Dihydroartemisinin inhibits TCTP-dependent metastasis in gallbladder cancer

Zhang, Fei; Ma, Qiang; Xu, Zihang; Liang, Haibin; Li, Huaifeng; Ye, Yuanyuan; Xiang, Sheng; Zhang, Yijian; Jiang, Lin; Hu, Yunping; Wang, Zheng; Wang, Xuefeng; Zhang, Yong; Gong, Wei; Liu, Yingbin

doi:10.1186/s13046-017-0531-3

Cited by 66 publications

(59 citation statements)

References 37 publications

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“…The data demonstrated that DHA synergizes with rapamycin and promotes cell death and apoptosis via the upregulation of DAPK and Atg7, which provides an indication for its usefulness in anticancer studies and clinical application. In accordance with the results of other studies regarding DHA, the effects of DHA on autophagy were further confirmed (28)(29)(30)(31)(32). The present study provides novel evidence regarding the effects of rapamycin combined with DHA and Atg7 knockdown; however, owing to the limitations of in vitro experiments, the associated combined effects should be investigated in in vivo animal models in the future, with further cell lines investigated.…”

Section: Discussionsupporting

confidence: 90%

“…Zhang et al (30) demonstrated that DHA can inhibit translationally controlled tumor protein (TCTP)-dependent cell migration and invasion by inhibiting TCTP and reducing cell division control protein 42 homolog (Cdc42) activation in the TCTP-positive cell lines NOZ, GBC-SD, OCUG-1 and EH-GB-1 in vitro. Additionally, this was also demonstrated in gallbladder cancer xenograft animal models established using a spleen-to-liver metastasis model in immunodeficient mice (30). Lemke et al (31) revealed that DHA exerted an anti-glioma activity, which included promotion of autophagy and induction of oxidative stress in the glioma cell lines LN-229 and LN-Z308 as well as in the primary T269 glioma cell line.…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with these previous studies, the present study identified that DHA induced autophagy. Despite the presence of numerous studies (28)(29)(30)(31)(32), there is limited knowledge regarding the effect of autophagy on the anticancer action of DHA. The present study revealed the role of autophagy in the anticancer action of DHA within MDA-MB-231 cells.…”

Section: Discussionmentioning

confidence: 99%

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Rapamycin promotes the anticancer action of dihydroartemisinin in breast cancer MDA-MB-231 cells by regulating expression of Atg7 and DAPK

Liu

Zhou

et al. 2018

Oncol Lett

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Abstract. There is limited knowledge regarding the influence of autophagy on the anticancer effect of dihydroartemisinin (DHA). The present study aimed to investigate this influence within human breast cancer cells. Changes in cell viability, cell cycle distribution, apoptosis and associated genes were analyzed in MDA-MB-231 cells subjected to DHA following alteration in autophagy levels; the autophagy level was decreased following autophagy-related 7 (Atg7) knockdown or increased using rapamycin. The data indicated that rapamycin had the ability to notably enhance the anticancer effect of DHA on MDA-MB-231 cells. Autophagy induction may be key in mediating the anticancer effects of DHA, and rapamycin may regulate the death-associated protein kinase via the alteration of Atg7 expression, which would influence cell apoptosis. The present study presented a novel insight into enhancing the effectiveness of future treatment regimens for breast cancer using DHA.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Rapamycin promotes the anticancer action of dihydroartemisinin in breast cancer MDA-MB-231 cells by regulating expression of Atg7 and DAPK

Liu

Zhou

et al. 2018

Oncol Lett

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“…Dihydroartemisinin (DHA), an antimalarial drug derivative from artemisinin, was reported own powerful anticancer effect on numerous kinds of cancers in vitro and in vivo, such as prostate cancer [8], ovarian cancer [9,10], cervical cancer [11], gallbladder cancer [12] and gastric cancer [13]. In esophageal cancer, Jiang and coauthors [14] reported that DHA performed a powerful anticancer effect toward EC cell lines Eca109 and Ec9706 in vitro and in vivo.…”

mentioning

confidence: 99%

Autophagy-dependent cell cycle arrest in esophageal cancer cells exposed to dihydroartemisinin

