Doxorubicin-induced inhibition of prolyl hydroxylation during collagen biosynthesis in human skin fibroblast cultures. Relevance to imparied wound healing.

Abstract

Previous clinical and experimental observations have indicated that wound healing is impaired as a result of treatment with doxorubicin, a chemotherapeutic agent. In this study, the effects of doxorubicin were examined in human skin fibroblast cultures with respect to collagen production and fibroblast proliferation. The results indicated that the synthesis of hydroxyproline as a marker of collagen production was markedly reduced, with an approximate concentration of inhibitor yielding 50% inhibition of 1 microM. This inhibition could be explained, in part, by generalized inhibition of total protein synthesis, but in addition, there was a significant inhibition of prolyl hydroxylation during collagen biosynthesis, as indicated by a reduction in the ratio of [3H]hydroxyproline/([3H]hydroxyproline + [3H]proline). The latter effect was shown to result from inhibition of prolyl hydroxylase by doxorubicin. As a consequence of reduced prolyl hydroxylation, the stability of newly synthesized procollagen triple helix was shown to be compromised. At the same time, doxorubicin significantly reduced fibroblast proliferation in vitro, as determined by [3H]thymidine incorporation. Thus, reduced collagen production and inhibition of fibroblast proliferation may explain the reduced wound healing in patients undergoing treatment with doxorubicin.