Inhibition of DNA and RNA polymerase reactions by chloroquine.

Abstract

Chloroquine is one of a series of 4-amiinoquinoline antimalarial compounds whose biology and chemistry were studied extensively during and immediately following World War II.'-3 Early investigations by Parker and Irvin4 demonstrated the ability of chloroquine to bind to both DNA and RNA in vitro, suggesting a possible mechanism by which this drug might interfere with cellular processes in malarial parasites. Subsequently, chloroquine has been found to be effective in controlling infestations by other species of parasites,5 and recently effects of this compound on the metamorphosis of tadpoles,6 and on cell division in tissue culture7 have been reported. The mechanism of action of chloroquine is not known, although effects on various enzyme systems have been described.8' Several years ago, it was demonstrated that chloroquinle can inhibit incorporation of radioactively labeled nucleic acid precursors in DNA and RNA of intact Plasmodium gallinaceunii and P. bergheij0 and more recently it has been shown that hydroxychloroquiine, a closely related analogue, has a similar effect on L-fibroblasts growing in tissue culture.1' The observations that, the binding of chloroquine to DNA can alter the biological'2 and physical'3 properties of the DNA helix suggests that this inhibition of cellular processes might indeed result from complex forma-Downloaded by guest on August 5, 2020

Stage independent chloroquine resistance and chloroquine toxicity revealed via spinning disk confocal microscopy

“…It is striking that a reduction in schizont nuclei is now also defined to be a result of CQ toxicity, and that this occurs regardless whether CQ is administered at R, T or S. As CQ disturbs Hz formation primarily by acting on heme and heme-related compounds, reactive oxygen species created as a result of this chemistry might be damaging DNA or DNA replication machinery, and therefore indirectly decrease the amount of the DNA formed during S. This explanation also requires early Hb catabolism in R. Alternatively the explanation could be more complicated, and involve yet undescribed interactions between CQ (or CQ -heme conjugates) and cyclins or other molecules that regulate the poorly understood nuclear division during S, or perhaps even direct interaction between DNA and CQ or CQ -heme adducts [2][3][4][5][6][7][8][9].…”

“…Cohen and Yielding further proposed that DNA synthesis is inhibited through an effect on DNA and RNA polymerase, due to the binding of CQ to DNA primer [4]. Hahn et al investigated aminoquinoline action vs. nucleic acids and proposed that CQ stabilizes double stranded DNA [5,6].…”

Autophagic Vacuoles Produced in Vitro

“…In bacteria this drug combines with deoxyribonucleic acid and blocks protein synthesis (20)(21)(22), but no evidence for a similar action in mammalian cells is available. The mechanism of the antimalarial effects of chloroquine are unknown.…”

Effects of certain antirheumatic drugs on normal human peripheral blood lymphocytes. Inhibition of mitogen‐ and antigen‐stimulated incorporation of tritiated thymidine

“…Sodium aurothiomalate has recently been shown to inactivate C1 but does not otherwise appear to alter immunologic function (26,27). Antimalarials inhibited L-cell lysis by cytotoxins; inhibited RNA, DNA, and protein synthesis by cells; inhibited DNA and RNA polymerase; and bound to dsDNA (25,28,29).…”