Dataset Information

Naringenin Enhances the Anti-Cancer Effect of Cyclophosphamide against MDA-MB-231 Breast Cancer Cells Via Targeting the STAT3 Signaling Pathway.

ABSTRACT: Naringenin is a natural compound with potential anti-cancer effects against several cancer types. Also, its precise molecular mechanisms regarding tumor growth suppression has not been completely elucidated. In the current study the apoptosis-inducing and anti-proliferative effects of Naringenin together with cyclophosphamide were studied in breast cancer cells and the participation of JAK2/STAT3 pathway was investigated. In this regard, MDA-MB-231 breast cancer cells were cultured and hence, treated with different concentrations of Naringenin. Apoptosis was measured via flowcytometric analysis of annexin V binding and cell viability was assessed via MTT assay. Protein and gene expression were investigated via Western blotting and real-time PCR, respectively. The function of caspase enzymes were also assessed. The results exhibited that Naringenin triggered apoptosis and markedly decreased cell viability. Furthermore its coadministration with cyclophosphamide improved its anti-tumor properties. Moreover, Naringenin up-regulated the expression of BAX while decreased the expression of Bcl-2. Caspases 3 and 9 were activated by Naringenin, an influence, which was augmented via cyclophosphamide. Docking studies revealed an interaction between Naringenin and STAT3 that was confirmed via attenuation of STAT3 phosphorylation subsequent to treating the cells with Naringenin. Furthermore, Naringenin exhibited the capacity to suppress the function of IL-6 in modulating apoptosis-associated genes expression. Overall, these results indicated that a Naringenin- cyclophosphamide combination impairs proliferation signaling and induces apoptosis to a greater extent than either compound alone and can serve as a potent chemotherapeutic regimen for breast cancer treatment.

SUBMITTER: Noori S

PROVIDER: S-EPMC7757999 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Naringenin Enhances the Anti-Cancer Effect of Cyclophosphamide against MDA-MB-231 Breast Cancer Cells Via Targeting the STAT3 Signaling Pathway.

Noori Shokoofe S Rezaei Tavirani Mostafa M Deravi Niloofar N Mahboobi Rabbani Mohammad Ismaiil MI Zarghi Afshin A

Iranian journal of pharmaceutical research : IJPR 20200101 3

Naringenin is a natural compound with potential anti-cancer effects against several cancer types. Also, its precise molecular mechanisms regarding tumor growth suppression has not been completely elucidated. In the current study the apoptosis-inducing and anti-proliferative effects of Naringenin together with cyclophosphamide were studied in breast cancer cells and the participation of JAK2/STAT3 pathway was investigated. In this regard, MDA-MB-231 breast cancer cells were cultured and hence, tr ...[more]

PMID: 33680016

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Project description:The receptor tyrosine kinase, anexelekto (Axl) is involved in tumor cell growth, migration and invasion, and has been associated with chemotherapy resistance, which makes it an attractive target for cancer therapy. In total, six Axl-targeted monoclonal antibodies (mAbs) and two antibody-drug conjugates have been reported in the last 10 years, which have been shown to have bioactivity in inhibiting tumor cell proliferation and migration. The Axl external cell domain (Axl-ECD), consisting of 426 amino acids, has always been used as an antigen in the screening process for all six of these Axl-targeted mAbs. However, the Axl functional domain, which interacts with its natural ligand, growth arrest-specific protein 6 (Gas6), is only a small part of the Axl-ECD. Antibodies targeting the Axl functional domain may efficiently block Gas6-Axl binding and attenuate its downstream signals and activities. To the best of our knowledge, no mAbs targeting the Axl functional domain have been reported. In the present study, a major Axl functional domain interacting with Gas6 was determined using bioinformatics and structural biology methods. In MDA-MB-231 breast cancer cell assays, anti-Axl mAbs targeting this relatively specific Axl functional domain almost completely neutralized the stimulation of Gas6 in both Axl phosphorylation and cell migration assays, and showed similar activity to the positive control drug R428 (a small molecular tyrosine kinase inhibitor of Axl currently in phase II clinical trials) in the cell migration assay. Given the important role of Axl in tumor development and chemotherapy resistance, Axl-targeted mAbs could be used to inhibit tumor cells directly, as well as reduce the development of chemotherapy resistance by blocking Axl activity. The application of Axl-targeted mAbs combined with chemotherapy provides a promising treatment strategy for patients with tumors, particularly those with triple-negative breast cancer, for whom no targeted therapy is currently available.

Project description:Epidemiological studies indicate that metformin, a widely used type 2 diabetes drug, might reduce breast cancer risk and mortality in patients with type 2 diabetes. Metformin might protect against breast cancer indirectly by ameliorating systemic glucose homeostasis. Alternatively, it might target breast cancer cells directly. However, experiments using MDA-MB-231 cells, a standard in vitro breast cancer model, produced inconsistent results regarding effectiveness of metformin as a direct anti-cancer agent. Metformin treatments in cultured MDA-MB-231 cells are usually performed for 48-96 hours, but protocols describing renewal of cell culture medium during these prolonged treatments are rarely reported. We determined whether medium renewal protocol might alter sensitivity of MDA-MB-231 cells treated with metformin. Using the MTS assay, BrdU incorporation and Hoechst staining we found that treatment with metformin for 48-72 hours failed to suppress viability and proliferation of MDA-MB-231 cells if low-glucose (1 g/L) medium was renewed every 24 hours. Conversely, metformin suppressed their viability and proliferation if medium was not renewed. Without renewal glucose concentration in the medium was reduced to 0.1 g/L in 72 hours, which likely explains increased sensitivity to metformin under these conditions. We also examined whether 2-deoxy-D-glucose (2-DG) reduces resistance to metformin. In the presence of 2-DG metformin reduced viability and proliferation of MDA-MB-231 cells with or without medium renewal, thus demonstrating that 2-DG reduces their resistance to metformin. In sum, we show that medium renewal blocks anti-proliferative effects of metformin during prolonged treatments in low-glucose medium. Differences in medium renewal protocols during prolonged treatments might therefore lead to apparently inconsistent results as regards effectiveness of metformin as a direct anti-cancer agent. Finally, our results indicate that co-therapy with 2-DG and metformin might provide an effective strategy to overcome metformin resistance of breast cancer cells.

Dataset Information

Naringenin Enhances the Anti-Cancer Effect of Cyclophosphamide against MDA-MB-231 Breast Cancer Cells Via Targeting the STAT3 Signaling Pathway.

Publications

Naringenin Enhances the Anti-Cancer Effect of Cyclophosphamide against MDA-MB-231 Breast Cancer Cells Via Targeting the STAT3 Signaling Pathway.

Similar Datasets

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