Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Investigating the Anti-tumor and Apoptosis-inducing Effects of Coumarin Derivatives as Potent 15-Lipoxygenase Inhibitors on PC-3 Prostate Cancer Cells

Author(s): Fatemeh Maleki, Hamid Sadeghian, Ahmad Reza Bahrami, Seyed Navid Goftari and Maryam Moghaddam Matin*

Volume 23, Issue 15, 2023

Published on: 05 June, 2023

Page: [1722 - 1730] Pages: 9

DOI: 10.2174/1871520623666230511102531

Price: $65

Open Access Journals Promotions 2
Abstract

Introduction: Prostate cancer is the second most prevalent cancer among men. Despite different treatments, including surgery, chemotherapy, radiation therapy, hormone therapy and immunotherapy for this disease, patients ultimately progress to advanced states. Thus, there is a need for new treatment options targeting cell growth and apoptosis to better control the proliferation and metastasis of these cells. There are many reports indicating overexpression of the 15-lipoxygenase-1 (15-LOX-1) enzyme in prostate tumors. Studies have also shown that inhibition of this enzyme prevents the progression of prostate cancer.

Objective: This study was conducted to assess the anti-cancer properties of some coumarin derivatives as possible 15- LOX-1 inhibitors, on PC-3 prostate cancer cells.

Methods: In this study, the activity of 15-LOX-1 was evaluated in PC-3 cells by a spectrophotometric assay. In addition, due to high similarity between the 15-LOX-1 and soybean 15-lipoxygenase (SLO) (L1; EC 1, 13, 11, 12) active sites, the soybean SLO was used to investigate inhibitory effects of synthetic coumarin compounds 8- isopentenyloxycoumarin (8-IC), 8-isopentenyloxy-3-carboxycoumarin (8-ICC), 8-geranyloxycoumarin (8-GC), 8- geranyloxy-3-carboxycoumarin (8-GCC), and 8-farnesyloxy-3-carboxycoumarin (8-FCC) on this enzyme. Moreover, the cytotoxic and anticancer effects of the coumarin compounds were examined on PC-3 (Prostate Cancer) and HDF-1 (Human Dermal Fibroblast) cells by alamarBlue assay. Finally, apoptosis-inducing effects of all synthetic compounds were determined by flow cytometry.

Results: The IC50 values obtained by the alamarBlue test revealed that 8-IC, 8-GC and 8-GCC had cytotoxic effects on PC-3 cells. Treating both PC-3 and HDF-1 cells with 8-ICC and 8-FCC did not significantly reduce cell number. Furthermore, the IC50 values of 8-IC on HDF-1 cells showed cytotoxic effects, while treating these cells with 8-GC and 8- GCC did not show any significant cytotoxicity on these normal human fibroblasts. Assessing the ability of 4-MMPB (as a specific inhibitor of 15-LOX-1), 8-GC, and 8-GCC compounds to inhibit SLO revealed that these compounds exerted strong 15-LOX-1 inhibitory activity, while 8-IC and 8-FCC had a weak inhibitory effect and also 8-ICC showed no inhibitory effect on SLO enzyme. In addition, flow cytometric analysis by FITC (fluorescein isothiocyanate)- annexin V and propidium iodide showed that treatment with IC50 values of 8-GC and 8-GCC induced apoptosis in 35.2% and 30.8% of PC-3 cells, respectively.

Conclusion: Thus, 8-GC and 8-GCC can be introduced as effective anticancer agents with apoptosis-inducing properties. Furthermore, our results suggest that the cytotoxic effects of these compounds might be related to the inhibition of 15-LOX-1 enzyme in PC-3 cells. On the other hand, the cytotoxic effects of 8-IC might be due to the inhibition of other signaling pathways in PC-3 cells. However, further in vivo experiments are required to determine the exact mechanisms involved in the anticancer effects of these coumarin compounds.

Keywords: Coumarin compounds, 15-LOX-1, PC-3 cells, HDF-1 cells, prostate cancer, alamarBlue assay, flow cytometry.

