Hesperidin Enhanced the Antimigratory Activity and Senescence-Mediated G2/M Arrest Effect of PGV-1 Against T47D Luminal Breast Cancer Cells
Keywords:
PGV-1, hesperidin, luminal breast cancer, cell cycle.
Abstract
Luminal breast cancer cells exhibit proliferative and metastatic characteristics. Exploration of the effective treatment with minimum side effects is necessary. This study aimed to confirm the combination treatment of a potent anticancer candidate PGV-1 and hesperidin on luminal breast cancer cells, T47D, covering its cytotoxic and anti-migratory activities. PGV-1 showed much stronger cytotoxicity with an IC50 value of 2 μM than that of hesperidin (200 μM) as evaluated by trypan blue exclusion assay, but the combination of the two compounds exhibited a synergistic effect. Propidium iodide (PI) staining with flow cytometry proved that the combination treatment increased the cell population in the G2/M phase. Additionally, the combination treatment increased senescent cells as shown in senescence associated β-galactosidase (SA-β-gal) assay which might correlate to its antiproliferative properties. In addition, the scratch wound healing assay showed that the combination also inhibited cell migration significantly. Molecular docking of the two compounds demonstrated potential interaction with their protein targets in cell cycle machinery, i.e. KIF1, CDK1, TOP2A, CA12, ESR1, FN1, and TYMS. Altogether, these findings strengthen the evidence of anti-cancer properties enhancement of PGV-1 in luminal breast cancer through combining the compound with hesperidin.
References
Abuhamad AY, Zamberi NNM, Sheen L, Naes SM, Yusuf SNHM, Tajudin AA, Mohtar MA, Hamzah ASA, and Syafruddin SE. 2022. Reverting TP53 Mutation in Breast Cancer Cells: Prime Editing Workflow and Technical Considerations. Cells. 11 (10): 1612. DOI: 10.3390/cells11101612.
Brett JO, Spring LM, Bardia A, Wander SA. 2021. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 23(1): 85-99. DOI: 10.1186/s13058-021-01462-3.
Chou T-C. 2010. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70(2): 440–446. DOI: 10.1158/0008-5472.CAN-09-1947.
Da’I M, Jenie U, Am S, Meiyanto E, Kawaichi M. 2012. The Effect of PGV-1, PGV-0 and Curcumin on Protein Involve in G2-M Phase of Cell Cycle and Apoptosis on T47D Breast Cancer Cell Line. Jurnal Ilmu Kefarmasian Indonesia. 10(2): 99–110. ISSN: 1693-1831.
Endah E, Wulandari F, Putri YM, Jenie RI, Meiyanto E. 2022. Piperine Increases Pentagamavunone-1 Anti-cancer Activity on 4T1 Breast Cancer through Mitotic Catastrophe Mechanism and Senescence with Sharing Targeting on Mitotic Regulatory Proteins. Iranian J Pharm Res. 21(1): 1–13. DOI: 10.5812/ijpr.123820.
Ferreira de Oliveira JMP, Santos C, Fernandes E. 2020. Therapeutic potential of hesperidin and its aglycone hesperetin: Cell cycle regulation and apoptosis induction in cancer models. Phytomedicine. 73: 152887. DOI: 10.1016/j.phymed.2019.152887.
Hasbiyani NAF, Wulandari F, Nugroho EP, Hermawan A, Meiyanto E. 2021. Bioinformatics Analysis Confirms the Target Protein Underlying Mitotic Catastrophe of 4T1 Cells under Combinatorial Treatment of PGV-1 and Galangin. Sci Pharm. 89(38): 1-14. DOI: 10.3390/scipharm89030038.
Ikawati M, Armandari I, Khumaira A, Ertanto Y. 2020. Effects of Peel Extract from Citrus reticulata and Hesperidin, A Citrus Flavonoid, on Macrophage Cell Line. Indonesian J Pharm. 30(4): 260-268. DOI: 10.14499/indonesianjpharm30iss4pp260.
Izadi S, Nikkhoo A, Hojjat-Farsangi M, Namdar A, Azizi G, Mohammadi H, et al. 2020. CDK1 in Breast Cancer: Implications for Theranostic Potential. Anticancer Agents Med Chem. 20: 758–767. DOI: 10.2174/1871520620666200203125712.
