Diosmin Enhances the Anti-migration Activity of Curcumin Analog PGV-1 on Colorectal Cancer Cells

Muthi Ikawati, Rohmad Yudi Utomo, Novia Permata Hapsari, Edy Meiyanto, Chio Oka

Abstract


BACKGROUND: Diosmin enhances the cytotoxicity of Pentagamavunone-1 (PGV-1) in cancer cells. PGV-1 and diosmin are predicted to target several matrix metalloproteinases (MMPs) in metastatic cancer, including colorectal cancer, but the anti-migration potency of their combination has not established yet. This study evaluates the anti-migration effect of PGV-1 and diosmin combination in colorectal cancer.

METHODS: The cytotoxicity assay using Cell Counting Kit 8 (CCK-8) method in WiDr colorectal cancer cells was carried out to determine the concentration for anti-migration experiments. The wound healing assay was used to observe the anti-migration activity by measuring the cell-free area. Gelatin zymography was employed to detect the MMP activity indicating by the clear band density. The interaction between PGV-1 or diosmin and MMP proteins was predicted by molecular dockings.

RESULTS: PGV-1 was cytotoxic (IC50 17 mM), while diosmin up to 100 mM did not affect cell viability. Both 10 mM PGV-1 as well as 50 and 100 mM diosmin slowed down the closure of cell-free area. A 100 mM diosmin was significantly enhance the anti-migratory activity of 50 and 100 mM PGV-1. The activity of MMP-9 and MMP-2 was also lower in the presence of diosmin compared to than that of PGV-1 alone. PGV-1 or diosmin was also able to interact with MMP proteins with a lower energy compared to than that of the native ligands.

CONCLUSION: Diosmin enhances the anti-migration activity of PGV-1 in WiDr cells, possibly by affecting MMPs’ activity. This study is an evidence that diosmin is a potential co-chemotherapy candidate for PGV-1, that can be utilized to overcome metastatis in colorectal cancer.

KEYWORDS: cancer, citrus flavonoid, co-chemotherapy, diosmin, matrix metalloproteinases (MMPs), migration, Pentagamavunone-1, WiDr cancer cell


Full Text:

PDF

References


Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71(3): 209-49, CrossRef.

Azwar S, Seow HF, Abdullah M, Faisal Jabar M, Mohtarrudin N. Recent updates on mechanisms of resistance to 5-fluorouracil and reversal strategies in colon cancer treatment. Biology. 2021; 10(9): e854, CrossRef.

Zhou M, Liu X, Li Z, Huang Q, Li F, Li CY. Caspase-3 regulates the migration, invasion and metastasis of colon cancer cells. Int J Cancer. 2018; 143(4): 921-30, CrossRef.

Riihimaki M, Hemminki A, Sundquist J, Hemminki K. Patterns of metastasis in colon and rectal cancer. Sci Rep. 2016; 15(6): e29765, CrossRef.

Reksohadiprodjo MS, Timmerman H, Sardjiman, Margono SA, Martono S, Hakim LR, et al. Derivatives of benzylidene cyclohexanone, benzylidene cyclopentanone, and benzylidene acetone, and therapeutic uses thereof. US Patent 6,777,447 B2. 2004, article.

Meiyanto E, Septisetyani EP, Utomo RY, Jenie RI, Ikawati M, Hermawan A, et al. Modification of pentagamavunon-1 (2,5-bis-(4-hydroxy-3,5-dimethylbenzylidene)-cyclopentanone synthesis technique and cytotoxic activity in breast and colon cancer cells. Indonesian Patent P00201809650. 2023, article.

Lestari B, Nakamae I, Yoneda-Kato N, Morimoto T, Kanaya S, Yokoyama T, et al. Pentagamavunon-1 (PGV-1) inhibits ROS metabolic enzymes and suppresses tumor cell growth by inducing M phase (prometaphase) arrest and cell senescence. Sci Rep. 2019; 9(1): e14867, CrossRef.

Meiyanto E, Septisetyani EP, Larasati YA, Kawaichi M. Curcumin analog pentagamavunon-1 (PGV-1) sensitizes WiDr cells to 5-fluorouracil through inhibition of NF-κB activation. Asian Pac J Cancer Prev. 2018; 19(1): 49-56, CrossRef.

Wulandari F, Ikawati M, Kirihata M, Kato JY, Meiyanto E. Curcumin analogs, PGV-1 and CCA-1.1 exhibit anti-migratory effects and suppress MMP9 expression on WiDr cells. Indones Biomed J. 2021; 13(3): 271-80, CrossRef.

Wulandari F, Ikawati M, Widyarini S, Kirihata M, Novitasari D, Kato JY, et al. Tumour‐suppressive effects of curcumin analogs CCA‐1.1 and pentagamavunone‐1 in colon cancer: in vivo and in vitro studies. J Adv Pharm Technol Res. 2023; 14(4): 317-24, CrossRef.

