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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 - Cancer Chemother. Pharmacol. (2009)

Bottom Line: 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).The in vivo antitumor activity of ART was similar to that of gemcitabine.

View Article: PubMed Central - PubMed

Affiliation: Central Laboratory, Nanshan Hospital, Guangdong Medical College, 518052 Shenzhen, Guangdong Province, People's Republic of China.

ABSTRACT
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.

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Cytotoxic effects of ART on human pancreatic cancer cells. A Chemical structure of ART. B Panc-1, BxPC-3, CFPAC-1, and normal (HL-7702) hepatic cells were treated with the indicated concentrations of ART for 48 h. Mean values for three independent cell viability MTT assays are plotted. C Phase-contrast micrographs of Panc-1 cells treated with vehicle (a, control), 50 μmol/l ART for 24 h (b), 50 μmol/l ART for 48 h (c) or 50 μmol/l cisplatin for 48 h (d) are shown. All images captured at 100× magnification
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Fig1: Cytotoxic effects of ART on human pancreatic cancer cells. A Chemical structure of ART. B Panc-1, BxPC-3, CFPAC-1, and normal (HL-7702) hepatic cells were treated with the indicated concentrations of ART for 48 h. Mean values for three independent cell viability MTT assays are plotted. C Phase-contrast micrographs of Panc-1 cells treated with vehicle (a, control), 50 μmol/l ART for 24 h (b), 50 μmol/l ART for 48 h (c) or 50 μmol/l cisplatin for 48 h (d) are shown. All images captured at 100× magnification

Mentions: Artesunate (ART) is a derivative of artemisinin (Fig. 1A), the principle active component of the Chinese herb Artemisiaannua L. Artesunate, which is approved for the treatment of multidrug-resistant malaria and has an excellent safety profile [5]. In addition to its anti-malarial activity, ART has been shown to have cytotoxic effects on a number of human cancer cell types, including leukemia, colon cancer, and melanoma cells [6]. Moreover, ART has recently been shown to possess cytotoxicity against hepatoma cells and ovarian cancer cells in vitro and in vivo [7, 8]. Mechanisms that might explain the antitumor activity of ART include induction of apoptosis of T leukemia cells [9], anti-proliferative or anti-angiogenic effects in xenografted Kaposi’s sarcoma in mice [10], inhibition of growth of C6 glioma cells by increasing levels of reactive oxygen species [11] or DNA damage [12]. However, little is known about the effects of ART on pancreatic cancers. Therefore, it is worth determining whether the known cytotoxic activity of ART extends to pancreatic cancer.Fig. 1


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 - Cancer Chemother. Pharmacol. (2009)

Cytotoxic effects of ART on human pancreatic cancer cells. A Chemical structure of ART. B Panc-1, BxPC-3, CFPAC-1, and normal (HL-7702) hepatic cells were treated with the indicated concentrations of ART for 48 h. Mean values for three independent cell viability MTT assays are plotted. C Phase-contrast micrographs of Panc-1 cells treated with vehicle (a, control), 50 μmol/l ART for 24 h (b), 50 μmol/l ART for 48 h (c) or 50 μmol/l cisplatin for 48 h (d) are shown. All images captured at 100× magnification
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2824122&req=5

Fig1: Cytotoxic effects of ART on human pancreatic cancer cells. A Chemical structure of ART. B Panc-1, BxPC-3, CFPAC-1, and normal (HL-7702) hepatic cells were treated with the indicated concentrations of ART for 48 h. Mean values for three independent cell viability MTT assays are plotted. C Phase-contrast micrographs of Panc-1 cells treated with vehicle (a, control), 50 μmol/l ART for 24 h (b), 50 μmol/l ART for 48 h (c) or 50 μmol/l cisplatin for 48 h (d) are shown. All images captured at 100× magnification
Mentions: Artesunate (ART) is a derivative of artemisinin (Fig. 1A), the principle active component of the Chinese herb Artemisiaannua L. Artesunate, which is approved for the treatment of multidrug-resistant malaria and has an excellent safety profile [5]. In addition to its anti-malarial activity, ART has been shown to have cytotoxic effects on a number of human cancer cell types, including leukemia, colon cancer, and melanoma cells [6]. Moreover, ART has recently been shown to possess cytotoxicity against hepatoma cells and ovarian cancer cells in vitro and in vivo [7, 8]. Mechanisms that might explain the antitumor activity of ART include induction of apoptosis of T leukemia cells [9], anti-proliferative or anti-angiogenic effects in xenografted Kaposi’s sarcoma in mice [10], inhibition of growth of C6 glioma cells by increasing levels of reactive oxygen species [11] or DNA damage [12]. However, little is known about the effects of ART on pancreatic cancers. Therefore, it is worth determining whether the known cytotoxic activity of ART extends to pancreatic cancer.Fig. 1

Bottom Line: 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).The in vivo antitumor activity of ART was similar to that of gemcitabine.

View Article: PubMed Central - PubMed

Affiliation: Central Laboratory, Nanshan Hospital, Guangdong Medical College, 518052 Shenzhen, Guangdong Province, People's Republic of China.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus