environment, preserved c-Raf expression and maintained viability of SBC-5 cells treated with 17-DMAG. Furthermore, the combined use of a bisphosphonate with 17-DMAG significantly attenuated the progression of metastases in both the liver and the bone. These findings suggest that therapeutic effects of HSP90 inhibitors may be organ-specific and should be carefully monitored in SCLC clinical trials.
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takeuchi
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Arai
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nanjo
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kita
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Division of Cancer Biology, the Cancer Institute, Japanese Foundation for Cancer Research, Koto-Ku, Tokyo, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Hara
authors.affiliation: Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishihara
authors.affiliation: Department of Molecular and Environmental Pathology, Institute of Health Biosciences, the University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Uehara
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D001859:Bone Neoplasms / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000008:administration & dosage; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D009928:Organ Specificity; D000090063:Proto-Oncogene Mas; D019908:Proto-Oncogene Proteins c-raf / Q000032:analysis; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000473:pathology; D000077211:Zoledronic Acid
chemical_list: D016227:Benzoquinones; D004164:Diphosphonates; D018841:HSP90 Heat-Shock Proteins; D007093:Imidazoles; D047029:Lactams, Macrocyclic; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D000077211:Zoledronic Acid; D019908:Proto-Oncogene Proteins c-raf
keywords: HSP90 inhibitor; metastasis model; small cell lung cancer