Apigenin and its combination with Vorinostat induces apoptotic-mediated cell death in TNBC by modulating the epigenetic and apoptotic regulators and related miRNAs.
Apigenin
/ pharmacology
Humans
MicroRNAs
/ genetics
Triple Negative Breast Neoplasms
/ drug therapy
Apoptosis
/ drug effects
Vorinostat
/ pharmacology
Epigenesis, Genetic
/ drug effects
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
/ drug effects
Female
Cell Movement
/ drug effects
Molecular Docking Simulation
Cell Proliferation
/ drug effects
Apigenin and MD simulations
Apoptosis
Flavonoids
HDACs
TNBC
miRNAs
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
25 04 2024
25 04 2024
Historique:
received:
20
02
2024
accepted:
23
04
2024
medline:
26
4
2024
pubmed:
26
4
2024
entrez:
25
4
2024
Statut:
epublish
Résumé
Triple-negative breast cancer (TNBC) is a metastatic disease and a formidable treatment challenge as it does not respond to existing therapies. Epigenetic regulators play a crucial role in the progression and metastasis by modulating the expression of anti-apoptotic, pro-apoptotic markers and related miRNAs in TNBC cells. We have investigated the anti-TNBC potential of dietary flavonoid 'Apigenin' and its combination with Vorinostat on MDA-MB-231 cells. At Apigenin generated ROS, inhibited cell migration, arrested the cell cycle at subG0/G1 phases, and induced apoptotic-mediated cell death. Apigenin reduced the expression of the class-I HDACs at the transcriptomic and proteomic levels. In the immunoblotting study, Apigenin has upregulated pro-apoptotic markers and downregulated anti-apoptotic proteins. Apigenin inhibited the enzymatic activity of HDAC/DNMT and increased HAT activity. Apigenin has manifested its effect on miRNA expression by upregulating the tumor-suppressor miR-200b and downregulation oncomiR-21. Combination study reduced the growth of TNBC cells synergistically by modulating the expression of epigenetic and apoptotic regulators. Molecular docking and MD simulations explored the mechanism of catalytic inhibition of HDAC1 and HDAC3 and supported the in-vitro studies. The overall studies demonstrated an anti-TNBC potential of Apigenin and may help to design an effective strategy to treat metastatic phenotype of TNBC.
Identifiants
pubmed: 38664447
doi: 10.1038/s41598-024-60395-x
pii: 10.1038/s41598-024-60395-x
doi:
Substances chimiques
Apigenin
7V515PI7F6
MicroRNAs
0
Vorinostat
58IFB293JI
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9540Informations de copyright
© 2024. The Author(s).
Références
https://www.who.int/news-room/fact-sheets/detail/breast-cancer .
https://www.cancer.org/cancer/breast-cancer/about/types-of-breast-cancer/triple-negative.html .
Sung, H. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71(3), 209–249. https://doi.org/10.3322/caac.21660 (2021) (Epub 2021 Feb 4).
doi: 10.3322/caac.21660
pubmed: 33538338
Derakhshan, F. & Reis-Filho, J. S. Pathogenesis of triple-negative breast cancer. Annu. Rev. Pathol. 24(17), 181–204. https://doi.org/10.1146/annurev-pathol-042420-093238 (2022).
doi: 10.1146/annurev-pathol-042420-093238
Bianchini, G., De Angelis, C., Licata, L. & Gianni, L. Treatment landscape of triple-negative breast cancer—expanded options, evolving needs. Nat. Rev. Clin. Oncol. 19(2), 91–113. https://doi.org/10.1038/s41571-021-00565-2 (2022) (Epub 2021 Nov 9).
doi: 10.1038/s41571-021-00565-2
pubmed: 34754128
Costa, P. M. D. S. et al. Epigenetic reprogramming in cancer: From diagnosis to treatment. Front. Cell Dev. Biol. 14(11), 1116805. https://doi.org/10.3389/fcell.2023.1116805 (2023).
doi: 10.3389/fcell.2023.1116805
Garcia-Martinez, L., Zhang, Y., Nakata, Y., Chan, H. L. & Morey, L. Epigenetic mechanisms in breast cancer therapy and resistance. Nat. Commun. 12(1), 1786. https://doi.org/10.1038/s41467-021-22024-3 (2021).
doi: 10.1038/s41467-021-22024-3
pubmed: 33741974
pmcid: 7979820
Temian, D. C., Pop, L. A., Irimie, A. I. & Berindan-Neagoe, I. The Epigenetics of triple-negative and basal-like breast cancer: Current knowledge. J. Breast Cancer. 21(3), 233–243. https://doi.org/10.4048/jbc.2018.21 (2018) (Epub 2018 Sep 20).
doi: 10.4048/jbc.2018.21
pubmed: 30275851
pmcid: 6158152
Sher, G. et al. Epigenetic and breast cancer therapy: Promising diagnostic and therapeutic applications. Semin Cancer Biol. 83, 152–165. https://doi.org/10.1016/j.semcancer.2020.08.009 (2022) (Epub 2020 Aug 25).
doi: 10.1016/j.semcancer.2020.08.009
pubmed: 32858230
Castro-Muñoz, L. J. et al. Modulating epigenetic modifications for cancer therapy (Review). Oncol Rep. 49(3), 59. https://doi.org/10.3892/or.2023.8496 (2023) (Epub 2023 Feb 17).
doi: 10.3892/or.2023.8496
pubmed: 36799181
pmcid: 9942256
Yang, F. et al. Sulforaphane induces autophagy by inhibition of HDAC6-mediated PTEN activation in triple negative breast cancer cells. Life Sci. 213, 149–157 (2018).