Novitasari D, Meiyanto E, Kato JY, Jenie RI. Antimigratory evaluation from curcumin-derived synthetic compounds PGV-1 and CCA-1.1 on HCC1954 and MDA-MB-231 cells. Indones J Cancer Chemoprev. 2022; 13(2): 71-82, CrossRef.

Novitasari D, Nakamae I, Jenie RI, Yoneda-Kato N, Kato JY, Meiyanto E. Pentagamavunone-1 inhibits aggressive breast cancer cell proliferation through mitotic catastrophe and ROS-mediated activities: in vitro and in vivo studies. Saudi Pharm J. 2023; 32(1): e101892, CrossRef.

Winer A, Adams S, Mignatti P. Matrix metalloproteinase inhibitors in cancer therapy: Turning past failures into future successes. Mol Cancer Ther. 2018; 17(6): 1147-55, CrossRef.

Meiyanto E, Husnaa U, Kastian RF, Putri H, Larasati YA, Khumaira A, et al. 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. 2021; 11(1): 188-96, CrossRef.

Ikawati M, Musyayyaah H, Putri YM, Zulfin UM, Wulandari F, Putri DDP, et al. The synergistic effect of combination of pentagamavunone-1 with diosmin, galangin, and piperine in WiDr colon cancer cells: in vitro and target protein prediction. J Tropical Biodiv Biotechnol. 2023; 8(2): e80975, CrossRef.

Meiyanto E, Putri DD, Susidarti RA, Murwanti R, Sardjiman, Fitriasri A, et al. 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. 2014; 15(1): 179-84, CrossRef.

Musyayyadah H, Wulandari F, Nangimi AF, Anggraeni AD, Ikawati M, Meiyanto E. The growth suppression activity of diosmin and PGV-1 co-treatment on 4T1 breast cancer targets mitotic regulatory proteins. Asian Pac J Cancer Prev. 2021; 22(9): 2929-38, CrossRef.

Utomo RY, Wulandari F, Novitasari D, Lestari B, Susidarti RA, Jenie RI, et al. Preparation and cytotoxic evaluation of PGV-1 derivative, CCA-1.1, as a new curcumin analog with improved-physicochemical and pharmacological properties. Adv Pharm Bull. 2022; 12(3): 603-12, CrossRef.

Ikawati M, Septisetyani EP. Pentagamavunone-0 (PGV-0), a curcumin analog, enhances cytotoxicity of 5-fluorouracil and modulates cell cycle in WiDr colon cancer cells. Indones J Cancer Chemoprev. 2018; 9(1): 23-31, CrossRef.

Ikawati M, Kawaichi M, Oka C. Loss of HtrA1 serine protease induces synthetic modulation of aortic vascular smooth muscle cells. PLoS One. 2018; 13(5): e0196628, CrossRef.

Susidarti RA, Meiyanto E, Ikawati M, Normaidah, Sida NA. Chemical constituents of Indonesian Micromelum minutum leaves and their cytotoxicity againts MCF-7 and 4T1 breast cancer cells. J Math Fund Sci. 2021; 53(1): 97-108, CrossRef.

Toth M, Fridman R. Assessment of gelatinases (MMP-2 and MMP-9) by gelatin zymography. Methods Mol Med. 2001; 57: 163-74, CrossRef.

Utomo RY, Ikawati M, Putri DDP, Salsabila IA, Meiyanto E. The chemopreventive potential of diosmin and hesperidin for COVID-19 and its comorbid diseases. Indones J Cancer Chemoprev. 2020; 11(3): 154-67, CrossRef.

Tallant C, Marrero A, Gomis-Ruth FX. Matrix metalloproteinases: Fold and function of their catalytic domains. Biochim Biophys Acta. 2010; 1803(1): 20-8, CrossRef.

Rahmawati DR, Nurrochmad A, Jenie RI, Meiyanto E. The synergistic cytotoxic effect of pentagamavunon-1 (PGV-1) and curcumin correlates with the cell cycle arrest to induce mitotic catastrophe in 4T1 and T47D breast cancer cells. Indones Biomed J. 2023; 15(5): 296-350, CrossRef.

Yue B. Biology of the extracellular matrix: An overview. J Glaucoma. 2014; 23(8 Suppl 1): S20-3, CrossRef.

Najafi M, Farhood B, Mortezaee K. Extracellular matrix (ECM) stiffness and degradation as cancer drivers. J Cell Biochem. 2019; 120(3): 2782-90, CrossRef.

Burg-Roderfeld M, Roderfeld M, Wagner S, Henkel C, Grotzinger J, Roeb E. MMP-9-hemopexin domain hampers adhesion and migration of colorectal cancer cells. Int J Oncol. 2007; 30(4): 985-92, CrossRef.

Duellman T, Chen X, Wakamiya R, Yang J. Nucleic acid-induced potentiation of matrix metalloproteinase-9 enzymatic activity. Biochem J. 2018; 475(9): 1597-610, CrossRef.




DOI: https://doi.org/10.18585/inabj.v16i1.2829

Copyright (c) 2024 The Prodia Education and Research Institute

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

 

Indexed by:

                  

               

                   

 

 

The Prodia Education and Research Institute