Effect of hypoxia on anti-tumor activity of the bioreductive drug AQ4N, and characterization of cancer stem-like cells from the human lung tumor line H460
Manley, Eugene Jr
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Tumor hypoxia is common and can contribute to drug resistance. To take advantage of hypoxia, bioreductive drugs that are activated to cytotoxic metabolites in a hypoxic tumor environment have been developed. The cytotoxicity of one such drug, AQ4N, was assessed under normoxic and hypoxic conditions across a panel of tumor cell lines. AQ4N showed significantly increased cytotoxicity under hypoxia in rat 9L gliosarcoma and H460 human non-small cell lung carcinoma cell cultures, but not in cultures often other human cancer cell lines. Thus, the bioreductive activation of AQ4N is not widespread in cancer cell lines. Protein levels of the quinone reductase DT-diaphorase were poorly correlated with AQ4N chemosensitivity across the cell line panel, and AQ4N chemosensitivity was unaffected by DT-diaphorase inhibitors, indicating little contribution of DT-diaphorase to AQ4N cytotoxicity. The vasodilator hydralazine decreased tumor perfusion and increased tumor hypoxia in 9L tumor xenografts, and to a lesser extent in H460 xenografts, but did not increase AQ4N-dependent anti-tumor activity. Combining of AQ4N with the anti-angiogenic drug axitinib did not augment AQ4N anti-tumor activity beyond that of axitinib alone, despite the increased hypoxic environment. Thus, AQ4N activation in vivo requires tumor hypoxia that is more extensive or prolonged than can readily be achieved by vasodilation or anti-angiogenic drug treatment. Cancer stem-like cells have been proposed to be critical for tumor growth, initiation, and drug resistance. Stem-like cells from six human tumor cell lines were isolated at frequencies ranging from 12-69% based on their characteristic holoclone morphology. All but one tumor cell line yielded holoclones with the capacity for self-renewal. Tumor xenografts grown from H460 holoclones showed significant increases in microvessel density and tumor blood perfusion compared to parental H460 tumors. Microarray analysis identified genes commonly dysregulated in holoclone-derived H460 tumors, including a network of genes associated with angiogenesis. These and other genes may serve as therapeutic targets to eliminate cancer stem-like cells or inhibit angiogenesis in H460 tumors. Together, these studies advance efforts to improve bioreductive drug activity through anti-angiogenesis and elucidate the role of stem-like cells in tumor angiogenesis.
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