pubmed: 30352240
doi: 10.1016/j.lfs.2018.10.034
Chai, R. C. et al. Histone deacetylase activity mediates acquired resistance towards structurally diverse HSP90 inhibitors. Mol. Oncol. 11(5), 567–583 (2017).
pubmed: 28306192
pmcid: 5527463
doi: 10.1002/1878-0261.12054
Schafer, C. et al. Class I histone deacetylases regulate p53/NF-κB crosstalk in cancer cells. Cell Signal. 29, 218–225 (2017).
pubmed: 27838375
doi: 10.1016/j.cellsig.2016.11.002
Ramaiah, M. J., Tangutur, A. D. & Manyam, R. R. Epigenetic modulation and understanding of HDAC inhibitors in cancer therapy. Life Sci. 277, 119504. https://doi.org/10.1016/j.lfs.2021.119504 (2021) (Epub 2021 Apr 16).
doi: 10.1016/j.lfs.2021.119504
pubmed: 33872660
Seto, E. & Yoshida, M. Erasers of histone acetylation: The histone deacetylase enzymes. Cold Spring Harb. Perspect. Biol. 6(4), a018713. https://doi.org/10.1101/cshperspect.a018713. (2014).
doi: 10.1101/cshperspect.a018713.
pubmed: 24691964
pmcid: 3970420
Alseksek, R. K., Ramadan, W. S., Saleh, E. & El-Awady, R. The role of HDACs in the response of cancer cells to cellular stress and the potential for therapeutic intervention. Int. J. Mol. Sci. 23(15), 8141. https://doi.org/10.3390/ijms23158141 (2022).
doi: 10.3390/ijms23158141
pubmed: 35897717
pmcid: 9331760
Szczepanek, J., Skorupa, M., Jarkiewicz-Tretyn, J., Cybulski, C. & Tretyn, A. Harnessing epigenetics for breast cancer therapy: The role of DNA methylation, histone modifications, and MicroRNA. Int. J. Mol. Sci. 24(8), 7235. https://doi.org/10.3390/ijms24087235 (2023).
doi: 10.3390/ijms24087235
pubmed: 37108398
pmcid: 10138995
Rahman, M. M., Brane, A. C. & Tollefsbol, T. O. MicroRNAs and epigenetics strategies to reverse breast cancer. Cells. 8(10), 1214. https://doi.org/10.3390/cells8101214 (2019).
doi: 10.3390/cells8101214
pubmed: 31597272
pmcid: 6829616
Pinto, R., De Summa, S., Pilato, B. & Tommasi, S. DNA methylation and miRNAs regulation in hereditary breast cancer: epigenetic changes, players in transcriptional and post- transcriptional regulation in hereditary breast cancer. Curr. Mol. Med. 14(1), 45–57. https://doi.org/10.2174/1566524013666131203101405 (2014).
doi: 10.2174/1566524013666131203101405
pubmed: 24295492
Garmpis, N. et al. Histone deacetylases as new therapeutic targets in triple-negative breast cancer: Progress and promises. Cancer Genomics Proteomics. 14(5), 299–313. https://doi.org/10.21873/cgp.20041 (2017).
doi: 10.21873/cgp.20041
pubmed: 28870998
pmcid: 5611517
Xu, P. et al. Histone deacetylase 2 knockout suppresses immune escape of triple-negative breast cancer cells via downregulating PD-L1 expression. Cell Death Dis. 12(8), 779. https://doi.org/10.1038/s41419-021-04047-2 (2021).
doi: 10.1038/s41419-021-04047-2
pubmed: 34365463
pmcid: 8349356
Yang, J. et al. Insights into the function and clinical application of HDAC5 in cancer management. Front Oncol. 10(11), 661620. https://doi.org/10.3389/fonc.2021.661620 (2021).
doi: 10.3389/fonc.2021.661620
Muller, B. M. et al. Differential expression of histone deacetylases HDAC1, 2 and 3 in human breast cancer–overexpression of HDAC2 and HDAC3 is associated with clinicopathological indicators of disease progression. BMC Cancer. 30(13), 215. https://doi.org/10.1186/1471-2407-13-215 (2013).
doi: 10.1186/1471-2407-13-215
Maiti, A. et al. Class I histone deacetylase inhibitor suppresses vasculogenic mimicry by enhancing the expression of tumor suppressor and anti-angiogenesis genes in aggressive human TNBC cells. Int. J. Oncol. 55(1), 116–130. https://doi.org/10.3892/ijo.2019.4796 (2019) (Epub 2019 May 6).
doi: 10.3892/ijo.2019.4796
pubmed: 31059004
pmcid: 6561627
Hanigan, T. W., Aboukhatwa, S. M., Taha, T. Y. & Frasor, J. Divergent JNK phosphorylation of HDAC3 in triple-negative breast cancer cells determines HDAC inhibitor binding and selectivity. Cell Chem. Biol. 24(11), 1356–1367. https://doi.org/10.1016/j.chembiol.2017.08.015 (2017) (Epub 2017 Sep 21).
doi: 10.1016/j.chembiol.2017.08.015
pubmed: 28943357
pmcid: 5693607
Yu, S. L. et al. Histone deacetylase 4 mediates SMAD family member 4 deacetylation and induces 5-fluorouracil resistance in breast cancer cells. Oncol. Rep. 30(3), 1293–1300. https://doi.org/10.3892/or.2013.2578 (2013) (Epub 2013 Jul 1).
doi: 10.3892/or.2013.2578
pubmed: 23817620
Cao, C. et al. Functional interaction of histone deacetylase 5 (HDAC5) and lysine-specific demethylase 1 (LSD1) promotes breast cancer progression. Oncogene. 36(1), 133–145. https://doi.org/10.1038/onc.2016.186 (2017) (Epub 2016 May 23).
