scholarly journals Triclabendazole Induces Pyroptosis by Activating Caspase-3 to Cleave GSDME in Breast Cancer Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Liang Yan ◽  
Yi Liu ◽  
Xue-feng Ma ◽  
Dan Hou ◽  
Yu-hui Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Caspase 3 ◽  
Xenograft Model ◽  
Specific Inhibitor ◽  
Apoptotic Pathway ◽  
Mitochondrial Apoptotic Pathway ◽  
Protein Levels

Pyroptosis is a form of programmed cell death, in which gasdermin E (GSDME) plays an important role in cancer cells, which can be induced by activated caspase-3 on apoptotic stimulation. Triclabendazole is a new type of imidazole in fluke resistance and has been approved by the FDA for the treatment of fascioliasis and its functions partially acting through apoptosis-related mechanisms. However, it remains unclear whether triclabendazole has obvious anti-cancer effects on breast cancer cells. In this study, to test the function of triclabendazole on breast cancer, we treated breast cancer cells with triclabendazole and found that triclabendazole induced lytic cell death in MCF-7 and MDA-MB-231, and the dying cells became swollen with evident large bubbles, a typical sign of pyroptosis. Triclabendazole activates apoptosis by regulating the apoptoic protein levels including Bax, Bcl-2, and enhanced cleavage of caspase-8/9/3/7 and PARP. In addition, enhanced cleavage of GSDME was also observed, which indicates the secondary necrosis/pyroptosis is further induced by active caspase-3. Consistent with this, triclabendazole-induced GSDME–N-terminal fragment cleavage and pyroptosis were reduced by caspase-3–specific inhibitor (Ac-DEVD-CHO) treatment. Moreover, triclabendazole induced reactive oxygen species (ROS) elevation and increased JNK phosphorylation and lytic cell death, which could be rescued by the ROS scavenger (NAC), suggesting that triclabendazole-induced GSDME-dependent pyroptosis is related to the ROS/JNK/Bax-mitochondrial apoptotic pathway. Besides, we showed that triclabendazole significantly reduced the tumor volume by promoting the cleavage of caspase-3, PARP, and GSDME in the xenograft model. Altogether, our results revealed that triclabendazole induces GSDME-dependent pyroptosis by caspase-3 activation at least partly through augmenting the ROS/JNK/Bax-mitochondrial apoptotic pathway, providing insights into this on-the-market drug in its potential new application in cancer treatment.

scholarly journals Betulin Sulfonamides as Carbonic Anhydrase Inhibitors and Anticancer Agents in Breast Cancer Cells

2021 ◽  
Vol 22 (16) ◽  
pp. 8808
Author(s):  
Antje Güttler ◽  
Yvonne Eiselt ◽  
Anne Funtan ◽  
Andreas Thiel ◽  
Marina Petrenko ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Carbonic Anhydrase ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Breast Cancer Cells ◽  
Clonogenic Survival ◽  
Breast Cancer Cell Lines ◽  
Protein Levels ◽  
Ca Ix

Hypoxia-regulated protein carbonic anhydrase IX (CA IX) is up-regulated in different tumor entities and correlated with poor prognosis in breast cancer patients. Due to the radio- and chemotherapy resistance of solid hypoxic tumors, derivatives of betulinic acid (BA), a natural compound with anticancer properties, seem to be promising to benefit these cancer patients. We synthesized new betulin sulfonamides and determined their cytotoxicity in different breast cancer cell lines. Additionally, we investigated their effects on clonogenic survival, cell death, extracellular pH, HIF-1α, CA IX and CA XII protein levels and radiosensitivity. Our study revealed that cytotoxicity increased after treatment with the betulin sulfonamides compared to BA or their precursors, especially in triple-negative breast cancer (TNBC) cells. CA IX activity as well as CA IX and CA XII protein levels were reduced by the betulin sulfonamides. We observed elevated inhibitory efficiency against protumorigenic processes such as proliferation and clonogenic survival and the promotion of cell death and radiosensitivity compared to the precursor derivatives. In particular, TNBC cells showed benefit from the addition of sulfonamides onto BA and revealed that betulin sulfonamides are promising compounds to treat more aggressive breast cancers, or are at the same level against less aggressive breast cancer cells.

scholarly journals Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Barbara Schroeder ◽  
Travis Vander Steen ◽  
Ingrid Espinoza ◽  
Chandra M. Kurapaty Venkatapoorna ◽  
Zeng Hu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Fatty Acid ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Fatty Acid Synthase ◽  
Xenograft Model ◽  
Fine Tuning ◽  
Bh3 Mimetic

