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Azole‐based heme oxygenase inhibitors and their effects on AC2M2 mouse breast cancer growth and metastasis in vivo
Author(s) -
Hum Maaike,
Dercho Ryan A,
Vlahakis Jason Z,
Szarek Walter A,
Elliott Bruce E,
Nakatsu Kanji
Publication year - 2013
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.27.1_supplement.671.2
Subject(s) - heme oxygenase , in vivo , heme , angiogenesis , breast cancer , azole , cancer research , metastasis , cancer , biliverdin , growth inhibition , cancer cell , pharmacology , cell growth , medicine , chemistry , biology , enzyme , biochemistry , antifungal , microbiology and biotechnology , dermatology
Heme oxygenase (HO) catalyzes the breakdown of heme to biliverdin, free iron, and carbon monoxide. The two major isoforms, HO‐1 (inducible) and HO‐2 (constitutive), are involved in a variety of physiological functions, including apoptosis, inflammation and angiogenesis ‐ important in the growth of some types of cancer. Previous work using metalloporphyrin‐based compounds identified HO inhibition as a potential therapy for some cancers. These compounds are limited by their lack of selectivity for HO and inhibit other heme‐dependent enzymes. Novel azole‐based HO inhibitors have demonstrated increased in vitro selectivity for HO and were tested for their effects on breast cancer growth & progression. In vitro experiments included observing the effects on AC2M2 cell viability and endothelial tube growth in an aortic ring model. In vivo experiments involved the implantation of AC2M2 cells into the mammary fat pad of female nude mice, which then received metronomic treatment with an azole‐based compound or vehicle. Primary tumours were removed on day 21 and metastases grew for another 14 days. Based on previous results, we hypothesized that the azole‐based HO inhibitors would decrease primary tumour volume and decrease the incidences of lung metastases, when compared to control. The findings will help determine whether HO is an appropriate target in the treatment of breast cancer. (Funded by the Ontario Institute of Cancer Research 08NOV‐142; MH is the recipient of a Fellowship from the Canadian Breast Cancer Foundation ‐ Ontario Region)