Targeting Tumor Hypoxia: Suppression of Breast Tumor Growth and Metastasis by Novel Carbonic Anhydrase IX Inhibitors
Yuanmei Lou,Paul C. McDonald,Arusha Oloumi,Stephen Chia,Christina Ostlund,Ardalan Ahmadi,Alastair H. Kyle,Ulrich auf dem Keller,Samuel Leung,David G. Huntsman,Blaise A. Clarke,Brent W. Sutherland,Dawn Waterhouse,Marcel B. Bally,Calvin D. Roskelley,Christopher M. Overall,Andrew I. Minchinton,Fabio Pacchiano,Fabrizio Carta,Andrea Scozzafava,Nadia Touisni,Jean-Yves Winum,Claudiu T. Supuran,Shoukat Dedhar +23 more
TLDR
The findings show that CAIX is vital for growth and metastasis of hypoxic breast tumors and is a specific, targetable biomarker for breast cancer metastasis.Abstract:
Carbonic anhydrase IX (CAIX) is a hypoxia and HIF-1–inducible protein that regulates intra- and extracellular pH under hypoxic conditions and promotes tumor cell survival and invasion in hypoxic microenvironments. Interrogation of 3,630 human breast cancers provided definitive evidence of CAIX as an independent poor prognostic biomarker for distant metastases and survival. shRNA-mediated depletion of CAIX expression in 4T1 mouse metastatic breast cancer cells capable of inducing CAIX in hypoxia resulted in regression of orthotopic mammary tumors and inhibition of spontaneous lung metastasis formation. Stable depletion of CAIX in MDA-MB-231 human breast cancer xenografts also resulted in attenuation of primary tumor growth. CAIX depletion in the 4T1 cells led to caspase-independent cell death and reversal of extracellular acidosis under hypoxic conditions in vitro . Treatment of mice harboring CAIX-positive 4T1 mammary tumors with novel CAIX-specific small molecule inhibitors that mimicked the effects of CAIX depletion in vitro resulted in significant inhibition of tumor growth and metastasis formation in both spontaneous and experimental models of metastasis, without inhibitory effects on CAIX-negative tumors. Similar inhibitory effects on primary tumor growth were observed in mice harboring orthotopic tumors comprised of lung metatstatic MDA-MB-231 LM2-4 Luc+ cells. Our findings show that CAIX is vital for growth and metastasis of hypoxic breast tumors and is a specific, targetable biomarker for breast cancer metastasis. Cancer Res; 71(9); 3364–76. ©2011 AACR .read more
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Targeting hypoxia in cancer therapy
William R. Wilson,Michael P. Hay +1 more
TL;DR: The two main approaches, namely bioreductive prodrugs and inhibitors of molecular targets upon which hypoxic cell survival depends are reviewed, and the particular challenges and opportunities these overlapping strategies present are addressed.
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Interfering with pH regulation in tumours as a therapeutic strategy
Dario Neri,Claudiu T. Supuran +1 more
TL;DR: Key pH regulators in tumour cells include: isoforms 2, 9 and 12 of carbonic anhydrase, isoforms of anion exchangers, Na+/HCO3− co-transporters, Na+./H+ exchanger, monocarboxylate transporters and the vacuolar ATPase.
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The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy.
TL;DR: Better understanding of the role of hypoxia in cancer progression will open new windows for the discovery of new therapeutics targeting hypoxic tumor cells and hypoxic microenvironment.
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Nanotechnology for Multimodal Synergistic Cancer Therapy
TL;DR: In this review, state-of-the-art studies concerning recent advances in nanotechnology-mediated multimodal synergistic therapy will be systematically discussed, with an emphasis on the construction of multifunctional nanomaterials for realizing bimodal and trimodal synergy therapy.
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