Anti-cancer effect of metformin on the metastasis and invasion of primary breast cancer cells through mediating NF-kB activity

Yenmiş, Güven; Saraç, Elif Yaprak; Besli, Nail; Soydaş, Tuğba; Taştan, Cihan; Kançağı, Derya Dilek; Yılancı, Muhammet; Şenol, Kazım; Karagülle, Onur Olgaç; Ekmekçi, Cumhur Gökhan; Ovalı, Ercüment; Tunçdemi̇r, Matem; Ulutin, Turgut; Sultuybek, Gönül Kanıgür

doi:10.1016/j.acthis.2021.151709

Cited by 29 publications

(19 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… Sethi et al, 2008 have found that TQ inhibited NF-κB in CML cells in experiments with incubation times up to 6 h ( Sethi et al, 2008 ). Metformin have shown an NF-κB inhibitory activity in various cancer cells ( Nguyen et al, 2019 ; Sultuybek et al, 2019 ; Yenmis et al, 2021 ). However, there are controversial results regarding metformin activity against phosphorylation of Akt in leukemia cells and this activity might depend on the mitochondrial energetic status and basal levels of Akt in each cell line tested ( Scotland et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Metformin and Thymoquinone Synergistically Inhibit Proliferation of Imatinib-Resistant Human Leukemic Cells

et al. 2022

View full text Add to dashboard Cite

Chemotherapy resistance is one of the major challenges in cancer treatment, including leukemia. A massive array of research is evaluating combinations of drugs directed against different intracellular signaling molecules to overcome cancer resistance, increase therapy effectiveness, and decrease its adverse effects. Combining chemicals with proven safety profiles, such as drugs already used in therapy and active substances isolated from natural sources, could potentially have superior effects compared to monotherapies. In this study, we evaluated the effects of metformin and thymoquinone (TQ) as monotherapy and combinatorial treatments in chronic myeloid leukemia (CML) cell lines sensitive and resistant to imatinib therapy. The effects were also evaluated in primary monocytic acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) cells. Both compounds induced a dose- and time-dependent decrease of viability and proliferation in tested cells. Metformin had similar IC50 values in imatinib-sensitive and imatinib-resistant cell lines. IC50 values of TQ were significantly higher in imatinib-resistant cells, but with a limited resistance index (2.4). Synergistic effects of combinatorial treatments were observed in all tested cell lines, as well as in primary cells. The strongest synergistic effects were observed in the inhibition of imatinib-resistant cell line proliferation. Metformin and TQ inhibited the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and induced apoptosis in tested cell lines and primary cells. The enhanced effects of combinatorial treatments on the induction of apoptosis were more dominant in imatinib-resistant compared to imatinib-sensitive CML cells. Primary cells were more sensitive to combinatorial treatments compared to cell lines. A combination of 1.25 mM metformin and 0.625 µM TQ increased the levels of cleaved poly (ADP-ribose) polymerase (PARP), decreased the levels of proliferation regulatory proteins, and inhibited protein kinase B (Akt) and NF-κB signaling in primary CLL cells. This study demonstrates that combinatorial treatments of imatinib-resistant malignant clones with metformin and TQ by complementary intracellular multi-targeting represents a promising approach in future studies.

show abstract

Section: Discussionmentioning

confidence: 99%

Metformin and Thymoquinone Synergistically Inhibit Proliferation of Imatinib-Resistant Human Leukemic Cells

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The NF-κB pathway plays an important role in a variety of cellular functions, including cell growth, apoptosis, and tumorigenesis ( Hwang et al, 2012 ). Interfering with NF-κB signaling can inhibit tumor cell proliferation and metastasis ( Yenmis et al, 2021 ). Therefore, NF-κB inhibitors are considered as potential anticancer drugs ( Wang et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of anticancer activity of quillaic acid derivatives: A cell cycle arrest and apoptosis inducer through NF-κB and MAPK pathways

et al. 2022

View full text Add to dashboard Cite

A series of quillaic acid derivatives with different substituents on the 28-carboxyl group were designed and synthesized. Five human cancer cell lines (HCT116, BEL7402, HepG2, SW620, and MCF-7) were evaluated for their antitumor activity in vitro. Some of the tested derivatives showed improved antiproliferative activity compared to the lead compound, quillaic acid. Among them, compound E (IC50 = 2.46 ± 0.44 μM) showed the strongest antiproliferative activity against HCT116 cells; compared with quillaic acid (IC50 > 10 μM), its efficacy against HCT116 cancer cells was approximately 4-fold higher than that of quillaic acid. Compound E also induces cell cycle arrest and apoptosis by modulating NF-κB and MAPK pathways. Therefore, the development of compound E is certainly valuable for anti-tumor applications.

show abstract

“…The biguanide metformin, an inhibitor of gluconeogenesis 12 – 14 and the most prescribed diabetes drug worldwide 15 , has been by far the most popular antihyperglycemic approach used for cancer. At supra-pharmacologic doses – several orders of magnitude higher than in human patients – metformin is capable of reducing breast cancer cell proliferation 16 – 19 , and slowing tumor growth in vivo in rodents 20 – 22 . Metformin is safe and shows good target engagement in women with breast cancer.…”

Section: Introductionmentioning

confidence: 99%

A precision medicine approach to metabolic therapy for breast cancer in mice

et al. 2022

View full text Add to dashboard Cite

Increasing evidence highlights approaches targeting metabolism as potential adjuvants to cancer therapy. Sodium-glucose transport protein 2 (SGLT2) inhibitors are the newest class of antihyperglycemic drugs. To our knowledge, SGLT2 inhibitors have not been applied in the neoadjuvant setting as a precision medicine approach for this devastating disease. Here, we treat lean breast tumor-bearing mice with the SGLT2 inhibitor dapagliflozin as monotherapy and in combination with paclitaxel chemotherapy. We show that dapagliflozin enhances the efficacy of paclitaxel, reducing tumor glucose uptake and prolonging survival. Further, the ability of dapagliflozin to enhance the efficacy of chemotherapy correlates with its effect to reduce circulating insulin in some but not all breast tumors. Our data suggest a genetic signature for breast tumors more likely to respond to dapagliflozin in combination with paclitaxel. In the current study, tumors driven by mutations upstream of canonical insulin signaling pathways responded to this combined treatment, whereas tumors driven by mutations downstream of canonical insulin signaling did not. These data demonstrate that dapagliflozin enhances the response to chemotherapy in mice with breast cancer and suggest that patients with driver mutations upstream of canonical insulin signaling may be most likely to benefit from this neoadjuvant approach.

show abstract

Anti-cancer effect of metformin on the metastasis and invasion of primary breast cancer cells through mediating NF-kB activity

Cited by 29 publications

References 38 publications

Metformin and Thymoquinone Synergistically Inhibit Proliferation of Imatinib-Resistant Human Leukemic Cells

Metformin and Thymoquinone Synergistically Inhibit Proliferation of Imatinib-Resistant Human Leukemic Cells

Synthesis and evaluation of anticancer activity of quillaic acid derivatives: A cell cycle arrest and apoptosis inducer through NF-κB and MAPK pathways

A precision medicine approach to metabolic therapy for breast cancer in mice

Contact Info

Product

Resources

About