doi: 10.1038/onc.2016.186
pubmed: 27212032
Saji, S. et al. Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer. Oncogene. 24, 4531–4539 (2005).
pubmed: 15806142
doi: 10.1038/sj.onc.1208646
Banik, D. et al. HDAC6 plays a noncanonical role in the regulation of antitumor immune responses, dissemination, and invasiveness of breast cancer. Cancer Res. 80(17), 3649–3662. https://doi.org/10.1158/0008-5472.CAN-19-3738 (2020) (Epub 2020 Jun 30).
doi: 10.1158/0008-5472.CAN-19-3738
pubmed: 32605998
pmcid: 7484424
Dowling Dowling, C. M. et al. Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer. Sci. Adv. 7(3), 4897. https://doi.org/10.1126/sciadv.abc4897 (2021).
doi: 10.1126/sciadv.abc4897
Bhattacharya, U., Kamran, M., Manai, M., Cristofanilli, M. & Ince, T. A. Cell-of-origin targeted drug repurposing for triple-negative and inflammatory breast carcinoma with HDAC and HSP90 inhibitors combined with niclosamide. Cancers (Basel). 15(2), 332. https://doi.org/10.3390/cancers15020332 (2023).
doi: 10.3390/cancers15020332
pubmed: 36672285
pmcid: 9856736
Li, J. et al. Histone deacetylase 8 triggers the migration of triple negative breast cancer cells via regulation of YAP signals. Eur. J. Pharmacol. 845, 16–23. https://doi.org/10.1016/j.ejphar.2018.12.030 (2019) (Epub 2018 Dec 21).
doi: 10.1016/j.ejphar.2018.12.030
pubmed: 30582912
Salgado, E., Bian, X., Feng, A., Shim, H. & Liang, Z. HDAC9 overexpression confers invasive and angiogenic potential to triple negative breast cancer cells via modulating microRNA-206. Biochem. Biophys. Res. Commun. 503(2), 1087–1091. https://doi.org/10.1016/j.bbrc.2018.06.120 (2018) (Epub 2018 Jun 23).
doi: 10.1016/j.bbrc.2018.06.120
pubmed: 29936177
pmcid: 6439468
Sulaiman, A. et al. Co-inhibition of mTORC1, HDAC and ESR1α retards the growth of triple-negative breast cancer and suppresses cancer stem cells. Cell Death Dis. 9(8), 815. https://doi.org/10.1038/s41419-018-0811-7 (2018).
doi: 10.1038/s41419-018-0811-7
pubmed: 30050079
pmcid: 6062597
Liu, S. S., Wu, F., Jin, Y. M., Chang, W. Q. & Xu, T. M. HDAC11: A rising star in epigenetics. Biomed. Pharmacother. 131, 110607. https://doi.org/10.1016/j.biopha.2020.110607 (2020) (Epub 2020 Aug 22).
doi: 10.1016/j.biopha.2020.110607
pubmed: 32841898
Maccallini, C. et al. HDAC inhibitors for the therapy of triple negative breast cancer. Pharmaceuticals (Basel). 15(6), 667. https://doi.org/10.3390/ph15060667 (2022).
doi: 10.3390/ph15060667
pubmed: 35745586
pmcid: 9230362
Kalyaanamoorthy, S. & Chen, Y. P. Energy based pharmacophore mapping of HDAC inhibitors against class I HDAC enzymes. Biochim Biophys Acta. 1834(1), 317–328. https://doi.org/10.1016/j.bbapap.2012.08.009 (2013).
doi: 10.1016/j.bbapap.2012.08.009
pubmed: 23457710
Ha, K. et al. Histone deacetylase inhibitor treatment induces “BRCAness” and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells. Oncotarget. 5(14), 5637–5650. https://doi.org/10.18632/oncotarget.2154 (2014).
doi: 10.18632/oncotarget.2154
pubmed: 25026298
pmcid: 4170637
Claude-Taupin, A., Boyer-Guittaut, M., Delage-Mourroux, R., & Hervouet, E. Use of epigenetic modulators as a powerful adjuvant for breast cancer therapies. In: Verma, M. (eds) Cancer Epigenetics. Methods in Molecular Biology (Methods and Protocols), vol 1238 (Humana Press, New York, NY, 2015).
Fedele, P., Orlando, L. & Cinieri, S. Targeting triple negative breast cancer with histone deacetylase inhibitors. Expert. Opin. Investig. Drugs. 26(11), 1199–1206. https://doi.org/10.1080/13543784.2017.1386172 (2017) (Epub 2017 Oct 8).
doi: 10.1080/13543784.2017.1386172
pubmed: 28952409
Milazzo, G. et al. Histone deacetylases (HDACs): Evolution, specificity, role in transcriptional complexes, and pharmacological actionability. Genes (Basel). 11(5), 556. https://doi.org/10.3390/genes11050556 (2020).
doi: 10.3390/genes11050556
pubmed: 32429325
pmcid: 7288346
Brancolini, C., Gagliano, T. & Minisini, M. HDACs and the epigenetic plasticity of cancer cells: Target the complexity. Pharmacol Ther. 238, 108190. https://doi.org/10.1016/j.pharmthera.2022.108190 (2022) (Epub 2022 Apr 14).
doi: 10.1016/j.pharmthera.2022.108190
pubmed: 35430294
Terranova-Barberio, M. et al. HDAC inhibition potentiates immunotherapy in triple negative breast cancer. Oncotarget. 8(69), 114156–114172 (2017).
