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Formononetin potentiates epirubicin-induced apoptosis via ROS production in HeLa cells in vitro.
Chem Biol Interact. 2013 Oct 05; 205(3):188-97.CB

Abstract

The frequent development of multidrug resistance (MDR) hampers the efficacy of available anticancer drugs in treating cervical cancer. In this study, we aimed to use formononetin (7-hydroxy-4'-methoxyisoflavone), a potential herbal isoflavone, to intensify the chemosensitivity of human cervical cancer HeLa cells to epirubicin, an anticancer drug. The reactive oxygen species (ROS) levels were correlated with MDR modulation mechanisms, including the transporter inhibition and apoptosis induction. Our results revealed that formononetin significantly enhanced the cytotoxicity of epirubicin. Co-incubation of epirubicin with formononetin increased the ROS levels, including hydrogen peroxide and superoxide free radicals. Epirubicin alone markedly increased the mRNA expression of MDR1, MDR-associated protein (MRP) 1, and MRP2. In contrast, formononetin alone or combined treatment decreased the mRNA expression of MRP1 and MRP2. This result indicates that efflux transporter-mediated epirubicin resistance is inhibited at different degrees by the addition of formononetin. This isoflavone significantly intensified epirubicin uptake into HeLa cells. Apoptosis was induced by formononetin and/or epirubicin, as signified by nuclear DNA fragmentation, chromatin condensation, increased sub-G1 and G2/M phases. The cotreatment triggered the mitochondrial apoptotic pathway indicated by increased Bax-to-Bcl-2 expression ratio, loss of mitochondrial membrane potential, and significant activation of caspase-9 and -3. In addition, extrinsic/caspases-8 apoptotic pathway was also induced by the cotreatment. N-acetyl cysteine abrogated these events induced by formononetin, supporting the involvement of ROS in the MDR reversal mechanism. This study pioneered in demonstrating that formononetin may potentiate the cytotoxicity of epirubicin in HeLa cells through the ROS-mediated MRP inhibition and concurrent activation of the mitochondrial and death receptor pathways of apoptosis. Hence, the circumvention of pump and non-pump resistance using formononetin and epirubicin may pave the way for a powerful chemotherapeutic regimen for treating human cervical cancer.

Authors+Show Affiliations

Department of Biological Sciences and Technology, National University of Tainan, Tainan, Taiwan ROC. yulilo@mail.nutn.edu.twNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23867903

Citation

Lo, Yu-Li, and Wanjen Wang. "Formononetin Potentiates Epirubicin-induced Apoptosis Via ROS Production in HeLa Cells in Vitro." Chemico-biological Interactions, vol. 205, no. 3, 2013, pp. 188-97.
Lo YL, Wang W. Formononetin potentiates epirubicin-induced apoptosis via ROS production in HeLa cells in vitro. Chem Biol Interact. 2013;205(3):188-97.
Lo, Y. L., & Wang, W. (2013). Formononetin potentiates epirubicin-induced apoptosis via ROS production in HeLa cells in vitro. Chemico-biological Interactions, 205(3), 188-97. https://doi.org/10.1016/j.cbi.2013.07.003
Lo YL, Wang W. Formononetin Potentiates Epirubicin-induced Apoptosis Via ROS Production in HeLa Cells in Vitro. Chem Biol Interact. 2013 Oct 5;205(3):188-97. PubMed PMID: 23867903.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Formononetin potentiates epirubicin-induced apoptosis via ROS production in HeLa cells in vitro. AU - Lo,Yu-Li, AU - Wang,Wanjen, Y1 - 2013/07/16/ PY - 2012/10/18/received PY - 2013/06/08/revised PY - 2013/07/05/accepted PY - 2013/7/23/entrez PY - 2013/7/23/pubmed PY - 2013/10/29/medline KW - 3,3′-dihexyloxacarbocyanine iodide KW - 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide KW - Apoptosis KW - DCF KW - DiOC(6) KW - Epirubicin KW - EtBr KW - Formononetin KW - HeLa KW - Isoflavone KW - MDR KW - MDR-associated proteins KW - MRPs KW - MTT KW - Multidrug resistance KW - P-glycoprotein KW - P-gp KW - ROS KW - Reactive oxygen species KW - TNF-alpha KW - TNF-related apoptosis-inducing ligand KW - TRAIL KW - dichlorofluorescein KW - ethidium bromide KW - human cervical cancer cells KW - mitochondrial transmembrane potential KW - multidrug resistance KW - reactive oxygen species KW - tumor necrosis factor-alpha KW - Δψ(m) SP - 188 EP - 97 JF - Chemico-biological interactions JO - Chem Biol Interact VL - 205 IS - 3 N2 - The frequent development of multidrug resistance (MDR) hampers the efficacy of available anticancer drugs in treating cervical cancer. In this study, we aimed to use formononetin (7-hydroxy-4'-methoxyisoflavone), a potential herbal isoflavone, to intensify the chemosensitivity of human cervical cancer HeLa cells to epirubicin, an anticancer drug. The reactive oxygen species (ROS) levels were correlated with MDR modulation mechanisms, including the transporter inhibition and apoptosis induction. Our results revealed that formononetin significantly enhanced the cytotoxicity of epirubicin. Co-incubation of epirubicin with formononetin increased the ROS levels, including hydrogen peroxide and superoxide free radicals. Epirubicin alone markedly increased the mRNA expression of MDR1, MDR-associated protein (MRP) 1, and MRP2. In contrast, formononetin alone or combined treatment decreased the mRNA expression of MRP1 and MRP2. This result indicates that efflux transporter-mediated epirubicin resistance is inhibited at different degrees by the addition of formononetin. This isoflavone significantly intensified epirubicin uptake into HeLa cells. Apoptosis was induced by formononetin and/or epirubicin, as signified by nuclear DNA fragmentation, chromatin condensation, increased sub-G1 and G2/M phases. The cotreatment triggered the mitochondrial apoptotic pathway indicated by increased Bax-to-Bcl-2 expression ratio, loss of mitochondrial membrane potential, and significant activation of caspase-9 and -3. In addition, extrinsic/caspases-8 apoptotic pathway was also induced by the cotreatment. N-acetyl cysteine abrogated these events induced by formononetin, supporting the involvement of ROS in the MDR reversal mechanism. This study pioneered in demonstrating that formononetin may potentiate the cytotoxicity of epirubicin in HeLa cells through the ROS-mediated MRP inhibition and concurrent activation of the mitochondrial and death receptor pathways of apoptosis. Hence, the circumvention of pump and non-pump resistance using formononetin and epirubicin may pave the way for a powerful chemotherapeutic regimen for treating human cervical cancer. SN - 1872-7786 UR - https://www.unboundmedicine.com/medline/citation/23867903/Formononetin_potentiates_epirubicin_induced_apoptosis_via_ROS_production_in_HeLa_cells_in_vitro_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0009-2797(13)00164-6 DB - PRIME DP - Unbound Medicine ER -