Abstract:
Artemisinin, isolated from the traditional Chinese medicinal plant qīng hāo 青蒿
(Artemisia annua) and its derivatives are used for treatment of malaria. With
treatment failures now being recorded for the derivatives and companion drugs
used in artemisinin combination therapies new drug combinations are urgently
required. The amino-artemisinins artemiside and artemisone display optimal
efficacies in vitro against asexual and sexual blood stages of the malaria parasite
Plasmodium falciparum and are active against tumour cell lines. In continuing
the evolution of combinations of the amino-artemisinins with new drugs, we
examine the triterpenoid quinone methide celastrol isolated from the traditional
Chinese medicinal plant léi gōng téng 雷公藤 (Tripterygium wilfordii). This
compound is redox active, and has attracted considerable attention because
of potent biological activities against manifold targets. We report that celastrol
displays good IC50 activities ranging from 0.50–0.82 µM against drug-sensitive
and resistant asexual blood stage Pf, and 1.16 and 0.28 µM respectively against
immature and late stage Pf NF54 gametocytes. The combinations of celastrol
with each of artemisone and methylene blue against asexual blood stage Pf are
additive. Given that celastrol displays promising antitumour properties, we
examined its activities alone and in combinations with amino-artemisinins
against human liver HepG2 and other cell lines. IC50 values of the aminoartemisinins and celastrol against HepG2 cancer cells ranged from
0.55–0.94 µM. Whereas the amino-artemisinins displayed notable
selectivities (SI > 171) with respect to normal human hepatocytes, in
contrast, celastrol displayed no selectivity (SI < 1). The combinations of
celastrol with artemiside or artemisone against HepG2 cells are synergistic.
Given the promise of celastrol, judiciously designed formulations or structural
modifications are recommended for mitigating its toxicity.