Liao

Liu

et al. 2020

Chin Med

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Background: Dihydroartemisinin (DHA), a derivate of artemisinin, is an effective antimalarial agent. DHA has been shown to exert anticancer activities to numerous cancer cells in the past few years, while the exact molecular mechanisms remain to be elucidated, especially in esophageal cancer. Methods: Crystal violet assay was conducted to determine the cell viability of human esophageal cancer cell line Eca109 treated with DHA. Tumor-bearing nude mice were employed to evaluate the anticancer effect of DHA in vivo. Soft agar and crystal violet assays were used to measure the tumorigenicity of Eca109 cells. Flow cytometry was performed to evaluate ROS or cell cycle distribution. GFP-LC3 plasmids were delivered into Eca109 cells to visualize autophagy induced by DHA under a fluorescence microscope. The mRNA and protein levels of each gene were tested by qRT-PCR and western blot, respectively. Results: Our results proved that DHA significantly reduced the viability of Eca109 cells in a dose-and time-dependent manner. Further investigation showed that DHA evidently induced cell cycle arrest at the G2/M phase in Eca109 cells. Mechanistically, DHA induced intracellular ROS generation and autophagy in Eca109 cells, while blocking ROS by an antioxidant NAC obviously inhibited autophagy. Furthermore, we found that telomere shelterin component TRF2 was down-regulated in Eca109 cells exposed to DHA through autophagy-dependent degradation, which could be rescued after autophagy was blocked by ROS inhibition. Moreover, the DNA damage response (DDR) was induced obviously in DHA treated cells. To further explore whether ROS or autophagy played a vital role in DHA induced cell cycle arrest, the cell cycle distribution of Eca109 cells was evaluated after ROS or autophagy blocking, and the results showed that autophagy, but not ROS, was essential for cell cycle arrest in DHA treated cells. Conclusion: Taken together, DHA showed anticancer effect on esophageal cancer cells through autophagy-dependent cell cycle arrest at the G2/M phase, which unveiled a novel mechanism of DHA as a chemotherapeutic agent, and the degradation of TRF2 followed by DDR might be responsible for this cell phenotype.

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“…Interestingly, TCTP not only induces multi-malignant cancer phenotypes but also confers chemo-and irradiation-resistance in various types of cancer by regulating oncogenic signaling such as the EGFR-AKT pathway [29][30][31][32] . Thus, clinically applicable agents that could target TCTP, such as dihydroartemisinin (DHA), rapamycin, sertraline, and thioridazine, were suggested to regress cancer [33][34][35][36] . Although the importance of TCTP as a therapeutic target continues to grow, the potential relationship between TCTP and immunotherapeutic resistance and the possibility of TCTP as a novel actionable target for combination strategies to reverse the immunotherapeutic resistance have not been explored.…”

mentioning

confidence: 99%

Targeting TCTP sensitizes tumor to T cell-mediated therapy by reversing immune-refractory phenotypes

Lee¹,

Song²,

Oh³

et al. 2020

Preprint

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Cancer immunotherapy has emerged as a potentially powerful approach to cancer treatment. However, immunotherapeutic resistance limits its clinical application. Therefore, identifying immune-resistant factors, which can be inhibited by clinically available drugs and it also can be a companion diagnostic marker, is needed to develop potential combination strategies. Here, using the transcriptome data of cancer patients treated with anti-PD-L1, and two independent tumor models immune-refractory to immune checkpoint blockade (ICB) and adoptive T cell transfer (ACT) therapy, we identified TCTP as a novel factor conferring immune-refractory phenotypes, including decreased T cell trafficking to the tumor and resistance of tumor cells to cytotoxic T lymphocyte (CTL)-mediated killing. Mechanistically, TCTP activated the EGFR-AKT-MCL-1/CXCL10 pathway by phosphorylation-dependent interaction with Na, K ATPase. Furthermore, by screening the clinical available TCTP-targeting agents, we identified dihydroartemisinin (DHA) as the most effective agent impeding the TCTP-mediated immune-refractoriness. Importantly, treatment with DHA synergized ACT as well as ICB to control immune-refractory tumors. Moreover, the TCTP levels within the tumors significantly correlated with the clinical outcome of anti-PD-L1 therapy. Thus, our findings provide a novel insight that TCTP plays a crucial role in immune-refractory phenotypes, thereby encouraging a rationale for combination therapies to enhance the efficacy of T cell-mediated therapy.

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Dihydroartemisinin inhibits TCTP-dependent metastasis in gallbladder cancer

Cited by 66 publications

References 37 publications

Rapamycin promotes the anticancer action of dihydroartemisinin in breast cancer MDA-MB-231 cells by regulating expression of Atg7 and DAPK

Rapamycin promotes the anticancer action of dihydroartemisinin in breast cancer MDA-MB-231 cells by regulating expression of Atg7 and DAPK

Autophagy-dependent cell cycle arrest in esophageal cancer cells exposed to dihydroartemisinin

Targeting TCTP sensitizes tumor to T cell-mediated therapy by reversing immune-refractory phenotypes

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