Abstract
Triple negative breast cancer (TNBC) is a breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expression. TNBC cells respond poorly to targeted chemotherapies currently in use and the mortality rate of TNBC remains high. Therefore, it is necessary to identify new chemotherapeutic agents for TNBC. In this study, the anti-cancer effects of 7-α-hydroxyfrullanolide (7HF), derived from Grangea maderaspatana, on MCF-7, MDA-MB-231 and MDA-MB-468 breast cancer cells were assessed using MTT assay. The mode of action of 7HF in TNBC cells treated with 6, 12 and 24 µM of 7HF was determined by flow cytometry and propidium iodide (PI) staining for cell cycle analysis and annexin V/fluorescein isothiocyanate + PI staining for detecting apoptosis. The molecular mechanism of action of 7HF in TNBC cells was investigated by evaluating protein expression using proteomic techniques and western blotting. Subsequently, 7HF exhibited the strongest anti-TNBC activity toward MDA-MB-468 cells and a concomitantly weak toxicity toward normal breast cells. The molecular mechanism of action of low-dose 7HF in TNBC cells primarily involved G2/M-phase arrest through upregulation of the expression of Bub3, cyclin B1, phosphorylated Cdk1 (Tyr 15) and p53-independent p21. Contrastingly, the upregulation of PP2A-A subunit expression may have modulated the suppression of various cell survival proteins such as p-Akt (Ser 473), FoxO3a and β-catenin. The concurrent apoptotic effect of 7HF on the treated cells was mediated via both intrinsic and extrinsic modes through the upregulation of Bax and active cleaved caspase-7–9 expression and downregulation of Bcl-2 and full-length caspase-7–9 expression. Notably, the proteomic approach revealed the upregulation of the expression of pivotal protein clusters associated with G1/S-phase arrest, G2/M-phase transition and apoptosis. Thus, 7HF exhibits promising anti-TNBC activity and at a low dose, it modulates signal transduction associated with G2/M-phase arrest and apoptosis.
Highlights
GLOBOCAN 2020 recently reported that female breast cancer is the most common diagnosis (2.3 million new cases) and the fifth leading cause of cancer mortality (0.68 million cases) worldwide [1,2]
Evaluation of the cytotoxicity of 7HF against various breast cancer cell lines at 72 h yielded a series of inhibitory concentrations (ICs): IC20, IC50 and IC90 (Table 1)
The inhibitory effects were observed in Molecules 2022, 27, 407 toxicity at IC50 was used for selecting the doses for subsequent experiments
Summary
GLOBOCAN 2020 recently reported that female breast cancer is the most common diagnosis (2.3 million new cases) and the fifth leading cause of cancer mortality (0.68 million cases) worldwide [1,2]. Triple negative breast cancer (TNBC) accounts for 15–20% of total breast cancer cases worldwide [3,4,5,6,7]. The treatment of patients with TNBC using various standard systematic drugs such as anthracyclines, taxanes and platinum agents has yielded satisfactory results; low survival, high rate of relapse, high risk of secondary cancers and strong adverse effects remain serious concerns [8,9,10,11]. Several chemotherapeutic agents derived from terrestrial plants such as taxanes and vinca alkaloids, which contain active compounds, are currently being used for cancer treatment [12,13]. Studies on the identification and development of potential therapeutic drugs from plant sources are continuously being conducted to develop new TNBC treatments
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