pubmed: 29371976
pmcid: 5768393
doi: 10.18632/oncotarget.23169
Li, M. et al. LIFR inhibition enhances the therapeutic efficacy of HDAC inhibitors in triple negative breast cancer. Commun. Biol. 4(1), 1235. https://doi.org/10.1038/s42003-021-02741-7 (2021).
doi: 10.1038/s42003-021-02741-7
pubmed: 34716410
pmcid: 8556368
Jiang, X. C. et al. Discovery of a novel G-quadruplex and histone deacetylase (HDAC) dual-targeting agent for the treatment of triple-negative breast cancer. J. Med. Chem. 65(18), 12346–12366. https://doi.org/10.1021/acs.jmedchem.2c01058 (2022) (Epub 2022 Sep 2).
doi: 10.1021/acs.jmedchem.2c01058
pubmed: 36053318
Ono, H. et al. The histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth of triple-negative breast cancer cells with the suppression of survivin, Bcl-xL, and the MAPK pathway. Breast Cancer Res. Treat. 171(1), 43–52. https://doi.org/10.1007/s10549-018-4815-x (2018) (Epub 2018 May 11).
doi: 10.1007/s10549-018-4815-x
pubmed: 29752686
Oba, T. et al. HDAC6 inhibition enhances the anti-tumor effect of eribulin through tubulin acetylation in triple-negative breast cancer cells. Breast Cancer Res. Treat. 186(1), 37–51. https://doi.org/10.1007/s10549-020-06033-2 (2021) (Epub 2021 Jan 16).
doi: 10.1007/s10549-020-06033-2
pubmed: 33452951
Min, A. et al. Histone deacetylase inhibitor, Suberoylanilide hydroxamic acid (SAHA), enhances anti-tumor effects of the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in triple-negative breast cancer cells. Breast Cancer Res. 7(17), 33. https://doi.org/10.1186/s13058-015-0534-y (2015).
doi: 10.1186/s13058-015-0534-y
Vasilatos, S. N. et al. Crosstalk between lysine-specific demethylase 1 (LSD1) and histone deacetylases mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer cells. Carcinogenesis. 34(6), 1196–1207. https://doi.org/10.1093/carcin/bgt033 (2013) (Epub 2013 Jan 25).
doi: 10.1093/carcin/bgt033
pubmed: 23354309
pmcid: 3670252
Chiu, H. W. et al. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, enhances radiosensitivity and suppresses lung metastasis in breast cancer in vitro and in vivo. PLoS One. 8(10), e76340. https://doi.org/10.1371/journal.pone.0076340 (2013).
doi: 10.1371/journal.pone.0076340
pubmed: 24130769
pmcid: 3794942
Rhodes, L. V. et al. Suppression of triple-negative breast cancer metastasis by pan-DAC inhibitor panobinostat via inhibition of ZEB family of EMT master regulators. Breast Cancer Res. Treat. 145(3), 593–604. https://doi.org/10.1007/s10549-014-2979-6 (2014).
doi: 10.1007/s10549-014-2979-6
pubmed: 24810497
pmcid: 4083690
Matossian, M. D. et al. Panobinostat suppresses the mesenchymal phenotype in a novel claudin-low triple negative patient-derived breast cancer model. Oncoscience. 5(3–4), 99–108 (2018).
pubmed: 29854878
pmcid: 5978446
doi: 10.18632/oncoscience.412
Subramanian, S., Bates, S. E., Wright, J. J., Espinoza-Delgado, I. & Piekarz, R. L. Clinical toxicities of histone deacetylase inhibitors. Pharmaceuticals (Basel). 3(9), 2751–2767. https://doi.org/10.3390/ph3092751 (2010).
doi: 10.3390/ph3092751
pubmed: 27713375
pmcid: 4034096
Yadav, R., Mishra, P. & Yadav, D. Histone deacetylase inhibitors: a prospect in drug discovery. Turk. J. Pharm. Sci. 16(1), 101–114. https://doi.org/10.4274/tjps.75047 (2019) (Epub 2018 Dec 31).
doi: 10.4274/tjps.75047
pubmed: 32454703
Tao, J. J., Visvanathan, K. & Wolff, A. C. Long term side effects of adjuvant chemotherapy in patients with early breast cancer. Breast. 24, S149–S153 (2015).
pubmed: 26299406
doi: 10.1016/j.breast.2015.07.035
Lee, A., Mustafa, B. & Djamgoz, A. Triple negative breast cancer: emerging therapeutic modalities and novel combination therapies. Cancer Treatm. Rev. 62, 110–122 (2018).
doi: 10.1016/j.ctrv.2017.11.003
Kaleem, M. et al. Epigenetics of triple-negative breast cancer via natural compounds. Curr. Med. Chem. 29(8), 1436–1458. https://doi.org/10.2174/0929867328666210707165530 (2022).
doi: 10.2174/0929867328666210707165530
pubmed: 34238140
Bouyahya, A. et al. The role of epigenetic modifications in human cancers and the use of natural compounds as epidrugs: Mechanistic pathways and pharmacodynamic actions. Biomolecules. 12(3), 367. https://doi.org/10.3390/biom12030367 (2022).
doi: 10.3390/biom12030367
pubmed: 35327559
pmcid: 8945214
Guo, X. et al. Long-term soy consumption and tumor tissue MicroRNA and gene expression in triple-negative breast cancer. Cancer 122, 2544–2551 (2016).
pubmed: 27183356
doi: 10.1002/cncr.29981
Peng, X. et al. 3,6-dihydroxyflavone suppresses breast carcinogenesis by epigenetically regulating miR-34a and miR-21. Cancer Prev. Res. (Phila). 8(6), 509–517 (2015).
