Artesunate acts as fuel to fire in sensitizing HepG2 cells towards TRAIL mediated apoptosis via STAT3 inhibition and DR4 augmentation

Ilamathi, M.; Sivaramakrishnan, V.

doi:10.1016/j.biopha.2017.01.086

Cited by 20 publications

(9 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…STAT3 is a transcription factor that plays critical roles in HCC [ 32 ]. Several studies have shown that blocking STAT3 sensitizes cancer cells to apoptotic stimuli [ 33 , 34 ]. To explore the effect of CK on STAT3 in HCC, we detected STAT3 and p-STAT3 (Tyr705) levels in several HCC cell lines following CK treatment.…”

Section: Discussionmentioning

confidence: 99%

Compound K Induces Endoplasmic Reticulum Stress and Apoptosis in Human Liver Cancer Cells by Regulating STAT3

Zhang

Sun

et al. 2018

Molecules

View full text Add to dashboard Cite

The ginsenoside compound K (20-O-β-d-glucopyranosyl-20(S)-protopanaxadiol; CK) is an intestinal bacterial metabolite of ginseng protopanaxadiol saponin that has been reported to induce apoptosis in many cancer cells; however, the precise mechanisms of its activity in human hepatocellular carcinoma (HCC) cells remain unclear. Herein, we demonstrated that CK inhibited the growth and colony formation of HepG2 and SMMC-7721 cells, phenotypes that were mediated by inducing apoptosis. Meanwhile, CK showed lower toxicity in normal hepatoma cells. After treating HepG2 and SMMC-7721 cells with CK, p-STAT3 levels decreased, the three branches of the unfolded protein response were activated, and levels of endoplasmic reticulum stress (ERS)-related proteins were increased. We also revealed that CK decreased the DNA-binding capacity of STAT3. Moreover, silencing STAT3 with CRISPR/Cas9 technology enhanced CK-induced ERS and apoptosis. Finally, we showed that CK inhibited the growth of liver cancer xenografts with little toxicity. Mice bearing human HCC xenografts that were treated with CK showed increased GRP78 expression and decreased p-STAT3 levels. Taken together, these data showed that CK induced ERS and apoptosis by inhibiting p-STAT3 in human liver cancer cells; thus, CK might be a potential therapeutic candidate for human HCC.

show abstract

Section: Discussionmentioning

confidence: 99%

Compound K Induces Endoplasmic Reticulum Stress and Apoptosis in Human Liver Cancer Cells by Regulating STAT3

Zhang

Sun

et al. 2018

Molecules

View full text Add to dashboard Cite

show abstract

“…As the most potent and rapidly acting antimalarial agents, artemisinin and its derivatives have been well tested in human bodies-better still, the usage and adverse reactions have been fully established. At the same time, multiple studies show artemisinin's anti-cancer properties and the possibility of overcoming TRAIL resistance in different cancer cell lines [20,21,42]. In this research, we found that ATS/DHA has even better anti-cancer activity compared to ART.…”

Section: Discussionmentioning

confidence: 53%

Artemisinin Derivatives Stimulate DR5-Specific TRAIL-Induced Apoptosis by Regulating Wildtype P53

Zhou

Zijlstra

Soto-Gamez

et al. 2020

Cancers

View full text Add to dashboard Cite

Artemisinin derivatives, widely known as commercial anti-malaria drugs, may also have huge potential in treating cancer cells. It has been reported that artemisinin derivatives can overcome resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in liver and cervical cancer cells. In our study, we demonstrated that artesunate (ATS) and dihydroartemisinin (DHA) are more efficient in killing colon cancer cells compared to artemisinin (ART). ATS/DHA induces the expression of DR5 in a P53 dependent manner in HCT116 and DLD-1 cells. Both ATS and DHA overcome the resistance to DHER-induced apoptosis in HCT116, mainly through upregulating death receptor 5 (DR5). We also demonstrate that DHA sensitizes HCT116 cells to DHER-induced apoptosis via P53 regulated DR5 expression in P53 knockdown assays. Nevertheless, a lower effect was observed in DLD-1 cells, which has a single Ser241Phe mutation in the P53 DNA binding domain. Thus, the status of P53 could be one of the determinants of TRAIL resistance in some cancer cells. Finally, the combination treatment of DHA and the TRAIL variant DHER increases cell death in 3D colon cancer spheroid models, which shows its potential as a novel therapy.