Jenie RI, Handayani S, Susidarti RA, Meiyanto E. 2020. The Effect of Brazilin from Caesalpinia sappan on Cell Cycle and Modulation and Cell Senescence in T47D cells. Indonesian J Pharm. 31(2): 84-91. DOI: 10.14499/indonesianjpharm31iss2pp84.
Kongtawelert P, Wudtiwai B, Shwe TH, Pothacharoen P, Phitak T. 2020. Inhibitory Effect of Hesperidin on the Expression of Programmed Death Ligand (PD-L1) in Breast Cancer. Molecules. 25(2): 252-262. DOI: 10.3390/molecules25020252.
Kulkarni A, Stroup AM, Paddock LE, Hill SM, Plascak JJ, and Llanos AAM. 2019. Breast Cancer Incidence and Mortality by Molecular Subtype: Statewide Age and Racial/Ethnic Disparities in New Jersey. Cancer Health Disparities. 3: e1–e17. DOI: 10.9777/chd.2019.1012.
Larasati YA, Yoneda-Kato N, Nakamae I, Yokoyama T, Meiyanto E, Kato J. 2018. Curcumin targets multiple enzymes involved in the ROS metabolic pathway to suppress tumor cell growth. Sci Rep. 8(1): 2039. DOI: 10.1038/s41598-018-20179-6.
Lestari B, Nakamae I, Yoneda-Kato N, Morimoto T, Kanaya S, Yokoyama T, et al. 2019. Pentagamavunon-1 (PGV-1) inhibits ROS metabolic enzymes and suppresses tumor cell growth by inducing M phase (prometaphase) arrest and cell senescence. Sci Rep. 9(1): 14867. DOI: 10.1038/s41598-019-51244-3.
Li X, Kong X, Wang Y, and Yang Q. 2013. BRCC2 Inhibits Breast Cancer Cell Growth and Metastasis in Vitro and in Vivo via Downregulating AKT Pathway. Cell Death & Disease. 4 (8): e757–e757. DOI: 10.1038/cddis.2013.290.
Meiyanto E, Husnaa U, Kastian RF, Putri H, Larasati YA, Khumaira A, et al. 2021. The Target Differences of Anti-Tumorigenesis Potential of Curcumin and its Analogues Against HER-2 Positive and Triple-Negative Breast Cancer Cells. Adv Pharm Bull. 11(1): 188–196. DOI: 10.34172/apb.2021.020.
Meiyanto E, Putri H, Arum Larasati Y, Yudi Utomo R, Istighfari Jenie R, Ikawati M, et al. 2019. Anti-proliferative and Anti-metastatic Potential of Curcumin Analogue, Pentagamavunon-1 (PGV-1), Toward Highly Metastatic Breast Cancer Cells in Correlation with ROS Generation. Adv Pharm Bull. 9: 445–452. DOI: 10.15171/apb.2019.053.
Meiyanto E, Septisetyani EP, Larasati YA, Kawaichi M. 2018. Curcumin Analog Pentagamavunon-1 (PGV-1) Sensitizes Widr Cells to 5-Fluorouracil through Inhibition of NF-κB Activation. Asian Pac J Cancer Prev. 19: 49–56. DOI: 10.22034/APJCP.2018.19.1.49.
Meiyanto E, Putri DDP, Susidarti RA, Murwanti R, Sardjiman, Fitriasari A, et al. 2014. Curcumin and its analogues (PGV-0 and PGV-1) enhance sensitivity of resistant MCF-7 cells to doxorubicin through inhibition of HER2 and NF-kB activation. Asian Pac J Cancer Prev. 15(1): 179–184. DOI: 10.7314/apjcp.2014.15.1.179.
Meneguzzo F, Ciriminna R, Zabini F, Pagliaro M. 2020. Review of Evidence Available on Hesperidin-Rich Products as Potential Tools against COVID-19 and Hydrodynamic Cavitation-Based Extraction as a Method of Increasing Their Production. Processes. 8: 549. DOI: 10.3390/pr8050549.
Musyayyadah H, Wulandari F, Nangimi AF, Anggraeni AD, Ikawati M, Meiyanto E. 2021. The Growth Suppression Activity of Diosmin and PGV-1 Co-Treatment on 4T1 Breast Cancer Targets Mitotic Regulatory Proteins. Asian Pac J Cancer Prev. 22(9): 2929–2938. DOI: 10.31557/APJCP.2021.22.9.2929.