pubmed: 25784176
doi: 10.1158/1940-6207.CAPR-14-0357
Lin, Z. et al. Mevastatin blockade of autolysosome maturation stimulates LBH589-induced cell death in triple-negative breast cancer cells. Oncotarget. 8(11), 17833–17848. https://doi.org/10.18632/oncotarget.14868 (2017).
doi: 10.18632/oncotarget.14868
pubmed: 28147319
pmcid: 5392290
Carlos-Reyes, Á. et al. Dietary compounds as epigenetic modulating agents in cancer. Front. Genet. 10, 79. https://doi.org/10.3389/fgene.2019.00079 (2019).
doi: 10.3389/fgene.2019.00079
pubmed: 30881375
pmcid: 6406035
Steed, K. L., Jordan, H. R. & Tollefsbol, T. O. SAHA and EGCG promote apoptosis in triple-negative breast cancer cells, possibly through the modulation of cIAP2. Anticancer Res. 40(1), 9–26. https://doi.org/10.21873/anticanres.13922 (2020).
doi: 10.21873/anticanres.13922
pubmed: 31892549
pmcid: 7032656
Fatima, N. et al. Role of flavonoids as epigenetic modulators in cancer prevention and therapy. Front. Genet. 9(12), 758733. https://doi.org/10.3389/fgene.2021.758733 (2021).
doi: 10.3389/fgene.2021.758733
Sinha, S., Sharma, S., Sharma, A., Vora, J. & Shrivastava, N. Sulforaphane-cisplatin combination inhibits the stemness and metastatic potential of TNBCs via down regulation of sirtuins-mediated EMT signaling axis. Phytomedicine. 84, 153492. https://doi.org/10.1016/j.phymed.2021.153492 (2021) (Epub 2021 Feb 5).
doi: 10.1016/j.phymed.2021.153492
pubmed: 33640782
Madunić, J., Madunić, I. V., Gajski, G., Popić, J. & Garaj-Vrhovac, V. Apigenin: A dietary flavonoid with diverse anticancer properties. Cancer Lett. 28(413), 11–22. https://doi.org/10.1016/j.canlet.2017.10.041 (2018) (Epub 2017 Oct 31).
doi: 10.1016/j.canlet.2017.10.041
Imran, M. et al. Apigenin as an anticancer agent. Phytother. Res. 34(8), 1812–1828. https://doi.org/10.1002/ptr.6647 (2020) (Epub 2020 Feb 14).
doi: 10.1002/ptr.6647
pubmed: 32059077
Nozhat, Z., Heydarzadeh, S., Memariani, Z. & Ahmadi, A. Chemoprotective and chemosensitizing effects of apigenin on cancer therapy. Cancer Cell Int. 21(1), 574. https://doi.org/10.1186/s12935-021-02282-3 (2021).
doi: 10.1186/s12935-021-02282-3
pubmed: 34715860
pmcid: 8555304
Rahmani, A. H. et al. The potential role of apigenin in cancer prevention and treatment. Molecules. 27(18), 6051. https://doi.org/10.3390/molecules27186051 (2022).
doi: 10.3390/molecules27186051
pubmed: 36144783
pmcid: 9505045
Singh, D., Gupta, M., Sarwat, M. & Siddique, H. R. Apigenin in cancer prevention and therapy: A systematic review and meta-analysis of animal models. Crit. Rev. Oncol. Hematol. 176, 103751. https://doi.org/10.1016/j.critrevonc.2022.103751 (2022) (Epub 2022 Jun 22).
doi: 10.1016/j.critrevonc.2022.103751
pubmed: 35752426
Zhou, Y. et al. Apigenin in cancer therapy: From mechanism of action to nano-therapeutic agent. Food Chem. Toxicol. 168, 113385. https://doi.org/10.1016/j.fct.2022.113385 (2022) (Epub 2022 Aug 22).
doi: 10.1016/j.fct.2022.113385
pubmed: 36007853
Jang, J. Y., Sung, B. & Kim, N. D. Role of induced programmed cell death in the chemo preventive potential of apigenin. Int. J. Mol. Sci. 23(7), 3757. https://doi.org/10.3390/ijms23073757 (2022).
doi: 10.3390/ijms23073757
pubmed: 35409117
pmcid: 8999072
Adel, M. et al. Chemotherapeutic effects of Apigenin in breast cancer: Preclinical evidence and molecular mechanisms; enhanced bioavailability by nanoparticles. Biotechnol. Rep. (Amst). 12(34), e00730. https://doi.org/10.1016/j.btre.2022.e00730 (2022).
doi: 10.1016/j.btre.2022.e00730
Bauer, D., Mazzio, E. & Soliman, K. F. A. Whole transcriptomic analysis of apigenin on TNFα immuno-activated MDA-MB-231 breast cancer cells. Cancer Genomics Proteom. 16(6), 421–431. https://doi.org/10.21873/cgp.20146 (2019).
doi: 10.21873/cgp.20146
Paul, M., Yuet-Kin, L., Wan-Yee, T., Charlotte, H. & Shuk-Mei, Ho. Apigenin suppresses cancer cell growth through ERB. Neoplasia. 8(11), 896–904 (2006).
doi: 10.1593/neo.06538
Li, Y. W. et al. Apigenin suppresses the stem cell-like properties of triple-negative breast cancer cells by inhibiting YAP/TAZ activity. Cell Death Discov. 20(4), 105. https://doi.org/10.1038/s41420-018-0124-8.PMID:30479839;PMCID:PMC6244166 (2018).
