Artesunate mitigates proliferation of tumor cells by alkylating heme-harboring nitric oxide synthase

Artesunate (ART), a semi-synthetic derivative of antimalarial artemisinin, kills cancer cells with uncertain mechanisms. Here, we report for the first time that ART may exert the anti-tumor activity by conjugating the prosthetic heme of hemoproteins in a hepatoma cell line, HepG2, which was evident by monitoring the shift of absorbance from heme (A(415)) to the ART-heme adduct (A(476)). Accordingly, a transient elevation of A(415) was observed with a synchronous burst of nitric oxide (NO) and a high rate of survival following incubation of HepG2 with 50 mu M ART. In contrast, ART at above 100 mu M led to an abrogation of NO generation and a decline of the survival rate in HepG2. These data implied that heme-containing nitric oxide synthase (NOS) may represent a major cellular target of ART in killing tumor cells. (C) 2010 Elsevier Inc. All rights reserved.