Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivo

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Cancer Chemother Pharmacol. 2009 Aug 19. [Epub ahead of print]

Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivo.
 
Du JH, Zhang HD, Ma ZJ, Ji KM.
Central
Laboratory, Nanshan Hospital, Guangdong Medical College, 518052,
Shenzhen, Guangdong Province, People's Republic of China.
Pancreatic
cancer is highly resistant to the currently available chemotherapeutic
agents. Less than 5% of patients diagnosed with this disease could
survive beyond 5 years. Thus, there is an urgent need for the
development of novel, efficacious drugs that can treat pancreatic
cancer. Herein we report the identification of artesunate (ART), a
derivative of artemisinin, as a potent and selective antitumor agent
against human pancreatic cancer cells in vitro and in vivo. ART
exhibits selective cytotoxic activity against Panc-1, BxPC-3 and
CFPAC-1 pancreatic cancer cells with IC(50) values that are 2.3- to
24-fold less than that of the normal human hepatic cells (HL-7702). The
pan caspase inhibitor zVAD-fmk did not inhibit the cytotoxic activity
of ART. Electron microscopy of ART-treated cells revealed severe
cytoplasmic swelling and vacuolization, swollen and internally
disorganized mitochondria, dilation (but not fragmentation) of the
nuclei without chromatin condensation, and cell lysis, yielding a
morphotype that is typical of oncosis. The ART-treated cells exhibited
a loss of mitochondrial membrane potential (DeltaPsim) and ART-induced
cell death was inhibited in the presence of the reactive oxygen species
(ROS) scavenger N-acetyl-cysteine (NAC). Importantly, ART produced a
dose-dependent tumor regression in an in vivo pancreatic cancer
xenografts model. The in vivo antitumor activity of ART was similar to
that of gemcitabine. Taken together, our study suggests that ART
exhibits antitumor activity against human pancreatic cancer via a novel
form of oncosis-like cell death, and that ART should be considered a
potential therapeutic candidate for treating pancreatic cancer.