Departmental Papers (Dental)

Document Type

Journal Article

Date of this Version

1-1-2010

Publication Source

International Journal of Cancer

Volume

126

Issue

1

Start Page

90

Last Page

103

DOI

10.1002/ijc.24710

Abstract

Adjunctive chemotherapy with bisphosphonates has been reported to delay bone metastasis and improve overall survival in breast cancer. Aside from its antiresorptive effect, bisphosphonates exhibit antitumor activities, in vitro and in vivo, via several mechanisms, including antiangiogenesis. In this study, we investigated the potential molecular mechanisms underlying the antiangiogenic effect of non-nitrogen-containing and nitrogen-containing bisphosphonates, clodronate and pamidronate, respectively, in insulin-like growth factor (IGF)-1 responsive human breast cancer cells. We tested whether bisphosphonates had any effects on hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) axis that plays a pivotal role in tumor angiogenesis, and our results showed that both pamidronate and clodronate significantly suppressed IGF-1-induced HIF-1α protein accumulation and VEGF expression in MCF-7 cells. Mechanistically, we found that either pamidronate or clodronate did not affect mRNA expression of HIF-1α, but they apparently promoted the degradation of IGF-1-induced HIF-1α protein. Meanwhile, we found that the presence of pamidronate and clodronate led to a dose-dependent decease in the newly-synthesized HIF-1α protein induced by IGF-1 in breast cancer cells after proteasomal inhibition, thus, indirectly reflecting the inhibition of protein synthesis. In addition, our results indicated that the inhibitory effects of bisphosphonates on the HIF-1α/VEGF axis are associated with the inhibition of the phosphoinositide 3-kinase/AKT/ mammalian target of rapamycin signaling pathways. Consistently, we demonstrated that pamidronate and clodronate functionally abrogated both in vitro and in vivo tumor angiogenesis induced by IGF-1-stimulated MCF-7 cells. These findings have highlighted an important mechanism of the pharmacological action of bisphosphonates in the inhibition of tumor angiogenesis in breast cancer cells. © 2009 UICC.

Comments

At the time of publication, author Qunzhou Zhang was affiliated with the University of Southern California, School of Dentistry. Currently, (s)he is a faculty member at the School of Dental Medicine at the University of Pennsylvania.

At the time of publication, author Shihong Shi was affiliated with the University of Southern California, School of Dentistry. Currently, (s)he is a faculty member at the School of Dental Medicine at the University of Pennsylvania.

At the time of publication, author Anh D. Le was affiliated with the University of Southern California, School of Dentistry. Currently, (s)he is a faculty member at the School of Dental Medicine at the University of Pennsylvania.

Keywords

Author keywords: Angiogenesis, Bisphosphonates, Breast cancer, HIF-1α, IGF-1, PI-3K/Akt, VEGF MeSH: Base Sequence, Breast Neoplasms, Cell Line, Tumor, Diphosphonates, DNA Primers, Enzyme-Linked Immunosorbent Assay, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Immunohistochemistry, Insulin-Like Growth Factor I, Neovascularization, Pathologic, Phosphatidylinositol 3-Kinases, Protein Kinases, Proto-Oncogene Proteins c-akt, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, TOR Serine-Threonine Kinases, Vascular Endothelial Growth Factor A EMTREE drug terms: clodronic acid, hypoxia inducible factor 1alpha, mammalian target of rapamycin, messenger RNA, nitrogen, pamidronic acid, phosphatidylinositol 3 kinase, protein kinase B beta, somatomedin C, vasculotropin EMTREE medical terms: article, breast cancer, carcinogenesis, controlled study, dose response, drug inhibition, human, human cell, priority journal, protein degradation, protein expression, protein synthesis, signal transduction

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Date Posted: 10 February 2023

This document has been peer reviewed.