Involvement of mitochondrial pathway in NCTD-induced cytotoxicity in human hepG2 cells

Chang, Cheng; Zhu, Yufan; Mei, Juanjuan; Liu, Shiquan; Luo, Jun

doi:10.1186/1756-9966-29-145

Cited by 53 publications

(46 citation statements)

References 30 publications

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“…N-hydroxycantharidimide, which is synthesized by cantharidin, has certain curative effects in liver cancer (16). Previous data showed that NCTD could induce cytotoxicity in HepG2 cells by inducing apoptosis (10); therefore, in the present study, we evaluated HepG2 cell apoptosis. The basal apoptotic population of the sham group was 0.3±0.1%.…”

Section: Discussionmentioning

confidence: 99%

Atg5 siRNA inhibits autophagy and enhances norcantharidin-induced apoptosis in hepatocellular carcinoma

Xiong

Zhang

et al. 2015

International Journal of Oncology

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Abstract. Cantharidin is a terpenoid isolated from Chinese blister beetles, and norcantharidin (NCTD) is a demethylated analog of cantharidin. It has been reported that cantharidin and norcantharidin have anticancer activities. Growing evidence suggests that inhibiting autophagy can induce apoptosis in the human hepatoma cell line HepG2. The objective of the present study was to determine whether inhibition of autophagy enhances NCTD-induced apoptosis in HepG2 cells. HepG2 cells were cultured in DMEM containing NCTD. Autophagy was upregulated in the presence of HBSS media supplemented with Ca 2+ and Mg 2+ and 10 mM HEPES and downregulated in the presence of 3-methyladenine (3-MA) and Atg5 siRNA. Autophagy, cell viability, and the expression of apoptotic proteins were assessed in HepG2 cells. Our data showed that cell apoptosis generally increased after norcantharidin treatment in HepG2 cells. Expression of LC3-II, an autophagosome marker, increased when cells were treated with HBSS media. It also increased cell viability. However, in the presence of 3-MA and Atg5 siRNA, autophagy was inhibited, LC3-II expression decreased and cell apoptosis increased. There was increased expression of Bax, cytochrome c, cleaved caspase-3, caspase-9 and PARP and the mitochondrial membrane potential was disrupted. Additionally, increased apoptosis was accompanied by increased reactive oxygen species (ROS) production. NCTD has anticancer activity, and Atg5 siRNA-mediated downregulation of autophagy enhanced its anticancer actions due to ROS generation and activation of the mitochondrial apoptosis pathway. IntroductionLiver cancer is the sixth most frequent cancer and the second leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) represents 90% of all primary liver cancers (1-3). The 5-year survival rate for HCC is <30% and the recurrence rate is ~70% (4,5). Current HCC treatments, including surgical resection, liver transplantation, chemotherapy, or immuno-biological cancer therapies, are typically not very effective.Cantharidin is a terpenoid isolated from Chinese blister beetles, and norcantharidin (NCTD) is a demethylated analog of cantharidin that has anticancer activity in breast cancer, lung cancer, leukemia, colon and liver cancer. One possible explanation for the anticancer actions of NCTD is its inhibition of protein phosphatases, through which G0/G1 or G2/M arrest is triggered. Thus, apoptosis is subsequently induced via ROS generation and the mitochondrial pathway (6,7).Autophagy, an important pathophysiological process, is crucial for cell development, differentiation, survival and homeostasis. Additionally, autophagy has an important role in liver cancer. Previous studies have shown that autophagy is induced in liver cancer.

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Section: Discussionmentioning

confidence: 99%

Atg5 siRNA inhibits autophagy and enhances norcantharidin-induced apoptosis in hepatocellular carcinoma

Xiong

Zhang

et al. 2015

International Journal of Oncology

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“…In China, norcantharidin as an anti-cancer drug is currently used to treat breast cancer, hepatoma, leukemia, colon cancer, etc. The well-studied mechanisms for the anti-cancer activity of norcantharidin are its activity of inducing apoptosis via regulation of Bcl-2 superfamily member proteins and caspase activities (Chang et al, 2010), interruption of cell cycle arrest at G2/M phase (Liao et al, 2011), and inhibition of cell metastasis by down-regulates MMP-9 expression (Chen et al, 2009b). It was recently reported that mitogen-activated protein kinases (MAPKs) and signal transducers and activators of transcription (STATs) pathways are also involved in norcantharidin-induced apoptogenesis (Yang et al, 2011b).…”

