| Inhibition of the Insulin-Like Growth Factor-1 Receptor Enhances Effects of Simvastatin on Prostate Cancer Cells in Co-Culture with Bone. | |
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MedLine Citation:
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PMID: 23335094 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Prostate cancer (PC) bone metastases show weak responses to conventional therapies. Bone matrix is rich in growth factors, with insulin-like growth factor-1 (IGF-1) being one of the most abundant. IGF-1 acts as a survival factor for tumor cells and we speculate that bone-derived IGF-1 counteracts effects of therapies aimed to target bone metastases and, consequently, that therapeutic effects could be enhanced if given in combination with IGF-1 receptor (IGF-1R) inhibitors. Simvastatin inhibits the mevalonate pathway and has been found to induce apoptosis of PC cells. The aims of this study were to confirm stimulating effects of bone-derived IGF-1 on PC cells and to test if IGF-1R inhibition enhances growth inhibitory effects of simvastatin on PC cells in a bone microenvironment. The PC-3 and 22Rv1 tumor cell lines showed significantly induced cell growth when co-cultured with neonatal mouse calvarial bones. The tumor cell IGF-1R was activated by calvariae-conditioned media and neutralization of bone-derived IGF-1 abolished the calvarium-induced PC-3 cell growth. Treatment of PC-3 and 22Rv1 cells with simvastatin, or the IGF-1R inhibitor NVP-AEW541, reduced tumor cell numbers and viability, and induced apoptosis. Combined simvastatin and NVP-AEW541 treatment resulted in enhanced growth inhibitory effects compared to either drug given alone. Effects of simvastatin involved down-regulation of IGF-1R in PC-3 and of constitutively active androgen receptor variants in 22Rv1 cells. In conclusion, we suggest that IGF-1 inhibition may be a way to strengthen effects of apoptosis-inducing therapies on PC bone metastases; a possibility that needs to be further tested in pre-clinical models. |
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Authors:
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Annika Nordstrand; Marie Lundholm; Andreas Larsson; Ulf H Lerner; Anders Widmark; Pernilla Wikström |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-22 |
Journal Detail:
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Title: Cancer microenvironment : official journal of the International Cancer Microenvironment Society Volume: - ISSN: 1875-2292 ISO Abbreviation: Cancer Microenviron Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-21 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101322634 Medline TA: Cancer Microenviron Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Radiation Sciences, Oncology, Umeå University, 901 85, Umeå, Sweden. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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