Graphical Abstract
[1]
Barsouk, A.; Padala, S.A.; Vakiti, A.; Mohammed, A.; Saginala, K.; Thandra, K.C.; Rawla, P.; Barsouk, A. Epidemiology, staging and management of prostate cancer. Med. Sci., 2020, 8(3), 28.
[http://dx.doi.org/10.3390/medsci8030028] [PMID: 32698438]
[2]
Bubendorf, L.; Schöpfer, A.; Wagner, U.; Sauter, G.; Moch, H.; Willi, N.; Gasser, T.C.; Mihatsch, M.J. Metastatic patterns of prostate cancer: An autopsy study of 1,589 patients. Hum. Pathol., 2000, 31(5), 578-583.
[http://dx.doi.org/10.1053/hp.2000.6698] [PMID: 10836297]
[3]
Lee, J.C.; Shin, E.A.; Kim, B.; Kim, B.I.; Chitsazian-Yazdi, M.; Iranshahi, M.; Kim, S.H. Auraptene induces apoptosis via myeloid cell leukemia 1-mediated activation of caspases in PC3 and DU145 prostate cancer cells. Phytother. Res., 2017, 31(6), 891-898.
[http://dx.doi.org/10.1002/ptr.5810] [PMID: 28383142]
[4]
Chen, Y.Q.; Edwards, I.J.; Kridel, S.J.; Thornburg, T.; Berquin, I.M. Dietary fat’gene interactions in cancer. Cancer Metastasis Rev., 2007, 26(3-4), 535-551.
[http://dx.doi.org/10.1007/s10555-007-9075-x] [PMID: 17849170]
[5]
Brash, A.R. Lipoxygenases: Occurrence, functions, catalysis, and acquisition of substrate. J. Biol. Chem., 1999, 274(34), 23679-23682.
[http://dx.doi.org/10.1074/jbc.274.34.23679] [PMID: 10446122]
[6]
Kühn, H.; Barnett, J.; Grunberger, D.; Baecker, P.; Chow, J.; Nguyen, B.; Bursztyn-Pettegrew, H.; Chan, H.; Sigal, E. Overexpression, purification and characterization of human recombinant 15-lipoxygenase. Biochim. Biophys. Acta Lipids Lipid Metab., 1993, 1169(1), 80-89.
[http://dx.doi.org/10.1016/0005-2760(93)90085-N] [PMID: 8334154]
[7]
Brash, A.R.; Boeglin, W.E.; Chang, M.S. Discovery of a second 15 S -lipoxygenase in humans. Proc. Natl. Acad. Sci., 1997, 94(12), 6148-6152.
[http://dx.doi.org/10.1073/pnas.94.12.6148] [PMID: 9177185]
[8]
Kelavkar, U.P.; Nixon, J.B.; Cohen, C.; Dillehay, D.; Eling, T.E.; Badr, K.F. Overexpression of 15-lipoxygenase-1 in PC-3 human prostate cancer cells increases tumorigenesis. Carcinogenesis, 2001, 22(11), 1765-1773.
[http://dx.doi.org/10.1093/carcin/22.11.1765] [PMID: 11698337]
[9]
Spindler, S.A.; Sarkar, F.H.; Sakr, W.A.; Blackburn, M.L.; Bull, A.W.; Lagattuta, M.; Reddy, R.G. Production of 13-hydroxyoctadecadienoic acid (13-HODE) by prostate tumors and cell lines. Biochem. Biophys. Res. Commun., 1997, 239(3), 775-781.
[http://dx.doi.org/10.1006/bbrc.1997.7471] [PMID: 9367845]
[10]
Shen, J-Q.; Zhang, Z-X.; Shen, C-F.; Liao, J-Z. Anticarcinogenic effect of Umbelliferone in human prostate carcinoma: An in vitro study. J. BUON, 2017, 22(1), 94-101.
[PMID: 28365941]
[11]
Garg, S.S.; Gupta, J.; Sharma, S.; Sahu, D. An insight into the therapeutic applications of coumarin compounds and their mechanisms of action. Eur. J. Pharm. Sci., 2020, 152, 105424.
[http://dx.doi.org/10.1016/j.ejps.2020.105424] [PMID: 32534193]