Nagasako-Akazome Y. 2014. Safety of high and long-term intake of polyphenols. In: Watson R, Preedy V, Zibadi S, (eds.). Polyphenols in human health and disease, Academic Press, Cambridge, MA, pp 747–56. DOI: 10.1016/B978-0-12-398456-2.00058-X.
Negro G, Aschenbrenner B, Brezar SK, Cemazar M, Coer A, Gasljevic G, Savic D, et al. 2020. Molecular Heterogeneity in Breast Carcinoma Cells with Increased Invasive Capacities. Radiology and Oncology. 54 (1): 103–18. DOI: 10.2478/raon-2020-0007.
Putri DDP, Maran GG, Kusumastuti Y, Susidarti RA, Meiyanto E, and Ikawati M. 2022. Acute Toxicity Evaluation and Immunomodulatory Potential of Hydrodynamic Cavitation Extract of Citrus Peels. Journal of Applied Pharmaceutical Science. 12(04): 136–45. DOI: 10.7324/JAPS.2022.120415.
Prayong P, Barusrux S, Weerapreeyakul N. 2008. Cytotoxic activity screening of some indigenous Thai plants. Fitoterapia. 79: 598–601. DOI: 10.1016/j.fitote.2008.06.007.
Sarmoko, Putri DPP, Susidarti RA, Nugroho AE, Meiyanto E. 2014. Increasing Sensitivity of MCF-7/Dox Cells Towards Doxorubicin by Hesperetin Through Suppression of P-Glycoprotein Expression. Indonesian J Pharm. 25(2): 84 – 90. DOI: 10.14499/ indonesianjpharm25iss2pp84.
Wulandari F, Ikawati M, Kirihata M, Kato J-Y, Meiyanto E. 2021. Curcumin Analogs, PGV-1 and CCA-1.1 Exhibit Anti-migratory Effects and Suppress MMP9 Expression on WiDr Cells. The Indonesian Biomedical Journal. 13: 271–280. DOI: 10.18585/inabj.v13i3.1583.
Zanwar AA, Badole AL, Shende PS, Hedge MV, Bodhankar SL. 2014. Cardiovascular effects of hesperidin: a flavanone glycoside. In: Watson R, Preedy V, Zibadi S, (eds.). Polyphenols in human health and disease, Academic Press, Cambridge, MA, pp 989–92. DOI: 10.1016/B978-0-12-398456-2.00076-1.
Zulfin U, Rahman A, Hanifa M, Utomo R, Haryanti S, Meiyanto E. 2021. Reactive oxygen species and senescence modulatory effects of rice bran extract on 4T1 and NIH-3T3 cells co-treatment with doxorubicin. Asian Pacific Journal of Tropical Biomedicine. 11(4): 174. DOI: 10.4103/2221-1691.310204.
Brett JO, Spring LM, Bardia A, Wander SA. 2021. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 23(1): 85-99. DOI: 10.1186/s13058-021-01462-3.
Chou T-C. 2010. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70(2): 440–446. DOI: 10.1158/0008-5472.CAN-09-1947.
Da’I M, Jenie U, Am S, Meiyanto E, Kawaichi M. 2012. The Effect of PGV-1, PGV-0 and Curcumin on Protein Involve in G2-M Phase of Cell Cycle and Apoptosis on T47D Breast Cancer Cell Line. Jurnal Ilmu Kefarmasian Indonesia. 10(2): 99–110. ISSN: 1693-1831.
Endah E, Wulandari F, Putri YM, Jenie RI, Meiyanto E. 2022. Piperine Increases Pentagamavunone-1 Anti-cancer Activity on 4T1 Breast Cancer through Mitotic Catastrophe Mechanism and Senescence with Sharing Targeting on Mitotic Regulatory Proteins. Iranian J Pharm Res. 21(1): 1–13. DOI: 10.5812/ijpr.123820.
Ferreira de Oliveira JMP, Santos C, Fernandes E. 2020. Therapeutic potential of hesperidin and its aglycone hesperetin: Cell cycle regulation and apoptosis induction in cancer models. Phytomedicine. 73: 152887. DOI: 10.1016/j.phymed.2019.152887.
