Adriamycin stimulates proliferation of human lymphoblastic leukaemic cells via a mechanism of hydrogen peroxide (H2O2) production

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Abstract
It is becoming clear that adriamycin cytotoxicity may be mediated by semiquinone‐free radicals derived from the drug itself and reactive oxygen species (ROS). Recent evidence supports the concept that low concentrations of ROS are able to stimulate cell proliferation, and, based on the observation that subtoxic concentrations of adriamycin can also induce cell proliferation, we hypothesize that low concentrations of adriamycin stimulate cell proliferation by a ROS generation mechanism. We have employed spin‐trapping and electron spin resonance (ESR) spectroscopy to investigate the nature of the adriamycin‐generated ROS. The spin trap 3,5‐dibromo‐4‐nitrosobenzenesulphonate (DBNBS), which is oxidized in the presence of H2O2 and peroxidase enzymes, was used to produce a characteristic three‐line spectrum, and it was found that an identical spectrum was produced by human lymphoblastic leukaemic cells (CCRF‐CEM cells) after exposure to adriamycin. We tested our hypothesis further by exposing CCRF‐CEM cells to subtoxic concentrations of adriamycin (10−8, 10−9 and 10−10 M) and low concentrations of H2O2 (10−8, 10−9 and 10−10 M) and subsequently monitored cell proliferation. We found that low concentrations of both adriamycin and H2O2 significantly stimulate CCRF‐CEM cell proliferation. We therefore conclude that subtoxic concentrations of adriamycin are likely to induce cell proliferation via an H2O2 mediated mechanism.

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