Citrus sinensis (L) Peels Extract Inhibits Metastasis of Breast Cancer Cells by Targeting the Downregulation Matrix Metalloproteinases-9

Authors

  • Meiny Suzery Department of Chemistry, Faculty of Sciences and Mathematics, Diponegoro University, Semarang, Indonesia
  • Bambang Cahyono Department of Chemistry, Faculty of Sciences and Mathematics, Diponegoro University, Semarang, Indonesia
  • Nur Dina Amalina Pharmacy Study Program, Faculty of Mathematics and Natural Sciences, Semarang State University, Semarang, Indonesia https://orcid.org/0000-0002-6314-3661

DOI:

https://doi.org/10.3889/oamjms.2021.6072

Keywords:

Citrus sinensis, Co-chemotherapy, Matrix metalloproteinases-9, Metastasis, MDA-MB-231 breast cancer cells

Abstract

Introduction:

Long-term use of doxorubicin (DOX) chemotherapy causes several side effects, especially induction of metastasis on breast cancer (BC). There is an urgent need to identify novel agent with low side effect targeting BC metastasis. Citrus sinensis (L.) peels extract (CSP) has long been used for the treatment of several cancer. However, its anti-metastatic potential against BC metastatic remains unclear.

Objective:

This study aimed to explore the role of CSP in combination with DOX in inhibiting the migration of metastatic breast cancer MDAMB-231 cells.

Material and Methods:

Potential cytotoxic in single and combination was analysed 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT assay). The anti-metastatic activities of several major compound on CSP including hesperetin, tangeretin, nobiletin, naringenin and hesperidin were screened by molecular docking under PLANTS software.

Results:

Based on molecular docking we revealed that the selected protein target MMP-9 (PBD ID:2OVX) has lower docking score for hesperetin, tangeretin, nobiletin, naringenin and hesperidin compare to DOX. CSP and DOX individually exhibited strong cytotoxic effect on MDA-MB-231 cells under MTT assay with IC50 value of 344 µg/mL and 85 nM, respectively. Furthermore, CSP in combination with DOX synergistically increased the cytotoxicity of DOX. Here, we showed that CSP can specifically suppress the side effect of DOX-induced metastasis by reduces doses of DOX. However, low doses of DOX in combination with CSP still potential inhibited cancer cells growth.

Conclusion:

In conclusion, CSP increased the cytotoxicity and inhibited the induction of metastasis by DOX in breast cancer cells. So that, CSP potential to be developed as co-chemotherapeutic agent.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Sinaga ES, Ahmad RA, Shivalli S, Hutajulu SH. Age at diagnosis predicted survival outcome of female patients with breast cancer at a tertiary hospital in Yogyakarta, Indonesia. Pan Afr Med J. 2018;31:1-9. https://doi.org/10.11604/pamj.2018.31.163.17284 PMid:31086616

Mythreye K, Blobe GC. Proteoglycan signaling co-receptors: Roles in cell adhesion, migration and invasion. Cell Signal. 2009;21(11):1548-58. https://doi.org/10.1016/j.cellsig.2009.05.001 PMid:19427900

Walker C, Mojares E, Del Río Hernández A. Role of extracellular matrix in development and cancer progression. Int J Mol Sci. 2018;19(10):3028. https://doi.org/10.3390/ijms19103028 PMid:30287763

Jabłońska-Trypuć A, Matejczyk M, Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhib Med Chem. 2016;31(1):177-83. https://doi.org/10.3109/14756366.2016.1161620 PMid:27028474

Ikawati M, Jenie RI, Utomo RY, Amalina ND, Nur Ilmawati GP, Kawaichi M, et al. Genistein enhances cytotoxic and antimigratory activities of doxorubicin on 4T1 breast cancer cells through cell cycle arrest and ROS generation. J Appl Pharm Sci. 2020;10(10):95-104. https://doi.org/10.7324/japs.2020.1010011

Ran S. The role of TLR4 in chemotherapy-driven metastasis. Cancer Res. 2015;75(12):2405-10. https://doi.org/10.1158/0008-5472.can-14-3525 PMid:25998620

Griffiths CL, Olin JL. Triple negative breast cancer: A brief review of its characteristics and treatment options. J Pharm Pract. 2012;25(3):319-23. https://doi.org/10.1177/0897190012442062 PMid:22551559

Bandyopadhyay A, Wang L, Agyin J, Tang Y, Lin S, Yeh IT, et al. Doxorubicin in combination with a small TGFbeta inhibitor: A potential novel therapy for metastatic breast cancer in mouse models. PLoS One. 2010;5(4):e10365. https://doi.org/10.1371/journal.pone.0010365 PMid:20442777

Amalina N, Nurhayati IP, Meiyanto E. Doxorubicin induces lamellipodia formation and cell migration. Indones J Cancer Chemoprev. 2017;8(2):61. https://doi.org/10.14499/indonesianjcanchemoprev8iss2pp61-67