Hasbiyani NAF, Wulandari F, Nugroho EP, Hermawan A, Meiyanto E. 2021. Bioinformatics Analysis Confirms the Target Protein Underlying Mitotic Catastrophe of 4T1 Cells under Combinatorial Treatment of PGV-1 and Galangin. Sci Pharm. 89(38): 1-14. DOI: 10.3390/scipharm89030038.
Ikawati M, Armandari I, Khumaira A, Ertanto Y. 2020. Effects of Peel Extract from Citrus reticulata and Hesperidin, A Citrus Flavonoid, on Macrophage Cell Line. Indonesian J Pharm. 30(4): 260-268. DOI: 10.14499/indonesianjpharm30iss4pp260.
Izadi S, Nikkhoo A, Hojjat-Farsangi M, Namdar A, Azizi G, Mohammadi H, et al. 2020. CDK1 in Breast Cancer: Implications for Theranostic Potential. Anticancer Agents Med Chem. 20: 758–767. DOI: 10.2174/1871520620666200203125712.
Jenie RI, Handayani S, Susidarti RA, Meiyanto E. 2020. The Effect of Brazilin from Caesalpinia sappan on Cell Cycle and Modulation and Cell Senescence in T47D cells. Indonesian J Pharm. 31(2): 84-91. DOI: 10.14499/indonesianjpharm31iss2pp84.
Kongtawelert P, Wudtiwai B, Shwe TH, Pothacharoen P, Phitak T. 2020. Inhibitory Effect of Hesperidin on the Expression of Programmed Death Ligand (PD-L1) in Breast Cancer. Molecules. 25(2): 252-262. DOI: 10.3390/molecules25020252.
Kulkarni A, Stroup AM, Paddock LE, Hill SM, Plascak JJ, and Llanos AAM. 2019. Breast Cancer Incidence and Mortality by Molecular Subtype: Statewide Age and Racial/Ethnic Disparities in New Jersey. Cancer Health Disparities. 3: e1–e17. DOI: 10.9777/chd.2019.1012.
Larasati YA, Yoneda-Kato N, Nakamae I, Yokoyama T, Meiyanto E, Kato J. 2018. Curcumin targets multiple enzymes involved in the ROS metabolic pathway to suppress tumor cell growth. Sci Rep. 8(1): 2039. DOI: 10.1038/s41598-018-20179-6.
Lestari B, Nakamae I, Yoneda-Kato N, Morimoto T, Kanaya S, Yokoyama T, et al. 2019. Pentagamavunon-1 (PGV-1) inhibits ROS metabolic enzymes and suppresses tumor cell growth by inducing M phase (prometaphase) arrest and cell senescence. Sci Rep. 9(1): 14867. DOI: 10.1038/s41598-019-51244-3.
Li X, Kong X, Wang Y, and Yang Q. 2013. BRCC2 Inhibits Breast Cancer Cell Growth and Metastasis in Vitro and in Vivo via Downregulating AKT Pathway. Cell Death & Disease. 4 (8): e757–e757. DOI: 10.1038/cddis.2013.290.
Meiyanto E, Husnaa U, Kastian RF, Putri H, Larasati YA, Khumaira A, et al. 2021. The Target Differences of Anti-Tumorigenesis Potential of Curcumin and its Analogues Against HER-2 Positive and Triple-Negative Breast Cancer Cells. Adv Pharm Bull. 11(1): 188–196. DOI: 10.34172/apb.2021.020.
Meiyanto E, Putri H, Arum Larasati Y, Yudi Utomo R, Istighfari Jenie R, Ikawati M, et al. 2019. Anti-proliferative and Anti-metastatic Potential of Curcumin Analogue, Pentagamavunon-1 (PGV-1), Toward Highly Metastatic Breast Cancer Cells in Correlation with ROS Generation. Adv Pharm Bull. 9: 445–452. DOI: 10.15171/apb.2019.053.
Meiyanto E, Septisetyani EP, Larasati YA, Kawaichi M. 2018. Curcumin Analog Pentagamavunon-1 (PGV-1) Sensitizes Widr Cells to 5-Fluorouracil through Inhibition of NF-κB Activation. Asian Pac J Cancer Prev. 19: 49–56. DOI: 10.22034/APJCP.2018.19.1.49.
