Low daunomycin concentrations protect colorectal cancer cells from hypoxia-induced apoptosis

University of Liège, Luik, Walloon, Belgium
Oncogene (Impact Factor: 8.46). 04/2005; 24(10):1788-93. DOI: 10.1038/sj.onc.1208436
Source: PubMed


Hypoxia, a common feature of solid tumors, is a direct stress that triggers apoptosis in many cell types. Poor or irregular tumor vascularization also leads to a decreased drug diffusion and cancer cells distant from blood vessels (hypoxic cells) are exposed to low drug concentrations. In this report, we show that low daunomycin concentrations protect HCT116 colorectal cancer cells from hypoxia-induced apoptosis. While hypoxia induced p53 accumulation without expression of its responsive genes (bax and p21), daunomycin treatment restored p53 transactivation activity and cell cycle progression. We also demonstrated a role for Akt activation in daunomycin-induced protection through phosphorylation and inactivation of the Bcl-2 family proapoptotic factor Bad. Our data therefore suggest that chemotherapy could possibly, because of low concentrations in poorly vascularized tumors, protect cancer cells from hypoxia-induced cytotoxicity.

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Available from: Nathalie Jacobs
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    • "AKT (protein kinase B) was activated by anoxia in DLD-1, Caco-2, and LS174T cells but not in HCT116 cells; SW480 cells did not show any detectable pAKT under these non-stimulated conditions (Fig. 3C), as has been reported previously [25] [26] [27] [28]. Interestingly, DCA (in the presence or absence of anoxia) increased phosphorylated AKT compared to control or anoxia in all cell lines except SW480 (Fig. 3C); this response did not correlate with DCA's effects on apoptosis, suggesting other pathways are likely involved in the differential cellular survival we report here. "
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    ABSTRACT: We examined the effect of hypoxia on apoptosis of human colorectal cancer (CRC) cells in vitro and in vivo. All cell lines tested were susceptible to hypoxia-induced apoptosis. DCA treatment caused significant apoptosis under normoxia in SW480 and Caco-2 cells, but these cells displayed decreased apoptosis when treated with DCA combined with hypoxia, possibly through HIF-1alpha dependent pathways. DCA treatment also induced significantly increased growth of SW480 tumor xenografts, and a decrease in TUNEL positive nuclei in hypoxic but not normoxic regions of treated tumors. Thus DCA is cytoprotective to some CRC cells under hypoxic conditions, highlighting the need for further investigation before DCA can be used as a reliable apoptosis-inducing agent in cancer therapy.
    Full-text · Article · Nov 2010 · Cancer letters
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    ABSTRACT: A defining characteristic of solid tumors is the capacity to divide aggressively and disseminate under conditions of nutrient deprivation, limited oxygen availability, and exposure to cytotoxic drugs or radiation. Survival pathways are activated within tumor cells to cope with these ambient stresses. We here describe a survival pathway activated by the anti-cancer drug docetaxel in prostate cancer cells. Docetaxel activates STAT3 phosphorylation and transcriptional activity, which in turns induces expression of the PIM1 gene, encoding a serine-threonine kinase activated by many cellular stresses. Expression of PIM1 improves survival of docetaxel-treated prostate cancer cells, and PIM1 knockdown or expression of a dominant-negative PIM1 protein sensitize cells to the cytotoxic effects of docetaxel. PIM1 in turn mediates docetaxel-induced activation of NFκB transcriptional activity, and PIM1 depends in part on RELA/p65 proteins for its prosurvival effects. The PIM1 kinase plays a critical role in this STAT3 → PIM1 → NFκB stress response pathway and serves as a target for intervention to enhance the therapeutic effects of cytotoxic drugs such as docetaxel.
    Preview · Article · Jul 2008 · Journal of Biological Chemistry