The effect of inhibiting topoisomerase I and II on the antiapoptotic response associated with pro-inflammatory crystals of calcium pyrophosphate dihydrate in human neutrophils

Abstract

These results suggest that although topoisomerase II antagonists are distinctively effective agents at reversing the pro-survival effects of crystals on neutrophils, camptothecin was unique as a topoisomerase I inhibitor in that it was significantly more effective as a pro-apoptosis inducer than the topoisomerase II poisons without affecting normal neutrophil activation responses.

The antioxidants curcumin and quercetin inhibit inflammatory processes associated with arthritis

“…The physiological purpose of this effect may be to allow an extended anti-bacterial action of neutrophils at infected sites. The pro-survival action of CPPD or MSUM crystals on neutrophils has been previously established and is considered a pro-inflammatory aspect of CIA [36][37][38]. The determination of caspase 3 activity in neutrophils may be used as a measure of apoptosis.…”

“…Using this assay, TNF-a was shown to increase caspase 3 activity and CPPD crystals inhibited both control (spontaneous) and TNF-a-induced increases in neutrophil apoptosis [36,37]. Drugs, such as the topoisomerase inhibitor camptothecin, can override this crystal-induced prosurvival signal and might be used to treat this aspect of CIA, and other neutrophil-dependent diseases [36]. However, drugs rarely have the ability to inhibit both crystal-induced neutrophil activation and apoptosis/survival aspects of CIA.…”

“…However, drugs rarely have the ability to inhibit both crystal-induced neutrophil activation and apoptosis/survival aspects of CIA. For example, although camptothecin inhibits pro-survival signaling, it has no effect on neutrophil activation, whereas other topoisomerase inhibitors such as b-lapachone or mitoxantrone exhibit the opposite inhibitory effects [36].…”

Topoisomerase inhibitors as anti-arthritic agents

“…Ficoll paque and dextran T5000 were obtained from Pharmacia (Uppsala, Sweden). Triclinic pyrophosphate dihydrate (CPPD) crystals were prepared and characterized as previously described [21]. All other materials were obtained from Sigma Chemical Co. (St. Louis, MO).…”

“…Our group has reported that camptothecin and β-laperchone (topoisomerase I inhibitors) and a range of topoisomerase II inhibitors (including etoposide, mitoxantrone and doxorubicin) inhibited neutrophil processes involved in crystal induced arthritis [21]. Since topoisomerase inhibitors are used in cancer therapy to inhibit the proliferation of tumor cells, the potential exists for these agents to inhibit similar proliferative processes involved in RA, namely synoviocytis and angiogenesis.…”