Meiyanto E, Putri DDP, Susidarti RA, Murwanti R, Sardjiman, Fitriasari A, et al. 2014. Curcumin and its analogues (PGV-0 and PGV-1) enhance sensitivity of resistant MCF-7 cells to doxorubicin through inhibition of HER2 and NF-kB activation. Asian Pac J Cancer Prev. 15(1): 179–184. DOI: 10.7314/apjcp.2014.15.1.179.
Meneguzzo F, Ciriminna R, Zabini F, Pagliaro M. 2020. Review of Evidence Available on Hesperidin-Rich Products as Potential Tools against COVID-19 and Hydrodynamic Cavitation-Based Extraction as a Method of Increasing Their Production. Processes. 8: 549. DOI: 10.3390/pr8050549.
Musyayyadah H, Wulandari F, Nangimi AF, Anggraeni AD, Ikawati M, Meiyanto E. 2021. The Growth Suppression Activity of Diosmin and PGV-1 Co-Treatment on 4T1 Breast Cancer Targets Mitotic Regulatory Proteins. Asian Pac J Cancer Prev. 22(9): 2929–2938. DOI: 10.31557/APJCP.2021.22.9.2929.
Nagasako-Akazome Y. 2014. Safety of high and long-term intake of polyphenols. In: Watson R, Preedy V, Zibadi S, (eds.). Polyphenols in human health and disease, Academic Press, Cambridge, MA, pp 747–56. DOI: 10.1016/B978-0-12-398456-2.00058-X.
Negro G, Aschenbrenner B, Brezar SK, Cemazar M, Coer A, Gasljevic G, Savic D, et al. 2020. Molecular Heterogeneity in Breast Carcinoma Cells with Increased Invasive Capacities. Radiology and Oncology. 54 (1): 103–18. DOI: 10.2478/raon-2020-0007.
Putri DDP, Maran GG, Kusumastuti Y, Susidarti RA, Meiyanto E, and Ikawati M. 2022. Acute Toxicity Evaluation and Immunomodulatory Potential of Hydrodynamic Cavitation Extract of Citrus Peels. Journal of Applied Pharmaceutical Science. 12(04): 136–45. DOI: 10.7324/JAPS.2022.120415.
Prayong P, Barusrux S, Weerapreeyakul N. 2008. Cytotoxic activity screening of some indigenous Thai plants. Fitoterapia. 79: 598–601. DOI: 10.1016/j.fitote.2008.06.007.
Sarmoko, Putri DPP, Susidarti RA, Nugroho AE, Meiyanto E. 2014. Increasing Sensitivity of MCF-7/Dox Cells Towards Doxorubicin by Hesperetin Through Suppression of P-Glycoprotein Expression. Indonesian J Pharm. 25(2): 84 – 90. DOI: 10.14499/ indonesianjpharm25iss2pp84.
Wulandari F, Ikawati M, Kirihata M, Kato J-Y, Meiyanto E. 2021. Curcumin Analogs, PGV-1 and CCA-1.1 Exhibit Anti-migratory Effects and Suppress MMP9 Expression on WiDr Cells. The Indonesian Biomedical Journal. 13: 271–280. DOI: 10.18585/inabj.v13i3.1583.
Zanwar AA, Badole AL, Shende PS, Hedge MV, Bodhankar SL. 2014. Cardiovascular effects of hesperidin: a flavanone glycoside. In: Watson R, Preedy V, Zibadi S, (eds.). Polyphenols in human health and disease, Academic Press, Cambridge, MA, pp 989–92. DOI: 10.1016/B978-0-12-398456-2.00076-1.
Zulfin U, Rahman A, Hanifa M, Utomo R, Haryanti S, Meiyanto E. 2021. Reactive oxygen species and senescence modulatory effects of rice bran extract on 4T1 and NIH-3T3 cells co-treatment with doxorubicin. Asian Pacific Journal of Tropical Biomedicine. 11(4): 174. DOI: 10.4103/2221-1691.310204.
Published
2024-03-25
How to Cite
Rifai, F. N. P., Zulfin, U. M., Tafrihani, A. S., Ikawati, M., & Meiyanto, E. (2024). Hesperidin Enhanced the Antimigratory Activity and Senescence-Mediated G2/M Arrest Effect of PGV-1 Against T47D Luminal Breast Cancer Cells. Indonesian Journal of Pharmacy, 35(1), 126-137. https://doi.org/10.22146/ijp.7979
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Section
Research Article
