Anticancer activity of botanical alkyl hydroquinones attributed to topoisomerase II poisoning

Cytotoxic alkyl hydroquinone compounds have been isolated from many plants. We previously isolated 3 structurally similar cytotoxic alkyl hydroquinone compounds from the sap of the lacquer tree Rhus succedanea L. belonging to the sumac family, which have a long history of medicinal use in Asia. Each has an unsaturated alkyl chain attached to the 2-position of a hydroquinone ring. One of these isolates, 10'(Z),13'(E),15'(E)-heptadecatrienylhydroquinone [HQ 17(3)], being the most cytotoxic, was chosen for studying the anticancer mechanism of these compounds. We found that HQ 17(3) was a topoisomerase (Topo) II poison. It irreversibly inhibited Topo II alpha activity through the accumulation of Topo II-DNA cleavable complexes. A cell-based assay showed that HQ 17(3) inhibited the growth of leukemia HL-60 cells with an EC50 of 0.9 mu M, inhibited the topoisomerase-II-deficient cells HL-60/MX2 with an EC50 of 9.6 mu M, and exerted no effect on peripheral blood mononuclear cells at concentrations up to 50 mu M. These results suggest that Topo II is the cellular drug target. In HL-60 cells, HQ17(3) promptly inhibited DNA synthesis, induced chromosomal breakage, and led to cell death with an EC50 about one-tenth that of hydroquinone. Pretreatment of the cells with N-acetylcysteine could not attenuate the cytotoxicity and DNA damage induced by HQ 17(3). However, N-acetylcysteine did significantly reduce the cytotoxicity of hydroquinone. In F344 rats, intraperitoneal injection of HQ17(3) for 28 days induced no clinical signs of toxicity. These results indicated that HQ17(3) is a potential anticancer agent, and its structural features could be a model for anticancer drug design. (c) 2007 Elsevier Inc. All rights reserved.