doi: 10.1038/s41420-018-0124-8.PMID:30479839;PMCID:PMC6244166
Saeed, M., Kadioglu, O., Khalid, H., Sugimoto, Y. & Efferth, T. Activity of the dietary flavonoid, apigenin, against multidrug-resistant tumor cells as determined by pharmacogenomics and molecular docking. J. Nutr. Biochem. 26(1), 44–56. https://doi.org/10.1016/j.jnutbio.2014.09.008 (2015) (Epub 2014 Oct 13).
doi: 10.1016/j.jnutbio.2014.09.008
pubmed: 25459885
Choi, E. J. & Kim, G. H. 5-Fluorouracil combined with apigenin enhances anticancer activity through induction of apoptosis in human breast cancer MDA-MB-453 cells. Oncol. Rep. 22(6), 1533–1537. https://doi.org/10.3892/or_00000598 (2009).
doi: 10.3892/or_00000598
pubmed: 19885610
Scafuri, B., Bontempo, P., Altucci, L., De Masi, L. & Facchiano, A. Molecular docking simulations on histone deacetylases (HDAC)-1 and -2 to investigate the flavone binding. Biomedicines. 8(12), 568. https://doi.org/10.3390/biomedicines8120568 (2020).
doi: 10.3390/biomedicines8120568
pubmed: 33291755
pmcid: 7761979
Chakrabarti, M., Banik, N. L. & Ray, S. K. miR-138 overexpression is more powerful than hTERT knockdown to potentiate apigenin for apoptosis in neuroblastoma in vitro and in vivo. Exp. Cell Res. 319(10), 1575–1585. https://doi.org/10.1016/j.yexcr.2013.02.025 (2013) (Epub 2013 Apr 3).
doi: 10.1016/j.yexcr.2013.02.025
pubmed: 23562653
pmcid: 3661724
Chen, X. J., Wu, M. Y., Li, D. H. & You, J. Apigenin inhibits glioma cell growth through promoting microRNA-16 and suppression of BCL-2 and nuclear factor-κB/MMP-9. Mol. Med. Rep. 14(3), 2352–2358. https://doi.org/10.3892/mmr.2016.5460 (2016) (Epub 2016 Jun 30).
doi: 10.3892/mmr.2016.5460
pubmed: 27430517
Wan, Y. et al. miR-423-5p knockdown enhances the sensitivity of glioma stem cells to apigenin through the mitochondrial pathway. Tumour Biol. 39(4), 1010428317695526. https://doi.org/10.1177/1010428317695526 (2017).
doi: 10.1177/1010428317695526
pubmed: 28381178
Gao, A. M., Zhang, X. Y., Hu, J. N. & Ke, Z. P. Apigenin sensitizes hepatocellular carcinoma cells to doxorubic through regulating miR-520b/ATG7 axis. Chem. Biol. Interact. 25(280), 45–50. https://doi.org/10.1016/j.cbi.2017.11.020 (2018) (Epub 2017 Dec 11).
doi: 10.1016/j.cbi.2017.11.020
Ozbey, U. et al. Apigenin as an effective anticancer natural product: Spotlight on TRAIL, WNT/β-catenin, JAK-STAT pathways, and microRNAs. J. Cell Biochem. 120(2), 1060–1067. https://doi.org/10.1002/jcb.27575 (2019) (Epub 2018 Oct 2).
doi: 10.1002/jcb.27575
pubmed: 30278099
Zhao, X., Zhou, H. B., Liu, J., Xie, J. & Hu, R. Apigenin suppresses proliferation, invasion, and epithelial-mesenchymal transition of cervical carcinoma cells by regulation of miR-152/BRD4 axis. Kaohsiung J. Med. Sci. 37(7), 583–593. https://doi.org/10.1002/kjm2.12370 (2021) (Epub 2021 Feb 20).
doi: 10.1002/kjm2.12370
pubmed: 33611824
Cheng, Y. et al. Apigenin inhibits the growth of colorectal cancer through down-regulation of E2F1/3 by miRNA-215-5p. Phytomedicine. 89, 153603. https://doi.org/10.1016/j.phymed.2021.153603 (2021) (Epub 2021 May 24).
doi: 10.1016/j.phymed.2021.153603
pubmed: 34175590
Aida, R. et al. miR-34a-5p might have an important role for inducing apoptosis by down-regulation of SNAI1 in apigenin-treated lung cancer cells. Mol. Biol. Rep. 48(3), 2291–2297. https://doi.org/10.1007/s11033-021-06255-7 (2021) (Epub 2021 Mar 6).
doi: 10.1007/s11033-021-06255-7
pubmed: 33675467
pmcid: 8060201
Husain, K. et al. Apigenin targets MicroRNA-155, enhances SHIP-1 expression, and augments anti-tumor responses in pancreatic cancer. Cancers (Basel). 14(15), 3613. https://doi.org/10.3390/cancers14153613 (2022).
doi: 10.3390/cancers14153613
pubmed: 35892872
pmcid: 9331563
Xie, Q. et al. Apigenin inhibits growth of melanoma by suppressing miR-512-3p and promoting the G1 phase of cell cycle involving the p27 Kip1 protein. Mol. Cell Biochem. 477(5), 1569–1582. https://doi.org/10.1007/s11010-022-04363-x (2022) (Epub 2022 Feb 22).
doi: 10.1007/s11010-022-04363-x
pubmed: 35194732
Kumbhar, N. et al. Repurposing of neprilysin inhibitor ‘sacubitrilat’as an anti-cancer drug by modulating epigenetic and apoptotic regulators. Sci. Rep. 13(1), 9952 (2023).
pubmed: 37336927
pmcid: 10279647
doi: 10.1038/s41598-023-36872-0
Gacche, R. N. et al. Flavonoids as a scaffold for development of novel anti-angiogenic agents: An experimental and computational enquiry. Arch. Biochem. Biophys. 577–578, 35–48 (2015).
