Organ-specific efficacy of HSP90 inhibitor in multiple-organ metastasis model of chemorefractory small cell lung cancer

Shinji Takeuchi, Koji Fukuda, Sachiko Arai, Shigeki Nanjo, Kenji Kita, Tadaaki Yamada, Eiji Hara, Hiroshi Nishihara, Hisanori Uehara, Seiji Yano

Research output: Contribution to journalArticle

8 Citations (Scopus)

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. What's new? Small cell lung cancer (SCLC) is an extremely aggressive disease characterized by increased incidence of multi-organ metastasis and acquired resistance to conventional chemotherapy. Here, the authors show that HSP90 inhibitor 17-DMAG efficiently inhibits the metastasis of chemorefractory SCLC cells to the liver, but worsens bone metastasis, indicating heterogeneity in 17-DMAG's anti-metastatic effect. Furthermore, they show that the combined use of a bisphosphonate with 17-DMAG significantly attenuates the progression of metastases in both the liver and the bone. The findings thus suggest that the therapeutic effects of HSP90 inhibitors may be organ-specific and should be carefully monitored in SCLC clinical trials.

Original languageEnglish
Pages (from-to)1281-1289
Number of pages9
JournalInternational Journal of Cancer
Volume138
Issue number5
DOIs
Publication statusPublished - 2016 Mar 1
Externally publishedYes

Fingerprint

17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
Small Cell Lung Carcinoma
Neoplasm Metastasis
Bone and Bones
Liver
Diphosphonates
Therapeutic Uses
Proto-Oncogene Proteins c-raf
Clinical Trials
Cell Line
Molecular Chaperones
Osteoclasts
Insulin-Like Growth Factor I

Keywords

  • HSP90 inhibitor
  • metastasis model
  • small cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Organ-specific efficacy of HSP90 inhibitor in multiple-organ metastasis model of chemorefractory small cell lung cancer. / Takeuchi, Shinji; Fukuda, Koji; Arai, Sachiko; Nanjo, Shigeki; Kita, Kenji; Yamada, Tadaaki; Hara, Eiji; Nishihara, Hiroshi; Uehara, Hisanori; Yano, Seiji.

In: International Journal of Cancer, Vol. 138, No. 5, 01.03.2016, p. 1281-1289.

Research output: Contribution to journalArticle

Takeuchi, S, Fukuda, K, Arai, S, Nanjo, S, Kita, K, Yamada, T, Hara, E, Nishihara, H, Uehara, H & Yano, S 2016, 'Organ-specific efficacy of HSP90 inhibitor in multiple-organ metastasis model of chemorefractory small cell lung cancer', International Journal of Cancer, vol. 138, no. 5, pp. 1281-1289. https://doi.org/10.1002/ijc.29858
Takeuchi, Shinji ; Fukuda, Koji ; Arai, Sachiko ; Nanjo, Shigeki ; Kita, Kenji ; Yamada, Tadaaki ; Hara, Eiji ; Nishihara, Hiroshi ; Uehara, Hisanori ; Yano, Seiji. / Organ-specific efficacy of HSP90 inhibitor in multiple-organ metastasis model of chemorefractory small cell lung cancer. In: International Journal of Cancer. 2016 ; Vol. 138, No. 5. pp. 1281-1289.
@article{16133767c4f446dca8f2886e7ba84a4f,
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. What's new? Small cell lung cancer (SCLC) is an extremely aggressive disease characterized by increased incidence of multi-organ metastasis and acquired resistance to conventional chemotherapy. Here, the authors show that HSP90 inhibitor 17-DMAG efficiently inhibits the metastasis of chemorefractory SCLC cells to the liver, but worsens bone metastasis, indicating heterogeneity in 17-DMAG's anti-metastatic effect. Furthermore, they show that the combined use of a bisphosphonate with 17-DMAG significantly attenuates the progression of metastases in both the liver and the bone. The findings thus suggest that the therapeutic effects of HSP90 inhibitors may be organ-specific and should be carefully monitored in SCLC clinical trials.",
keywords = "HSP90 inhibitor, metastasis model, small cell lung cancer",
author = "Shinji Takeuchi and Koji Fukuda and Sachiko Arai and Shigeki Nanjo and Kenji Kita and Tadaaki Yamada and Eiji Hara and Hiroshi Nishihara and Hisanori Uehara and Seiji Yano",
year = "2016",
month = "3",
day = "1",
doi = "10.1002/ijc.29858",
language = "English",
volume = "138",
pages = "1281--1289",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "5",

}

TY - JOUR

T1 - Organ-specific efficacy of HSP90 inhibitor in multiple-organ metastasis model of chemorefractory small cell lung cancer

AU - Takeuchi, Shinji

AU - Fukuda, Koji

AU - Arai, Sachiko

AU - Nanjo, Shigeki

AU - Kita, Kenji

AU - Yamada, Tadaaki

AU - Hara, Eiji

AU - Nishihara, Hiroshi

AU - Uehara, Hisanori

AU - Yano, Seiji

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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. What's new? Small cell lung cancer (SCLC) is an extremely aggressive disease characterized by increased incidence of multi-organ metastasis and acquired resistance to conventional chemotherapy. Here, the authors show that HSP90 inhibitor 17-DMAG efficiently inhibits the metastasis of chemorefractory SCLC cells to the liver, but worsens bone metastasis, indicating heterogeneity in 17-DMAG's anti-metastatic effect. Furthermore, they show that the combined use of a bisphosphonate with 17-DMAG significantly attenuates the progression of metastases in both the liver and the bone. The findings thus suggest that the therapeutic effects of HSP90 inhibitors may be organ-specific and should be carefully monitored in SCLC clinical trials.

AB - 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. What's new? Small cell lung cancer (SCLC) is an extremely aggressive disease characterized by increased incidence of multi-organ metastasis and acquired resistance to conventional chemotherapy. Here, the authors show that HSP90 inhibitor 17-DMAG efficiently inhibits the metastasis of chemorefractory SCLC cells to the liver, but worsens bone metastasis, indicating heterogeneity in 17-DMAG's anti-metastatic effect. Furthermore, they show that the combined use of a bisphosphonate with 17-DMAG significantly attenuates the progression of metastases in both the liver and the bone. The findings thus suggest that the therapeutic effects of HSP90 inhibitors may be organ-specific and should be carefully monitored in SCLC clinical trials.

KW - HSP90 inhibitor

KW - metastasis model

KW - small cell lung cancer

UR - http://www.scopus.com/inward/record.url?scp=84955663953&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84955663953&partnerID=8YFLogxK

U2 - 10.1002/ijc.29858

DO - 10.1002/ijc.29858

M3 - Article

C2 - 26379118

AN - SCOPUS:84955663953

VL - 138

SP - 1281

EP - 1289

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 5

ER -