<p>β-Elemene Enhances the Chemotherapeutic Effect of 5-Fluorouracil in Triple-Negative Breast Cancer via PI3K/AKT, RAF-MEK-ErK, and NF-κB Signaling Pathways</p>

Abstract

Background:The most common chemotherapeutic drug for triple-negative breast cancer (TNBC) treatment is 5-fluorouracil (5-FU), but its therapeutic index is low due to its toxicity. β-Elemene (ELE) possesses antitumor activity against different cancers, but it has never been used in combination with 5-FU to improve its chemotherapeutic effect against TNBC. Materials and Methods: We treated MDA-MB-231 and BT549 cells of TNBC with ELE alone, 5-FU alone, or their combination to investigate their treatment effects on cell viability, proliferation, migration, invasion, and colony formation. We verified the molecular mechanisms of our results through confocal immunofluorescence, immunohistochemistry, and Western blot analysis in vitro and in vivo. Results: Our result revealed that ELE enhanced the 5-FU effect against cell viability, proliferation, migration, invasion, and colony formation through different mechanisms in MDA-MB-231 and BT549 cell lines. In molecular mechanisms, ELE and 5-FU in combination enhances apoptosis in both cell lines through Bl-2 family protein and caspase cascade modulation, thereby inhibiting NF-kB pathway through IKKβ, IKKα, and p65 downregulation in the cytoplasm and p50 and p65 downregulation in the nucleus. ELE and 5-FU in combination regulated the PI3K/AKT pathway through p-AKT, P-85, p110r, p-PDK1, and p110a protein and RAF-MEK-ERK pathway inhibition through the p-c-raf and p-ERK downregulation. The PI3K inhibitor LY294002 or RAF-MEK-ERK inhibitor U0126 in combination with ELE and 5-FU decreased cell viability in both cell lines significantly, thereby showing the involvement of these pathways in cell apoptosis. In mouse xenograft model, ELE and 5-FU in combination inhibited the tumor growth and modulated its molecular markers. Conclusion:The conclusion obtained, considering that the results suggest that the combination may be important specifically in the treatment of TNBC.

MicroRNA-941 regulates the proliferation of breast cancer cells by altering histone H3 Ser 10 phosphorylation

“…Further studies are required in detail to warrant any conclusion. Fluorouracil (5-FU) is used as a single palliative treatment in combination with other antineoplastic agents for the therapy of breast cancers 69 . According to National Comprehensive Cancer Network guidelines, 5-fluorouracil, epirubicin and cyclophosphamide (FEC) adjuvant chemotherapy regimen is the recommended regimen for breast cancer 70 .…”

An updated review on the potential antineoplastic actions of oleuropein

“…Numerous studies (Ahn, Sethi, & Aggarwal, 2008;Dana, Vaseghi, & Haghjooy Javanmard, 2020;M. Deng, Dai, Yu, Tao, & Lung, 2020;Fu et al, 2020;Ghasemi et al, 2019;Khalil et al, 2020;Monisha et al, 2017;Morgan, Garg, Tergaonkar, Tan, & Sethi, 2020;Su, Ahmad, Zou, & Zou, 2020;Xiaomeng et al, 2020;Zou, Hu, & Jiang, 2020) have confirmed that NF-κB is a key regulator of stress and inflammation, participates in cell proliferation and apoptosis, and is important in signal transduction during tumorigenesis and progression. Oleuropein reduced the expression of nuclear factor-kappa Β (NF-κB) in different tumor models (Elamin et al, 2019;Giner et al, 2016;L.…”

Targeting Thymidylate Synthase Enhances the Chemosensitivity of Triple-Negative Breast Cancer Towards 5-FU-Based Combinatorial Therapy

“…Even though 5-FU is not a key drug in the current clinical scenario of breast cancer chemotherapy, it is used either alone or in combination with other drugs for the successful treatment and management of metastatic breast cancer (50). Recent reports also demonstrate that 5-FU can be used either alone or in combination with other drugs to treat triple negative breast cancer effectively (51,52). Though numerous studies have demonstrated the anticancer potential of curcumin against various cancers, none of the clinical trials conducted using this phytochemical has generated substantial outputs.…”