Inhibition of Leishmania donovani promastigote DNA topoisomerase I and human monocyte DNA topoisomerases I and II by antimonial drugs and classical antitopoisomerase agents.
We have compared the inhibitor sensitivities of DNA topoisomerase I (TOPI) from Leishmania donovani promastigotes and TOPs I and II of human monocytes using pentavalent and trivalent antimonials (SbV, SbIII) and classical TOP inhibitors. Bis-benzimidazoles (Hoechst-33258 and -33342) were potent inhibitors of both parasite and human TOPI, but Hoechst-33342 was markedly less cytotoxic to promastigotes than to monocytes in vitro. Leishmania donovani was also considerably less sensitive than monocytes to camptothecin, both at enzyme and cellular levels. Sodium stibogluconate (SSG) was the only antimonial to inhibit TOPI, exhibiting a significant (P < 0.05) 3-fold greater potency against the L. donovani enzyme but showed low cytotoxicities against intact promastigotes. The SbV meglumine antimoniate failed to inhibit TOPI and showed negligible cytotoxicities, whereas SbIII drugs were lethal to parasites and monocytes yet poor inhibitors of TOPI. Monocyte TOPII was inhibited by bis-benzimidazoles and insensitive to antimonials and camptothecin. The disparity between the high leishmanicidal activity and low anti-TOPI potency of SbIII indicates that in vivo targeting of L. donovani TOPI by the reductive pathway of antimonial activation is improbable. Nevertheless, the potent direct inhibition of TOPI by SSG and the differential interactions of camptothecin with L. donovani and human TOPI support the possibility of developing parasite-specific derivatives.
Walker
John
J
Centro Internacional de Entrenamiento e Investigaciones Medicas Avenida 1 Norte No. 3-03, AA 5390, Cali, Colombia. john_walker@cideim.org.co
Saravia
Nancy G
NG
D000818:Animals; D000965:Antimony / Q000494:pharmacology; D000966:Antimony Potassium Tartrate / Q000494:pharmacology; D000967:Antimony Sodium Gluconate / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D006690:Bisbenzimidazole / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects / Q000201:enzymology*; D008536:Meglumine / Q000494:pharmacology; D000077485:Meglumine Antimoniate; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology*; D009942:Organometallic Compounds / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D020298:U937 Cells
D000981:Antiprotozoal Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D008536:Meglumine; D000077485:Meglumine Antimoniate; D000965:Antimony; D000966:Antimony Potassium Tartrate; D006690:Bisbenzimidazole; C017807:bisbenzimide ethoxide trihydrochloride; D000967:Antimony Sodium Gluconate; D002166:Camptothecin