[12]
Stoyanov, E.; Mezger, J. Pechmann reaction promoted by boron trifluoride dihydrate. Molecules, 2005, 10(7), 762-766.
[http://dx.doi.org/10.3390/10070762] [PMID: 18007344]
[13]
Bruneton, J. Pharmacognosy, phytochemistry, medicinal plants; Lavoisier Publishing Inc, 1995.
[14]
Orafaie, A.; Sadeghian, H.; Bahrami, A.R.; Saboormaleki, S.; Matin, M.M. 5-farnesyloxycoumarin: A potent 15-LOX-1 inhibitor, prevents prostate cancer cell growth. Med. Chem. Res., 2017, 26(1), 227-234.
[http://dx.doi.org/10.1007/s00044-016-1737-1]
[15]
Hosseinymehr, M.; Matin, M.M.; Sadeghian, H.; Bahrami, A.R.; Kaseb-Mojaver, N. 8-Farnesyloxycoumarin induces apoptosis in PC-3 prostate cancer cells by inhibition of 15-lipoxygenase-1 enzymatic activity. Anticancer Drugs, 2016, 27(9), 854-862.
[http://dx.doi.org/10.1097/CAD.0000000000000399] [PMID: 27362790]
[16]
Saboormaleki, S.; Sadeghian, H.; Bahrami, A.R.; Orafaie, A.; Matin, M.M. 7-farnesyloxycoumarin exerts anti-cancer effects on a prostate cancer cell line by 15-LOX-1 inhibition. Arch. Iran Med., 2018, 21(6), 251-259.
[PMID: 29940744]
[17]
Jabbari, A.; Mousavian, M.; Seyedi, S.M.; Bakavoli, M.; Sadeghian, H. O-prenylated 3-carboxycoumarins as a novel class of 15-LOX-1 inhibitors. PLoS One, 2017, 12(2), e0171789.
[http://dx.doi.org/10.1371/journal.pone.0171789] [PMID: 28182779]
[18]
Tveden-Nyborg, P.; Bergmann, T.K.; Jessen, N.; Simonsen, U.; Lykkesfeldt, J. BCPT policy for experimental and clinical studies. Basic Clin. Pharmacol. Toxicol., 2021, 128(1), 4-8.
[http://dx.doi.org/10.1111/bcpt.13492] [PMID: 32955760]
[19]
Iranshahi, M.; Jabbari, A.; Orafaie, A.; Mehri, R.; Zeraatkar, S.; Ahmadi, T.; Alimardani, M.; Sadeghian, H. Synthesis and SAR studies of mono O-prenylated coumarins as potent 15-lipoxygenase inhibitors. Eur. J. Med. Chem., 2012, 57, 134-142.
[http://dx.doi.org/10.1016/j.ejmech.2012.09.006] [PMID: 23047230]
[20]
Choudhary, M.I.; Thomsen, W.J. Bioassay techniques for drug development; CRC Press: Boca Raton, Florida, 2001.
[21]
Anthon, G.E.; Barrett, D.M. Colorimetric method for the determination of lipoxygenase activity. J. Agric. Food Chem., 2001, 49(1), 32-37.
[http://dx.doi.org/10.1021/jf000871s] [PMID: 11170556]
[22]
Vega-Avila, E.; Pugsley, M.K. An overview of colorimetric assay methods used to assess survival or proliferation of mammalian cells. Proc. West. Pharmacol. Soc., 2011, 54, 10-14.
[PMID: 22423572]
[23]
Prigge, S.T.; Boyington, J.C.; Gaffney, B.J.; Amzel, L.M. Structure conservation in lipoxygenases: Structural analysis of soybean lipoxygenase-1 and modeling of human lipoxygenases. Proteins, 1996, 24(3), 275-291.
[http://dx.doi.org/10.1002/(SICI)1097-0134(199603)24:3<275:AID-PROT1>3.0.CO;2-G] [PMID: 8778775]
[24]
Pandalai, P.K.; Pilat, M.J.; Yamazaki, K.; Naik, H.; Pienta, K.J. The effects of omega-3 and omega-6 fatty acids on in vitro prostate cancer growth. Anticancer Res., 1996, 16(2), 815-820.
