Journal
CANCER LETTERS
Volume 364, Issue 2, Pages 156-164Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2015.05.008
Keywords
HIF-1; Obatoclax; Drug resistance; 5-Fluorouracil; Colon cancer; Oxaliplatin
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Activation of hypoxia-inducible factor (HIF)-1 is a feature of hypoxic solid tumors that has been associated with drug resistance, mainly due to disruption of Bcl-2 family dynamics. Resetting the balance in favor of proapoptotic family members is an attractive therapeutic goal that has been pursued by developing BH3-mimetic compounds. In the present study we evaluated the response of human colon adenocarcinoma cells to the BH3-mimetic obatoclax (OBX), in terms of growth arrest, apoptosis and autophagy, in the presence or absence of HIF-1 alpha-stabilizing conditions; its possible effect on HIF-1 alpha expression and HIF-1 activity; and the possibility to improve the response of colon cancer cells to cytotoxic chemotherapeutics by combining them with OBX. Colon cancer cell response to the BH3-mimetic was unmodified by HIF-1 activation and OBX induced a decrease in HIF-1 alpha protein levels and HIF-1 transcriptional activity, probably by decreasing HIF-1 alpha synthesis and facilitating a VHL-independent proteasomal degradation pathway. Finally, a chemosensitizing effect of OBX with respect to 5-fluorouracil or oxaliplatin treatment was observed, highlighting the possibility that patients with hypoxic colon tumors might benefit from combined regimens including OBX. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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