show abstract

“…The number of caspase 8 + , caspase 9 + and cytochrome c + cells was significantly upregulated after incubation with ARS ( Figure 3). The mechanisms by which ARS induces apoptosis in tumor cells have been extensively investigated (Beccafico et al, 2015;Ilamathi & Sivaramakrishnan, 2017). In contrast, the mechanisms involved in programmed cell death triggered by ARS in normal control cells is considerably less known (Cheng et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Both reactive oxygen species (ROS)-dependent and ROS-independent apoptosis were reported to occur after ARS exposure in several kinds of tumor cells (Ba et al, 2012;Greenshields et al, 2017;Pang et al, 2016;Qin et al, 2015). Likewise, both caspase-dependent and caspaseindependent mechanisms of apoptotic cell death were observed to happen in cancer cell lines subjected to ARS treatment (Greenshields et al, 2017;Ilamathi & Sivaramakrishnan, 2017;Li et al, 2017;Papanikolaou et al, 2014). Additionally, ARS triggers cell death mechanisms other than apoptosis, such as necrosis, autophagy, oncosis and ferroptosis, which might be coupled with elevated ROS production (Berdelle et al, 2011;Chen et al, 2014;Du, Zhang, Ma, & Ji, 2010;Eling, Reuter, Hazin, & Hamacher-brady, 2015;Greenshields et al, 2017;Roh et al, 2017).…”

mentioning

confidence: 99%

Markers of oxidative‐nitrosative stress induced by artesunate are followed by clastogenic and aneugenic effects and apoptosis in human lymphocytes

Mota

Garcia

Bonfim

et al. 2019

J of Applied Toxicology

View full text Add to dashboard Cite

Artesunate (ARS) is a semi‐synthetic derivative of artemisinin, used as an outstanding antimalarial drug, which also displays antitumor, anti‐inflammatory and immunosuppressive effects. In spite of the numerous reports showing the antitumor activity of ARS, the particular mechanisms associated with its cytotoxicity and genotoxicity in non‐neoplastic human cells remain unclear. Here we aimed to verify the specific chromosome damages and the changes in markers of oxidative‐nitrosative stress and apoptosis triggered by ARS exposure in human peripheral blood lymphocytes. Cultures were incubated in the presence of ARS and the number of binucleated cells was determined. To discriminate between micronuclei (MN) containing a whole chromosome or an acentric chromosome, the MN test was employed in combination with the fluorescence in situ hybridization assay. Alterations in the levels of superoxide anion (O2−) and nitric oxide (NO) were measured by the nitroblue tetrazolium and Griess assay, respectively. Changes in the expression of the apoptotic markers were assessed by immunocytochemistry. We found that ARS induced a significant formation of both centromere‐positive MN (C+ MN) and centromere‐negative MN (C– MN). These alterations were accompanied by an increase in both cellular levels of O2− and total NO production, and a remarkable enhancement in the expression of the apoptotic markers cytochrome c and caspases 8 and 9. Together these findings reveal that ARS induces changes in the oxidative‐nitrosative status of human lymphocytes, which are followed by apoptosis and clastogenic and aneugenic effects.

show abstract

Artesunate acts as fuel to fire in sensitizing HepG2 cells towards TRAIL mediated apoptosis via STAT3 inhibition and DR4 augmentation

Cited by 20 publications

References 14 publications

Compound K Induces Endoplasmic Reticulum Stress and Apoptosis in Human Liver Cancer Cells by Regulating STAT3

Compound K Induces Endoplasmic Reticulum Stress and Apoptosis in Human Liver Cancer Cells by Regulating STAT3

Artemisinin Derivatives Stimulate DR5-Specific TRAIL-Induced Apoptosis by Regulating Wildtype P53

Markers of oxidative‐nitrosative stress induced by artesunate are followed by clastogenic and aneugenic effects and apoptosis in human lymphocytes

Contact Info

Product

Resources

About