[PMID: 8687134]
[25]
Kelavkar, U.; Lin, Y.; Landsittel, D.; Chandran, U.; Dhir, R. The yin and yang of 15-lipoxygenase-1 and delta-desaturases: Dietary omega-6 linoleic acid metabolic pathway in prostate. J. Carcinog., 2006, 5(1), 9.
[http://dx.doi.org/10.1186/1477-3163-5-9] [PMID: 16566819]
[26]
Hu, E; Kim, JB; Sarraf, P; Spiegelman, BM Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPAR gamma. Science, 1996, 274, 2100.
[http://dx.doi.org/10.1126/science.274.5295.2100]
[27]
Hsi, L.C.; Wilson, L.C.; Eling, T.E. Opposing effects of 15-lipoxygenase-1 and -2 metabolites on MAPK signaling in prostate. Alteration in peroxisome proliferator-activated receptor γ. J. Biol. Chem., 2002, 277(43), 40549-40556.
[http://dx.doi.org/10.1074/jbc.M203522200] [PMID: 12189136]
[28]
Dudek, H.; Datta, SR; Franke, TF; Birnbaum, MJ; Yao, R; Cooper, GM Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science, 1997, 275, 661-665.
[http://dx.doi.org/10.1126/science.275.5300.661]
[29]
Datta, S.R.; Dudek, H.; Tao, X.; Masters, S.; Fu, H.; Gotoh, Y.; Greenberg, M.E. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell, 1997, 91(2), 231-241.
[http://dx.doi.org/10.1016/S0092-8674(00)80405-5] [PMID: 9346240]
[30]
Szliszka, E.; Czuba, Z.P. Sędek, Ł.; Paradysz, A.; Król, W. Enhanced TRAIL-mediated apoptosis in prostate cancer cells by the bioactive compounds neobavaisoflavone and psoralidin isolated from Psoralea corylifolia. Pharmacol. Rep., 2011, 63(1), 139-148.
[http://dx.doi.org/10.1016/S1734-1140(11)70408-X] [PMID: 21441621]
[31]
Li, C.L.; Han, X.C.; Zhang, H.; Wu, J.S.; Li, B. Effect of scopoletin on apoptosis and cell cycle arrest in human prostate cancer cells in vitro. Trop. J. Pharm. Res., 2015, 14(4), 611-617.
[http://dx.doi.org/10.4314/tjpr.v14i4.8]
[32]
Song, X.F.; Fan, J.; Liu, L.; Liu, X.F.; Gao, F. Coumarin derivatives with anticancer activities: An update. Arch. Pharm., 2020, 353(8), 2000025.
[http://dx.doi.org/10.1002/ardp.202000025] [PMID: 32383190]
[33]
Rawat, A.; Reddy, A.V.B. Recent advances on anticancer activity of coumarin derivatives. Eur J. Med. Chem. Reports, 2022, 5, 100038.
[http://dx.doi.org/10.1016/j.ejmcr.2022.100038]
[34]
Fylaktakidou, K.; Hadjipavlou-Litina, D.; Litinas, K.; Nicolaides, D. Natural and synthetic coumarin derivatives with anti-inflammatory/antioxidant activities. Curr. Pharm. Des., 2004, 10(30), 3813-3833.
[http://dx.doi.org/10.2174/1381612043382710] [PMID: 15579073]
[35]
Curini, M.; Cravotto, G.; Epifano, F.; Giannone, G. Chemistry and biological activity of natural and synthetic prenyloxycoumarins. Curr. Med. Chem., 2006, 13(2), 199-222.
[http://dx.doi.org/10.2174/092986706775197890] [PMID: 16472213]
[36]
