The presence of hypoxic cells in solid
tumors has long been considered a problem in
cancer treatment. Resistance of hypoxic cells to ionizing radiation and anticancer drugs has in part been attributed to changes in altered gene expression by
hypoxia. We previously reported an activation of heat shock factor (Hsf) in murine
tumor RIF cells following
hypoxia and suggested that a subsequent accumulation of
heat shock protein(s) (Hsp) is likely to contribute to the malignant progression of hypoxic
tumor cells (Baek et al., 2001). In this study, we showed that
hypoxia induced
a DNA-binding activity of Hsf and activation of hsp70 gene expression in
colon cancer Clone A cells, and that a
naphthazarin derivative, S64, significantly inhibited the
hypoxia-inducible hsp70 gene expression in Clone A cells. We also showed that S64 significantly reduced the cellular
glutathione levels in this cell line. Considering the proposed effects of Hsp and
glutathione on radiation and
chemotherapy sensitivity, we suggest that the inhibitory effects of S64 on Hsf activation and cellular
glutathione levels have potentially important clinical implications. We believe that the previously reported in vitro and in vivo anti-
tumor effect of S64 (Song et al., 2000a, 2001) might be attributed, at least in part, to its effect on Hsf activation and/or
glutathione depletion. We also believe that the detailed molecular mechanisms underlying the effects of S64 on Hsf and
glutathione level following
hypoxia deserve a more rigorous future study, the results of which could offer novel strategy to manipulate the resistance mechanisms of solid
tumors.