Dihydroartemisinin exhibits antitumor activity toward hepatocellular carcinoma in vitro and in vivo

Zhang, Chris Zhiyi; Zhang, Haitao; Yun, Jing‐Ping; Chen, George G; Lai, Paul B.S.

doi:10.1016/j.bcp.2012.02.002

Cited by 106 publications

(100 citation statements)

References 42 publications

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“…There are increasing evidences on the dominant role of Bak in apoptosis induced by apoptotic stimuli in the presence of Bax [25,27,46,49,50]. Our recent studies showed that resveratrol, a natural plant polyphenol found in red grape skins, and ARS induced apoptosis dominantly via a Bak-mediated intrinsic pathway in human lung cancer cells [31,42], as well as the Bak-mediated intrinsic Apoptosis pathway controlled the synergistic pro-apoptotic actions of the combined treatment with DHA and gemcitabine in A549 cells [13].…”

Section: Discussionmentioning

confidence: 95%

“…Moreover, Bak but not Bax has also been demonstrated to be the key regulator to trigger the intrinsic apoptosis pathway in DHA-induced apoptosis of Jurkat T-lymphoma cells [25]. In contrast to previous reports on the important roles of Bax [15,26], Zhang and co-workers recently demonstrated the key role of Bak-dependent intrinsic apoptosis pathway in DHA-induced apoptosis of HCC cells [27,28].…”

Section: Introductionmentioning

confidence: 92%

“…In human lung cancer cells, our recent studies found that Bid was not involved in ART-induced apoptosis [35] but might be involved in DHA-induced apoptosis [13,24]. Recently, Zhang and coworkers found that Bid was not involved in DHA-induced apoptosis of HCC cells [27]. To our best knowledge, few studies have reported the roles of Bim and Puma in ARTs-induced apoptosis in HCC cells.…”

Section: Introductionmentioning

confidence: 95%

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Dihydroartemisinin induces apoptosis preferentially via a Bim-mediated intrinsic pathway in hepatocarcinoma cells

et al. 2015

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This report is designed to dissect the detail molecular mechanism by which dihydroartemisinin (DHA), a derivative of artemisinin, induces apoptosis in human hepatocellular carcinoma (HCC) cells. DHA induced a loss of the mitochondrial transmemberane potential (ΔΨm), release of cytochrome c, activation of caspases, and externalization of phosphatidylserine indicative of apoptosis induction. Compared with the modest inhibitory effects of silencing Bax, silencing Bak largely prevented DHA-induced ΔΨm collapse and apoptosis though DHA induced a commensurable activation of Bax and Bak, demonstrating a key role of the Bak-mediated intrinsic apoptosis pathway. DHA did not induce Bid cleavage and translocation from cytoplasm to mitochondria and had little effects on the expressions of Puma and Noxa, but did increase Bim and Bak expressions and decrease Mcl-1 expression. Furthermore, the cytotoxicity of DHA was remarkably reduced by silencing Bim, and modestly but significantly reduced by silencing Puma or Noxa. Silencing Bim or Noxa preferentially reduced DHA-induced Bak activation, while silencing Puma preferentially reduced DHA-induced Bax activation, demonstrating that Bim and to a lesser extent Noxa act as upstream mediators to trigger the Bak-mediated intrinsic apoptosis pathway. In addition, silencing Mcl-1 enhanced DHA-induced Bak activation and apoptosis. Taken together, our data demonstrate a crucial role of Bim in preferentially regulating the Bak/Mcl-1 rheostat to mediate DHA-induced apoptosis in HCC cells.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 95%

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Dihydroartemisinin induces apoptosis preferentially via a Bim-mediated intrinsic pathway in hepatocarcinoma cells

et al. 2015

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“…It has been recommended by the World Health Organization as a first line anti-malarial therapy [4]. In addition to its potent anti-malarial activity, emerging studies have shown that DHA may also be a potential chemopreventive drug, exhibiting strong antitumor activity in various human cancer cells by blocking cell proliferation [5], arresting cell cycle [6], promoting apoptosis [7], and inhibiting angiogenesis and metastasis [8, 9]. In addition, DHA can potentiate the anticancer effect of chemotherapeutic agents and photodynamic therapy to induce cell apoptosis in various kinds of cancers [10-13].…”