AbstractInhibitors of the lipogenic enzyme fatty acid synthase (FASN) have attracted much attention in the last decade as potential targeted cancer therapies. However, little is known about the molecular determinants of cancer cell sensitivity to FASN inhibitors (FASNis), which is a major roadblock to their therapeutic application. Here, we find that pharmacological starvation of endogenously produced FAs is a previously unrecognized metabolic stress that heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors. Evaluation of the death decision circuits controlled by the BCL-2 family of proteins revealed that FASN inhibition is accompanied by the upregulation of the pro-death BH3-only proteins BIM, PUMA, and NOXA. Cell death triggered by FASN inhibition, which causally involves a palmitate/NADPH-related redox imbalance, is markedly diminished by concurrent loss of BIM or PUMA, suggesting that FASN activity controls cancer cell survival by fine-tuning the BH3 only proteins-dependent mitochondrial threshold for apoptosis. FASN inhibition results in a heightened mitochondrial apoptosis priming, shifting cells toward a primed-for-death state “addicted” to the anti-apoptotic protein BCL-2. Accordingly, co-administration of a FASNi synergistically augments the apoptosis-inducing activity of the dual BCL-XL/BCL-2 inhibitor ABT-263 (navitoclax) and the BCL-2 specific BH3-mimetic ABT-199 (venetoclax). FASN inhibition, however, fails to sensitize breast cancer cells to MCL-1- and BCL-XL-selective inhibitors such as S63845 and A1331852. A human breast cancer xenograft model evidenced that oral administration of the only clinically available FASNi drastically sensitizes FASN-addicted breast tumors to ineffective single-agents navitoclax and venetoclax in vivo. In summary, a novel FASN-driven facet of the mitochondrial priming mechanistically links the redox-buffering mechanism of FASN activity to the intrinsic apoptotic threshold in breast cancer cells. Combining next-generation FASNis with BCL-2-specific BH3 mimetics that directly activate the apoptotic machinery might generate more potent and longer-lasting antitumor responses in a clinical setting.

scholarly journals Transcriptome Investigation and In Vitro Verification of Curcumin-Induced HO-1 as a Feature of Ferroptosis in Breast Cancer Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-18
Author(s):  
Ruihua Li ◽  
Jing Zhang ◽  
Yongfeng Zhou ◽  
Qi Gao ◽  
Rui Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Group Treatment ◽  
Breast Cancer Cells ◽  
Target Genes ◽  
Specific Inhibitor ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Intracellular Iron

Ferroptosis is a form of oxidative cell death and has become a chemotherapeutic target for cancer treatment. Curcumin (CUR), a well-known cancer inhibitor, significantly inhibits the viability of breast cancer cells. Through transcriptomic analysis and flow cytometry experiments, it was found that after 48 hours of treatment of breast cancer cells at its half maximal inhibitory concentration (IC50), curcumin suppressed the viability of cancer cells via induction of ferroptotic death. Use of the ferroptosis inhibitor ferrostatin-1 and the iron chelator deferoxamine rescued cell death induced by curcumin. Furthermore, in subsequent cell validation experiments, the results showed that curcumin caused marked accumulation of intracellular iron, reactive oxygen species, lipid peroxides, and malondialdehyde, while glutathione levels were significantly downregulated. These changes are all manifestations of ferroptosis. Curcumin upregulates a variety of ferroptosis target genes related to redox regulation, especially heme oxygenase-1 (HO-1). Using the specific inhibitor zinc protoporphyrin 9 (ZnPP) to confirm the above experimental results showed that compared to the curcumin treatment group, treatment with ZnPP not only significantly improved cell viability but also reduced the accumulation of intracellular iron ions and other ferroptosis-related phenomena. Therefore, these data demonstrate that curcumin triggers the molecular and cytological characteristics of ferroptosis in breast cancer cells, and HO-1 promotes curcumin-induced ferroptosis.

scholarly journals Curcumin as an Anti-Proliferative Agent in Breast Cancer through RASSF1A, Bax, and Caspase-3 Protein

2021 ◽  
Vol 2 (1) ◽  
pp. 19-27
Author(s):  
Nunung Ainur Rahma ◽  
Harliansyah ◽  
Fransiscus D. Suyatna ◽  
Mpu Kanoko ◽  
Primariadewi Rustamadji ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Caspase 3 ◽  
Cell Types ◽  
Specific Mechanism ◽  
Protein Levels ◽  
Bax Protein ◽  
The Relationship ◽  
Apoptotic Mechanism