Iranshahi, M.; Askari, M.; Sahebkar, A.; Hadjipavlou, L.D. Evaluation of antioxidant, anti-inflammatory and lipoxygenase inhibitory activities of the prenylated coumarin umbelliprenin. DARU J. Pharm. Sci., 2009, 17(2), 99-103.
[37]
Aghasizadeh, M.; Moghaddam, T.; Bahrami, A.R.; Sadeghian, H.; Alavi, S.J.; Matin, M.M. 8-Geranyloxycarbostyril as a potent 15-LOX-1 inhibitor showed great anti-tumor effects against prostate cancer. Life Sci., 2022, 293, 120272.
[http://dx.doi.org/10.1016/j.lfs.2021.120272] [PMID: 35065164]
[38]
Sadeghian, H.; Attaran, N.; Jafari, Z.; Saberi, M.R.; Pordel, M.; Riazi, M.M.; Pordel, M.; Riazi, M.M. Design and synthesis of 4-methoxyphenylacetic acid esters as 15-lipoxygenase inhibitors and SAR comparative studies of them. Bioorg. Med. Chem., 2009, 17(6), 2327-2335.
[http://dx.doi.org/10.1016/j.bmc.2009.02.009] [PMID: 19251422]
[39]
Bakavoli, M.; Nikpour, M.; Rahimizadeh, M.; Saberi, M.R.; Sadeghian, H. Design and synthesis of pyrimido[4,5-b][1,4]benzothiazine derivatives, as potent 15-lipoxygenase inhibitors. Bioorg. Med. Chem., 2007, 15(5), 2120-2126.
[http://dx.doi.org/10.1016/j.bmc.2006.12.022] [PMID: 17210254]
[40]
Jabbari, A.; Davoodnejad, M.; Alimardani, M.; Assadieskandar, A.; Sadeghian, A.; Safdari, H.; Movaffagh, J.; Sadeghian, H. Synthesis and SAR studies of 3-allyl-4-prenyloxyaniline amides as potent 15-lipoxygenase inhibitors. Bioorg. Med. Chem., 2012, 20(18), 5518-5526.
[http://dx.doi.org/10.1016/j.bmc.2012.07.025] [PMID: 22917856]
[41]
Yildirim, H.; Aydemir, A.T. Multidrug resistance gene expression response to cisplatin and 5FU treatment in hepatoma, prostate and colon cancer cells. J BAUN Inst Sci Technol, 2020, 22, 698-708.
[42]
Hahm, J.C.; Lee, I.K.; Kang, W.K.; Kim, S.U.; Ahn, Y.J. Cytotoxicity of neolignans identified in Saururus chinensis towards human cancer cell lines. Planta Med., 2005, 71(5), 464-469.
[http://dx.doi.org/10.1055/s-2005-864143] [PMID: 15931587]
[43]
Dowling, C.M.; Claffey, J.; Cuffe, S.; Fichtner, I.; Pampillón, C.; Sweeney, N.J. Antitumor activity of titanocene Y in xenografted PC3 tumors in mice. Lett. Drug Des. Discov., 2008, 5, 141-144.
[http://dx.doi.org/10.2174/157018008783928463]
[44]
Matsumura, T.; Takigawa, N.; Kiura, K.; Shibayama, T.; Chikamori, M.; Tabata, M. Determinants of cisplatin and irinotecan activities in human lung adenocarcinoma cells: Evidence of cisplatin accumulation and topoisomerase I activity. In Vivo, 2005, 19, 717-721.
[45]
Gumulec, J.; Balvan, J.; Sztalmachova, M.; Raudenska, M.; Dvorakova, V.; Knopfova, L.; Polanska, H.; Hudcova, K.; Ruttkay-Nedecky, B.; Babula, P.; Adam, V.; Kizek, R.; Stiborova, M.; Masarik, M. Cisplatin-resistant prostate cancer model: Differences in antioxidant system, apoptosis and cell cycle. Int. J. Oncol., 2014, 44(3), 923-933.
[http://dx.doi.org/10.3892/ijo.2013.2223] [PMID: 24366574]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy