| The extent of tumour hypoxia has been correlated with the development of chemoresistance in a variety of malignant cell lines. One likely mechanism of hypoxia-induced chemoresistance involves decreased intracellular cyclic 3', 5'-guanosine monophosphate (cGMP) concentrations and the subsequent decrease in cGMP-dependent protein kinase (PKG) activity. Atrial natriuretic peptide (ANP) increases intracellular cGMP concentrations by activating particulate guanylyl cyclase, resulting in the activation of PKG. The hypothesis of the present study is that ANP can attenuate hypoxia-induced chemoresistance in cancer cells through this cGMP-mediated pathway. These results indicate that ANP is capable of chemosensitizing prostate and breast cancer cells through a mechanism involving cGMP production and likely PKG activation. ANP appears to modulate hypoxia-induced chemoresistance through a mechanism involving an intracellular cGMP cascade, suggesting that adjuvant therapies which modulate the cGMP signalling pathway may be of therapeutic significance in preventing chemoresistance. (Abstract shortened by UMI.)... |