Introduction: Curcumin is a polyphenol that has pharmacological activity that can inhibit tumor cell growth and induce apoptosis through various mechanisms. However, the specific mechanism of curcumin cytotoxicity remains controversial because of many anti- and pro-apoptotic signaling pathways in various cell types. This study aims to examine the relationship among curcumin on RASSF1A, Bax protein levels, and caspase-3 activity in supporting the apoptotic mechanism in CSA03 breast cancer cells. Method: Curcumin administration to cancer cells is based on differences in dosage with 24-hour incubation. Cytotoxicity after curcumin administration was determined using MTS. RASSF1A and Bax protein levels were tested through ELISA. Caspase-3 activity was used to determine apoptosis and was tested using flow cytometry. Results: The results indicated that curcumin had a cytotoxicity effect of 40.85 µg/mL. At concentrations of 40 µg/mL and 50 µg/mL, curcumin increases levels of protein RASSF1A (∆ = 26.53% and 47.35%, respectively), Bax (∆ = 48.79% and 386.15%), and caspase-3 (∆ = 1,678.51% and 1,871.889%) significantly. Conclusions: Curcumin exhibits anti-proliferative activity and apoptotic (Caspase-3) effects through activation of RASSF1A and Bax.

scholarly journals The Anticancer Activity of Cetraria Islandica (L.) Ach in Breast Cancer Cells Through Crosstalk of Ampk-α1 and Erk1/2 Signalling

2018 ◽  
Vol 6 (6) ◽  
pp. 783
Author(s):  
Celal Güven ◽  
Eylem Taskın ◽  
Onder Yumtutas ◽  
Leyla Turker Sener ◽  
Yusuf Ozay ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Viability ◽  
Cancer Cells ◽  
Protein Level ◽  
Breast Cancer Cells ◽  
Caspase 3 ◽  
Breast Cancer Cell Lines ◽  
High Dose ◽  
Protein Levels ◽  
Mcf 7

In the present study, we aimed to evaluate the anticancer activities of Cetraria islandica (C.islandica) extracts on MCF-7 breast cancer cell lines. Cell viability, protein levels, apoptotic cells number, F-actin distribution were measured. Cell viability of MCF-7 breast cancer cells was found to be reduced in a dose-dependent manner.EC50 values of C.islandica on MCF-7 cells were found to be 9.2047 E-5 g/ml (cell amount) by using intelligence system. Expressions of p53, caspase 3 and Bcl-2, were shown to be elevated after low doses of extract and diminished after high dose treatments. PPAR- protein level was decreased, although AMP-activated kinases-α1 (AMPK-α1) protein level was increasedin its extract groups. ERK1/2 protein level was also elevated in its extract groups. 125 mg/ml of extract treated cells show a low decrease in actin filament density. MCF-7 cells with C.islandica treatment for 24 h increased the apoptotic cell percentage, though the cells-treated with C.islandica for 48 was high necrotic cells percentage. Consequently, the C.islandica extract treatment causes to elevate ERK1/2 and AMPK-α1 protein levels, resulting in PPAR- and then triggers the apoptosis by modulation caspase-3 and P53 protein levels. Therefore, C.islandica might be a good candidate for anticancer tissue, especially soft tissue tumours.

Recombinant human PDCD5 protein enhances chemosensitivity of breast cancer in vitro and in vivo

2013 ◽  
Vol 91 (6) ◽  
pp. 526-531 ◽  
Author(s):  
Lanlan Wang ◽  
Changjun Wang ◽  
Bingnan Su ◽  
Quansheng Song ◽  
Yingmei Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Intraperitoneal Administration ◽  
Xenograft Model ◽  
Cell Types ◽  
Antitumor Effects ◽  
Protein Levels

Resistance to paclitaxel is common for treatment of breast cancer. Programmed cell death 5 (PDCD5) accelerates apoptosis in different cell types in response to various stimuli; moreover PDCD5 has been shown to be down-regulated in many tumors. In this study, protein levels of PDCD5 were found to be up-regulated in paclitaxel-treated MDA-MB-231 breast cancer cells. MTT, CCK-8, and clonogenic assays have shown that recombinant human PDCD5 (rhPDCD5) alone could not produce an obvious growth inhibition. However, upon paclitaxel triggering apoptosis, rhPDCD5 protein potentiated chemotherapeutic drugs-induced growth arrest in MDA-MB-231, SK-BR-3, and ZR-75-1 breast cancer cells. In vivo, we use a human breast cancer xenograft model to study. We found that rhPDCD5 dramatically improves the antitumor effects of paclitaxel treatment by intraperitoneal administration. These data suggest that rhPDCD5 has the potential to use as a therapeutic agent to enhance the paclitaxel sensitivity of breast cancer cells.

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