Section: Cantharidin and Cantharidin Derivativesmentioning

confidence: 99%

Fighting fire with fire: Poisonous Chinese herbal medicine for cancer therapy

Wang

Tan

et al. 2012

Journal of Ethnopharmacology

148

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“…The median disease-free survival following complete resection of the pancreatic tumor and adjuvant chemotherapy with the first line chemotherapeutic agent gemcitabine is 13.4 and 6.9 months, respectively (3)(4)(5)(6). Although camptothecin has a positive effect on arresting pancreatic tumor growth, many unwanted sideeffects limit its clinical application (5,7). All these dismal data highlight an urgent need for new therapeutic agents that could produce better clinical outcomes for this deadly disease.…”

Section: Introductionmentioning

confidence: 99%

Involvement of the mitochondrial pathway in bruceine D-induced apoptosis in Capan-2 human pancreatic adenocarcinoma cells

et al. 2012

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Abstract. The fruit of Brucea javanica L. is a common herb used in Chinese medicine for the treatment of a variety of cancers. Our research group has previously identified bruceine D (BD), a quassinoid found abundantly in B. javanica, to have potent cytotoxic effect on a number of pancreatic cancer cell lines, including Panc-1, SW1990 and Capan-1 cells. In the present study, we showed that BD was also able to inhibit the growth of the Capan-2 human pancreatic adenocarcinoma cell line, but it exerted only modest cytotoxicity on the WRL68 human hepatocyte cell line and a human pancreatic progenitor cell line. The antiproliferative effects of BD were comparable to those exhibited by camptothecin and gemcitabine in our culture system. We found a dose-dependent decrease of the mitochondrial membrane potential in BD-treated Capan-2 cells as measured by the JC-1 assay. BD exposure was able to attenuate the expression of Bcl-2 protein in Capan-2 cells as detected by western blot analysis. In addition, the expression of both caspase 9 and caspase 3 in BD-treated Capan-2 cells was significantly accentuated. Moreover, BD was capable of inducing the fragmentation of genomic DNA in Capan-2 cells as evidenced by Hoechst staining. Cell cycle analysis demonstrated that BD could increase the percentage of Capan-2 cells in the subG 1 phase in a dose-related manner. An increase in the apoptosis of Capan-2 cells was also observed by Annexin V and PI staining. These results unequivocally indicate that BD induces cytotoxicity in Capan-2 cells via the induction of cellular apoptosis involving the mitochondrial pathway. IntroductionHuman pancreatic cancer is a gastrointestinal malignancy with extremely poor prognosis owing to a lack of early clinical diagnosis and its intrinsic resistance to radiotherapy and chemotherapy (1,2). According to the Hong Kong Cancer Registry in 2009 pancreatic cancer was the 8th and 6th major cause of cancer-related deaths in males and females, respectively. As for the management of pancreatic cancer, surgical resection remains the only potentially curative treatment of pancreatic cancer. However, only 5-25% of the patients diagnosed with pancreatic cancer were operable, and chemotherapy thus remains the mainstay of palliative management for the locally advanced and metastatic stage of this cancer. The median disease-free survival following complete resection of the pancreatic tumor and adjuvant chemotherapy with the first line chemotherapeutic agent gemcitabine is 13.4 and 6.9 months, respectively (3-6). Although camptothecin has a positive effect on arresting pancreatic tumor growth, many unwanted sideeffects limit its clinical application (5,7). All these dismal data highlight an urgent need for new therapeutic agents that could produce better clinical outcomes for this deadly disease.Our previous studies have shown that the fruit of Brucea javanica L., a Chinese medicinal plant commonly used for cancer treatment, has potent in vitro anti-pancreatic cancer activity (8). Furthermore, bruceine D (BD), a qu...

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Involvement of mitochondrial pathway in NCTD-induced cytotoxicity in human hepG2 cells

Cited by 53 publications

References 30 publications

Atg5 siRNA inhibits autophagy and enhances norcantharidin-induced apoptosis in hepatocellular carcinoma

Atg5 siRNA inhibits autophagy and enhances norcantharidin-induced apoptosis in hepatocellular carcinoma

Fighting fire with fire: Poisonous Chinese herbal medicine for cancer therapy

Involvement of the mitochondrial pathway in bruceine D-induced apoptosis in Capan-2 human pancreatic adenocarcinoma cells

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