Nurhayati IP, Khumaira A, Ilmawati GP, Meiyanto E, Hermawan A. Cytotoxic and antimetastatic activity of hesperetin and doxorubicin combination toward her2 expressing breast cancer cells. Asian Pac J Cancer Prev. 2020;21(5):1259-67. https://doi.org/10.31557/apjcp.2020.21.5.1259 PMid:32458631

Febriansah R, Putri DD, Sarmoko S, Nurulita NA, Meiyanto E, Nugroho AE. Hesperidin as a preventive resistance agent in MCF-7 breast cancer cells line resistance to doxorubicin. Asian Pac J Trop Biomed. 2014;4(3):228-33. https://doi.org/10.1016/s2221-1691(14)60236-7 PMid:25182442

Tanvir EM, Hossen MS, Hossain MF, Afroz R, Gan SH, Khalil MI, et al. Antioxidant properties of popular turmeric (Curcuma longa) varieties from Bangladesh. J Food Qual. 2017;2017:8471785. https://doi.org/10.1155/2017/8471785

Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65(1-2):55-63. https://doi.org/10.1016/0022-1759(83)90303-4 PMid:6606682

Suzery M, Cahyono B, Amalina ND. Antiproliferative and apoptosis effect of hyptolide from Hyptis pectinata (L.) poit on human breast cancer cells. 2020;10(2):1-6. https://doi. org/10.7324/japs.2020.102001

Khamis AA, Ali EM, El-Moneim MA, Abd-Alhaseeb MM, El-Magd MA, Salim EI. Hesperidin, piperine and bee venom synergistically potentiate the anticancer effect of tamoxifen against breast cancer cells. Biomed Pharmacother. 2018;105:1335-43. https://doi.org/10.1016/j.biopha.2018.06.105 PMid:30021371

Meiyanto E, Hermawan A, Anindyajati A. Natural productsfor cancer-targeted therapy: Citrus flavonoids as potentchemopreventive agents. Asian Pac J Cancer Prev.2012;13(2):427-36. https://doi.org/10.7314/apjcp.2012.13.2.427PMid:22524801 PMid:22524801

Park HJ, Kim MJ, Ha E, Chung JH. Apoptotic effect of hesperidin through caspase3 activation in human colon cancer cells, SNU-C4. Phytomedicine. 2008;15(1-2):147-51. https://doi.org/10.1016/j.phymed.2007.07.061 PMid:17897817

Korga A, Ostrowska M, Jozefczyk A, Iwan M, Wojcik R, Zgorka G, et al. Apigenin and hesperidin augment the toxic effect of doxorubicin against HepG2 cells. BMC Pharmacol Toxicol. 2019;20(1):22. https://doi.org/10.1186/s40360-019-0301-2 PMid:31053173

Priscilla DH, Jayakumar M, Thirumurugan K. Flavanone naringenin: An effective antihyperglycemic and antihyperlipidemic nutraceutical agent on high fat diet fed streptozotocin induced Type 2 diabetic rats. J Funct Foods. 2015;14:363-73. https://doi.org/10.1016/j.jff.2015.02.005

Tun JO, Salvador-Reyes LA, Velarde MC, Saito N, Suwanborirux K, Concepcion GP. Synergistic cytotoxicity of renieramycin M and doxorubicin in MCF-7 breast cancer cells. Mar Drugs. 2019;17(9):536. https://doi.org/10.3390/md17090536 PMid:31527453

Xia R, Sheng X, Xu X, Yu C, Lu H. Hesperidin induces apoptosis and G0/G1 arrest in human non-small cell lung cancer A549 cells. Int J Mol Med. 2018;41(1):464-72. https://doi.org/10.3892/ijmm.2017.3250 PMid:29138795

Jenie RI, Amalina ND, Ilmawati GP, Utomo RY, Ikawati M, Khumaira A, et al. Cell cycle modulation of CHO-K1 cells under genistein treatment correlates with cells senescence, apoptosis and ROS level but in a dose-dependent manner. Adv Pharm Bull. 2019;9(3):453-61. https://doi.org/10.15171/apb.2019.054 PMid:31592434

Amalina ND, Suzery M, Cahyono B. Mengungkap potensi metabolit sekunder tanaman herbal Indonesia untuk menghentikan metastasis kanker payudara: Pendekatan in-silico. Indones J. 2020;9(3):154-9.

Ujfaludi Z, Tuzesi A, Majoros H, Rothler B, Pankotai T, Boros IM. Coordinated activation of a cluster of MMP genes in response to UVB radiation. Sci Rep. 2018;8(1):1-10. https://doi.org/10.1038/ s41598-018-20999-6

Downloads

Published

2021-06-27

How to Cite

1.
Suzery M, Cahyono B, Amalina ND. Citrus sinensis (L) Peels Extract Inhibits Metastasis of Breast Cancer Cells by Targeting the Downregulation Matrix Metalloproteinases-9. Open Access Maced J Med Sci [Internet]. 2021 Jun. 27 [cited 2021 Sep. 20];9(B):464-9. Available from: https://oamjms.eu/index.php/mjms/article/view/6072