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 [HQ17(3)], being the most cytotoxic, was chosen for studying the anticancer mechanism of these compounds. We found that HQ17(3) was a topoisomerase (Topo) II poison. It irreversibly inhibited Topo IIalpha activity through the accumulation of Topo II-DNA cleavable complexes. A cell-based assay showed that HQ17(3) inhibited the growth of leukemia HL-60 cells with an EC50 of 0.9 microM, inhibited the topoisomerase-II-deficient cells HL-60/MX2 with an EC50 of 9.6 microM, and exerted no effect on peripheral blood mononuclear cells at concentrations up to 50 microM. 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 HQ17(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.
Huang
Cheng-Po
CP
Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan, ROC.
Fang
Woei-Horng
WH
Lin
Liang-In
LI
Chiou
Robin Y
RY
Kan
Lou-Sing
LS
Chi
Nai-Hui
NH
Chen
Yun-Ru
YR
Lin
Tin-Yu
TY
Lin
Shwu-Bin
SB
D000818:Animals; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006873:Hydroquinones / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D023421:Models, Animal; D051381:Rats; D011916:Rats, Inbred F344; D029045:Rhus / Q000737:chemistry; D044967:Serum / Q000737:chemistry; D059005:Topoisomerase II Inhibitors
C471674:10'(Z),13'(E),15'(E)-heptadecatrienylhydroquinone; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006873:Hydroquinones; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II