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Anti‐angiogenic effects of zoledronic acid on osteotropic breast cancer cells
Author(s) -
Contreras Cynthia,
Morshedian Shaghayegh,
Hamud Walid,
Dhakal Bishal,
Khanal Bijay,
Bush Jason A
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.999.6
Subject(s) - zoledronic acid , bisphosphonate , angiogenesis , cancer research , apoptosis , chemistry , cell growth , downregulation and upregulation , cytotoxicity , pharmacology , medicine , biochemistry , osteoporosis , in vitro , gene
Emerging data suggest the bisphosphonate, zoledronic acid (ZOL), exerts both indirect and direct anti‐tumor effects by decreasing tumor cell proliferation, increasing apoptosis, and inhibiting angiogenesis. Recent data indicate that anti‐angiogenic factors exert cellular effects via suppression of mitochondrial oxidative phosphorylation/respiration and elevation of intracellular ROS levels. This project intended to define proteins involved in response to ZOL‐treatment of an osteotropic breast cancer cell line, MDA‐231BO. Results demonstrate that MDA‐231BO cells are more sensitive to ZOL cytotoxicity and salutary effects are both media‐ and calcium‐dependent. To investigate pro‐apoptotic mechanisms of ZOL, total RNA, whole cell protein lysates, or mitochondrial‐enriched fractions were isolated from MDA‐231BO cells and using a combination of RT‐PCR, 1D/2D‐PAGE separation and MALDI‐MS/MS, we identified several angiogenesis inhibitors that were upregulated and pro‐angiogenic factors that were downregulated after ZOL treatment. Functional studies demonstrate the improved efficacy of ZOL on MDA‐231BO compared to MDA‐MB‐231 controls. Taken together, these results further support a model that ZOL tips the ‘angiogenic switch’ in favor of anti‐angiogenic factors in cancer cells with a propensity for bone metastases.