Section: Introductionmentioning

confidence: 99%

Dihydroartemisinin and Curcumin Synergistically Induce Apoptosis in SKOV3 Cells Via Upregulation of MiR-124 Targeting Midkine

Zhao

Pan

et al. 2017

Cell Physiol Biochem

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Background/Aim: Women with advanced ovarian carcinoma are less likely to receive platinum-based chemotherapy and surgery due to a greater risk of cytotoxicity and poorer outcomes. We attempted to improve a promising therapy against ovarian cancer by using a combination of dihydroartemisinin (DHA) and curcumin (Cur). Methods: Human ovarian cancer SKOV3 cells were treated with DHA, Cur alone, or a combination of both. The viability of SKOV3 cells was measured by Cell Counting Kit-8 (CCK-8) and a colony formation assay. The cell cycle and apoptosis of SKOV3 cells were monitored by flow cytometry. The mRNA and protein expression levels of target genes were respectively examined by qRT-PCR and western blot. The biological effects of miR-124 on midkine (MK) were verified by a luciferase activity analysis. Results: Combined treatment of DHA and Cur synergistically decreased cell viability, arrested cell cycle, and promoted apoptosis in SKOV3 cells. Moreover, it significantly attenuated the expression of oncogene MK and synergistically upregulated the expression of miR-124. Furthermore, miR-124 was verified to bind directly to the 3ʹ-untranslated region of MK mRNA, resulting in mRNA degradation and reduced MK protein levels. The combination of DHA with Cur significantly inhibited tumor growth in xenograft nude mice without obvious toxicity. Conclusion: Co-treatment with DHA and Cur exhibited a synergistic anti-tumor effect on SKOV3 cells both in vitro and in vivo.

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“…A number of additional pharmacological effects of DHA have been identified, including antitumor activity towards hepatocellular carcinoma in vitro and in vivo (25). Furthermore, DHA was identified to prevent breast cancer-induced osteolysis via inhibiting breast cancer cells and osteoclasts (26).…”

Section: Discussionmentioning

confidence: 99%

Dihydroartemisinin-induced apoptosis in human acute monocytic leukemia cells

Cao

Wang

et al. 2017

Oncol Lett

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Abstract. Dihydroartemisinin (DHA) is a derivative of artemisinin. The present study aimed to investigate whether DHA induces apoptosis in the THP-1 human acute monocytic leukemia cell line (AMoL), and to identify the relative molecular mechanisms. The results of the present study demonstrated that the viability of THP-1 cells were inhibited by DHA in a dose-and time-dependent manner, which was accompanied by morphological characteristics associated with apoptosis. After 24 h of 200 µM DHA treatment, the proportion of apoptotic cells was significantly increased compared with the untreated controls (P<0.01). In addition, DHA downregulated the levels of B-cell lymphoma (Bcl)-2, protein kinase B (Akt)1, Akt2 and Akt3 gene expression, and increased the expression of the Bcl-2-associated X protein apoptosis regulator. The protein expression of phospho-Akt and phospho-extracellular signal-regulated kinase (ERK) was also decreased, and the protein expression level of cleaved caspase-3 was increased following treatment with DHA. Therefore, DHA may induce apoptosis in the AMoL THP-1 cell line via currently unknown underlying molecular mechanisms, including the downregulation of ERK and Akt, and the activation of caspase-3.

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Dihydroartemisinin exhibits antitumor activity toward hepatocellular carcinoma in vitro and in vivo

Cited by 106 publications

References 42 publications

Dihydroartemisinin induces apoptosis preferentially via a Bim-mediated intrinsic pathway in hepatocarcinoma cells

Dihydroartemisinin induces apoptosis preferentially via a Bim-mediated intrinsic pathway in hepatocarcinoma cells

Dihydroartemisinin and Curcumin Synergistically Induce Apoptosis in SKOV3 Cells Via Upregulation of MiR-124 Targeting Midkine

Dihydroartemisinin-induced apoptosis in human acute monocytic leukemia cells

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