(Z)-6-6--7-3-a-Diligustilide and Breast-Neoplasms

Breast cancer (BC) is the leading female malignancy, with one million new cases diagnosed worldwide per year. However, the current treatment options for BC patients have difficulty achieving satisfactory efficacy. Ferroptosis is a new mode of regulated cell death that plays a key role in the inhibition of tumorigenesis. Levistilide A (LA), as an active compound extracted from Chuanxiong Rhizoma, might prevent the development of tumors by regulating the critical cellular processes of ferroptosis.. In this study, the underlying mechanisms of LA on ferroptosis in BC were explored in vitro. The effect of LA on the viability and mitochondrial function of BC cells was determined. Moreover, the effect of LA on the expression levels of key molecules involved in ferroptosis and the nuclear factor erythroid-2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway was evaluated.. LA significantly reduced cell viability and damaged the mitochondrial structure and function of BC cells in a dose-dependent manner. Furthermore, LA treatment markedly enhanced reactive oxygen species (ROS)-induced ferroptosis by activating the Nrf2/HO-1 signaling pathway.. These findings suggest that LA may be a potential lead compound for breast cancer therapy by inducing ferroptosis in tumor cells.

Topics: Breast Neoplasms; Female; Ferroptosis; Heme Oxygenase-1; Heterocyclic Compounds, Bridged-Ring; Humans; NF-E2-Related Factor 2; Signal Transduction

The aim of the present study was to investigate the reversing effect of levistolide A (LA) on P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in human breast carcinoma Bcap37/MDR1 cells.. After chemotherapeutic drugs (adriamycin or vincristine) used alone or in combination with LA, cell proliferation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay and cell cycle distribution by flow cytometry. RT-PCR was used to detect MDR1 gene transcription and the Western blot assay was used to assess P-gp expression and the cleavages of poly(ADP-ribose) polymerase and caspase-3. Apoptosis was detected by terminal transferase-mediated dUTP nick end-labeling assay. Moreover, the P-gp function was evaluated by the intracellular accumulation of the P-gp substrate detected by flow cytometry.. We found the subcytotoxic doses of LA significantly enhanced adriamycin- or vincristine- induced G2/M arrest and apoptosis. These effects were consistent with the ability of LA to inhibit P-gp function. Moreover, LA dramatically enhanced the verapamil (VER) ability to reverse drug resistance.. LA has the potential to be developed as a novel P-gp modulator. Furthermore, the combination of LA and VER might represent a more sufficient but less toxic anti-MDR regimen.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzofurans; Breast Neoplasms; Cell Line, Tumor; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Feasibility Studies; Female; Humans; Inhibitory Concentration 50; Molecular Structure; Molecular Weight; Prohibitins; Reference Values; Verapamil; Vincristine