In vitro and in vivo combination of cepharanthine with anti-malarial drugs

Abstract

BackgroundStephania rotunda is used by traditional health practitioners in Southeast Asia to treat a wide range of diseases and particularly symptoms related to malaria. Cepharanthine (CEP) is an alkaloid isolated from this plant with potential innovative antiplasmodial activity. The analysis of interactions between antiplasmodial drugs is necessary to develop new drugs combinations to prevent de novo emergence of resistance. The objective of this study was to evaluate the anti-malarial activity of CEP in combination with usual anti-malarial compounds, both in vitro and in vivo.MethodsA fixed ratio method using the isotopic micro test was performed on the chloroquine-resistant plasmodial strain W2 to build isobolograms from eight CEP-based combinations with standard anti-malarial drugs. The efficacy of two combinations was then evaluated in the BALB/c mouse infected with Plasmodium berghei ANKA strain.ResultsIn vitro, efficiency gains were observed when CEP was combined with chloroquine (CQ), lumefantrine (LUM), atovaquone (ATO), piperaquine (PPQ) and particularly monodesethylamodiaquine (MdAQ), whereas an antagonistic interaction was observed with dihydroartemisinin (DHA) and mefloquine (MQ). In vivo, the combination of CEP with CQ or amodiaquine (AQ) improved significantly the survival of mice and extended the delay for parasitic recrudescence.ConclusionAll these observations suggest that CEP could be an interesting lead compound in the development of a combination therapy against malaria.

Stephanine from Stephania venosa (Blume) Spreng Showed Effective Antiplasmodial and Anticancer Activities, the Latter by Inducing Apoptosis through the Reverse of Mitotic Exit

“…The aporphine compound 3 , stephanine, was the most active compound against P. falciparum with IC 50 of 0.69 ± 0.15 μM (0.21 ± 0.06 μg/mL) against 3D7 and 1.32 ± 0.38 μM (0.41 ± 0.12 μg/mL) against W2 (Table 4). This antiplasmodial activity was close to that of cepharantine, the major alkaloid isolated from S. rotunda (Chea et al , ; Desgrouas et al , ; Desgrouas et al , ; Tamez et al , ). However, stephanine 3 showed high cytotoxic effect on non‐cancer breast cell line 184B5 (6.25 ± 0.14 μM).…”

“…In addition, cepharanthine was not only effective against cultured cells originated from murine skins, but also inhibited tumor promotion in two‐stage carcinogensis in mouse (Nakaoji et al , ; Yasukawa et al , ). Furthermore, the compound also showed strong activity against P. falciparum parasites, synergistically when combined with chloroquine, lumefantrine, piperaquine or monodesethylamodiaquine (Chea et al , ; Desgrouas et al , ; Desgrouas et al , ; Haruki et al , ; Tamez et al , ).…”

Cepharanthine: An update of its mode of action, pharmacological properties and medical applications

“…The cepharanthine-chloroquine association is synergistic (Chea et al, 2007). The combination of CEP with chloroquine (or amodiaquine) improved significantly the survival of mice and extended the delay for parasitic recrudescence (Desgrouas et al, 2014c). CEP blocks P. falciparum development in ring stage, affecting multiple metabolic pathways, such as cell-cell interactions, glycolysis and isoprenoid pathways (Desgrouas et al, 2014d).…”

A critical review: traditional uses, phytochemistry, pharmacology and toxicology of Stephania tetrandra S. Moore (Fen Fang Ji)

“…Whereas the mechanism by which this bioactivity occurs should be further investigated. The combination of cepharanthine (21 mg/kg or 63 mg /kg) with chloroquine (30 mg/kg) or amodiaquine (10 mg/kg) was demonstrated to significantly improve the survival of mice and delay parasitic recrudescence (Desgrouas et al 2014b). The mechanism by which cepharanline acts against plasmodia is to block the development of P. falciparum in the ring stage via down-regulation of Maurer's clefts (Desgrouas et al 2014c).…”