pubmed: 25937258
doi: 10.1016/j.abb.2015.04.009
Utage, B. G., Patole, M. S., Nagvenkar, P. V., Kamble, S. S. & Gacche, R. N. Prosopis juliflora (Sw.), DC induces apoptosis and cell cycle arrest in triple negative breast cancer cells: in vitro and in vivo investigations. Oncotarget. 9(54), 30304–30323 (2018).
pubmed: 30100991
pmcid: 6084402
doi: 10.18632/oncotarget.25717
Kamble, S. S. et al. Chloroxylon swietenia (Roxb.) DC induces cell death and apoptosis by down-regulating the NF-κB pathway in MCF-7 breast cancer cells: In vitro and in vivo investigations. Cancer Rep. (Hoboken). 5(10), e1600 (2022).
pubmed: 35274824
pmcid: 9575507
doi: 10.1002/cnr2.1600
Choudhari, J. et al. DC phytochemicals induce apoptosis and inhibit cell proliferation signaling pathways, EMT, Migration, Invasion, angiogenesis, and stem cell markers in melanoma cell lines. J. Ethanopharmacol. 312, 116472 (2023).
doi: 10.1016/j.jep.2023.116472
Chou, T. C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev. 58(3), 621–681 (2006).
pubmed: 16968952
doi: 10.1124/pr.58.3.10
Schmittgen, T. D. & Livak, K. J. Analyzing real-time PCR data by the comparative C(T) method. Nat. Protoc. 3(6), 1101–1108 (2008).
pubmed: 18546601
doi: 10.1038/nprot.2008.73
Urb, M. et al. Glucocorticoid receptor stimulation resulting from early life stress affects expression of DNA methyltransferases in rat prefrontal cortex. J. Mol. Neurosci. https://doi.org/10.1007/s12031-019-01286-z (2019).
doi: 10.1007/s12031-019-01286-z
pubmed: 30852742
Verdonk, M. L. et al. Improved protein-ligand docking using GOLD. Proteins 52(4), 609–623 (2003).
pubmed: 12910460
doi: 10.1002/prot.10465
Watson, P. J. et al. Insights into the activation mechanism of class I HDAC complexes by inositol phosphates. Nat. Commun. 7, 11262 (2016).
pubmed: 27109927
pmcid: 4848466
doi: 10.1038/ncomms11262
Watson, P. J. et al. Structure of HDAC3 bound to co-repressor and inositol tetraphosphate. Nature 481(7381), 335–340 (2012).
pubmed: 22230954
pmcid: 3272448
doi: 10.1038/nature10728
Van Der Spoel, D. et al. GROMACS: Fast, flexible, and free. J. Comput. Chem. 26(16), 1701–1718 (2005).
pubmed: 16211538
doi: 10.1002/jcc.20291
Oostenbrink, C. et al. A biomolecular force field based on the free enthalpy of hydration and solvation: The GROMOS force-field parameter sets 53A5 and 53A6. J. Comput. Chem. 25, 1656–1676 (2004).
pubmed: 15264259
doi: 10.1002/jcc.20090
Schuettelkopf, A. W. & van Aalten, D. M. F. PRODRG—a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallograph. D60, 1355–1363 (2004).
Hoover, W. G. Canonical dynamics: Equilibrium phase-space distributions. Phys. Rev. A 31, 1695–1697 (1985).
doi: 10.1103/PhysRevA.31.1695
Parrinello, M. & Rahman, A. Polymorphic transitions in single crystals: A new molecular dynamics method. J. Appl. Phys. 52, 7182 (1981).
doi: 10.1063/1.328693
Hess, B. et al. LINCS: A linear constraint solver for molecular simulations. J. Comput. Chem. 18, 1463–1472 (1997).
doi: 10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H
Darden, T., York, D. & Pedersen, L. Particle mesh Ewald: An N-log(N) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089–10092 (1993).
doi: 10.1063/1.464397
Son, M. et al. Exploration of virtual candidates for human HMG-CoA reductase inhibitors using pharmacophore modelling and molecular dynamics simulations. PLoS One 8(12), e83496 (2013).
pubmed: 24386216
pmcid: 3875450
doi: 10.1371/journal.pone.0083496
Kumari, R., Kumar, R. & Lynn, A. G-Mmpbsa-A GROMACS tool for high-throughput MM-PBSA calculations. J. Chem. Inf. Model. 54, 1951–1962 (2014).
pubmed: 24850022
doi: 10.1021/ci500020m
Zhang, H. et al. Enhanced anticancer effect of ABT-737 in combination with naringenin on gastric cancer cells. Exp. Ther. Med. 11, 669–673 (2016).
pubmed: 26893664
doi: 10.3892/etm.2015.2912
Granado-Serrano, A. B. et al. Molecular mechanisms of (-)-epicatechin and chlorogenic acid on the regulation of the apoptotic and survival/proliferation pathways in a human hepatoma cell line. J. Agric. Food Chem. 55, 2020–2027 (2007).
pubmed: 17286412
doi: 10.1021/jf062556x
Sun, S., Gong, F., Liu, P. & Miao, Q. Metformin combined with quercetin synergistically repressed prostate cancer cells via inhibition of VEGF/PI3K/Akt signaling pathway. Gene 664, 50–57 (2018).
pubmed: 29678660
doi: 10.1016/j.gene.2018.04.045
Johari, S. A. T., Hashim, F., Ismail, W. I. & Ali, A. M. Combinatorial cytotoxic effects of gelam honey and 5-fluorouracil against human adenocarcinoma colon cancer HT-29 cells in vitro. Int. J. Cell Biol. 21(2019), 3059687. https://doi.org/10.1155/2019/3059687 (2019).
