Effects of topoisomerases inhibitors protoberberine on Leishmania donovani growth, macrophage function, and infection.
DNA topoisomerases play a pivotal role in the regulation of cell division. Inhibition of Leishmania spp. topoisomerases represents an alternative to control parasite growth. Cancer research led to the development of several potent topoisomerase inhibitors such as topoisomerase I, topoisomerase II, or both (monobenzimidazole, terbenzimidazole, and protoberberine alkaloid-related compounds) that are effective antitumor agents. In the present study, we evaluated the efficacy of these compounds against Leishmania spp. growth in vitro. Some protoberberine compounds showed pronounced antileishmanial activity and were selected for further analysis in macrophages. These compounds did not affect macrophage viability and only slightly reduced macrophage nitric oxide generation in response to interferon-gamma. Moreover, exposure of infected macrophages to these compounds significantly reduced parasite loads. Collectively, our data suggest that protoberberine-related compounds have powerful antileishmania action and that minor structural variations among them can substantially improve their activity to restrict Leishmania spp. infection in vitro.
Marquis
Jean-François
JF
Département de Biologie Médicale, Faculté de Médecine, Centre de Recherche en Infectiologie du CHUQ, Université Laval, Sainte-Foy, Québec, Canada G1V 4G2.
Makhey
Darshan
D
LaVoie
Edmond J
EJ
Olivier
Martin
M
D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D001600:Berberine Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007371:Interferon-gamma / Q000494:pharmacology; D007893:Leishmania donovani / Q000187:drug effects* / Q000254:growth & development; D008264:Macrophages / Q000187:drug effects* / Q000469:parasitology / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis; D059003:Topoisomerase Inhibitors
D000981:Antiprotozoal Agents; D001562:Benzimidazoles; D001600:Berberine Alkaloids; D059003:Topoisomerase Inhibitors; C009090:protoberberine; D009569:Nitric Oxide; D007371:Interferon-gamma