doi: 10.1155/2019/3059687
Kopustinskiene, D. M., Jakstas, V., Savickas, A. & Bernatoniene, J. Flavonoids as anticancer agents. Nutrients. 12(2), 457. https://doi.org/10.3390/nu12020457 (2020).
doi: 10.3390/nu12020457
pubmed: 32059369
pmcid: 7071196
Kashafi, E., Moradzadeh, M., Mohamadkhani, A. & Erfanian, S. Kaempferol increases apoptosis in human cervical cancer HeLa cells via PI3K/AKT and telomerase pathways. Biomed. Pharmacother. 89, 573–577 (2017).
pubmed: 28258039
doi: 10.1016/j.biopha.2017.02.061
Tavsan, Z. & Kayali, H. A. Flavonoids showed anticancer effects on the ovarian cancer cells: Involvement of reactive oxygen species, apoptosis, cell cycle and invasion. Biomed. Pharmacother. 116, 109004. https://doi.org/10.1016/j.biopha.2019.109004 (2019) (Epub 2019 May 22).
doi: 10.1016/j.biopha.2019.109004
pubmed: 31128404
Liu, R. et al. Apigenin enhances the cisplatin cytotoxic effect through p53-modulated apoptosis. Oncol. Lett. 13, 1024–1030 (2017).
pubmed: 28356995
doi: 10.3892/ol.2016.5495
Zhang, Y. et al. Flavonoids from Chinese bayberry leaves induced apoptosis and G1 cell cycle arrest via Erk pathway in ovarian cancer cells. Eur. J. Med. Chem. 147, 218–226. https://doi.org/10.1016/j.ejmech.2018.01.084 (2018) (Epub 2018 Jan 31).
doi: 10.1016/j.ejmech.2018.01.084
pubmed: 29438890
pmcid: 5823286
Zhang, Y. et al. Dietary compound proanthocyanidins from Chinese bayberry (Myrica rubra Sieb. et Zucc.) leaves attenuate chemotherapy-resistant ovarian cancer stem cell traits via targeting the Wnt/β-catenin signaling pathway and inducing G1 cell cycle arrest. Food Funct. 9(1), 525–533. https://doi.org/10.1039/c7fo01453h (2018).
doi: 10.1039/c7fo01453h
pubmed: 29256569
pmcid: 5962270
Pandey, M. et al. Plant flavone apigenin inhibits HDAC and remodels chromatin to induce growth arrest and apoptosis in human prostate cancer cells: In vitro and in vivo study. Mol. Carcinog. 51, 952–962 (2012).
pubmed: 22006862
doi: 10.1002/mc.20866
Niu, G. et al. Quercetin induces apoptosis by activating caspase-3 and regulating Bcl-2 and cyclooxygenase-2 pathways in human HL-60 cells. Acta Biochim. Biophys. Sin. 43, 30–37 (2011).
pubmed: 21173056
doi: 10.1093/abbs/gmq107
Chou, C. C. et al. Quercetin-mediated cell cycle arrest and apoptosis involving activation of a caspase cascade through the mitochondrial pathway in human breast cancer MCF-7 cells. Arch. Pharmacal. Res. 33, 1181–1191 (2010).
doi: 10.1007/s12272-010-0808-y
Zhao, D., Li, F. L., Cheng, Z. L. & Lei, Q. Y. Impact of acetylation on tumor metabolism. Mol. Cell. Oncol. 29(3), e963452. https://doi.org/10.4161/23723548.2014.963452 (2014).
doi: 10.4161/23723548.2014.963452
Zhang, W. & Xu, J. DNA methyltransferases and their roles in tumorigenesis. Biomark. Res. 5, 1. https://doi.org/10.1186/s40364-017-0081-z (2017).
doi: 10.1186/s40364-017-0081-z
pubmed: 28127428
pmcid: 5251331
Wang, D. F. et al. Toward selective histone deacetylase inhibitor design: Homology modelling, docking studies, and molecular dynamics simulations of human class I histone deacetylases. J. Med. Chem. 48(22), 6936–6947 (2005).
pubmed: 16250652
doi: 10.1021/jm0505011
Sangeetha, S. et al. Breast cancer specific histone deacetylase inhibitors and lead discovery using molecular docking and descriptor study. Trends Bioinf. 6, 25–44 (2013).
doi: 10.3923/tb.2013.25.44
Halder, A. K. et al. Design of dual MMP-2/HDAC-8 inhibitors by pharmacophore mapping, molecular docking, synthesis, and biological activity. RSC Adv. 5(88), 72373–72386 (2015).
doi: 10.1039/C5RA12606A
Kumbhar, N. M. et al. Identification of novel leads as potent inhibitors of HDAC3 using ligand-based pharmacophore modelling and MD simulation. Sci. Rep. 12, 1712 (2022).
pubmed: 35110603
pmcid: 8810932
doi: 10.1038/s41598-022-05698-7
Barale, S. S. et al. Molecular insights into destabilization of Alzheimer’s Aβ protofibril by arginine containing short peptides: A molecular modelling approach. ACS Omega 4(1), 892–903 (2019).
doi: 10.1021/acsomega.8b02672
Ganai, S. A., Farooq, Z., Banday, S. & Altaf, M. In silico approaches for investigating the binding propensity of apigenin and luteolin against class I HDAC isoforms. Future Med. Chem. 10(16), 1925–1945. https://doi.org/10.4155/fmc-2018-0020 (2018) (Epub 2018 Jul 11).
doi: 10.4155/fmc-2018-0020
pubmed: 29992822