Document Type : Original Article(s)
Authors
1 Department of Genetics, College of Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran
2 Cellular and Molecular Research Center, Social Determinants of Health Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
Abstract
Background: Malignant melanoma is an aggressive skin cancer whose survival rate is extremely low. Commencing apoptosis is believed to be a significant issue in cancer treatment and targeting the apoptosis and WNT signaling pathways, which is probably a potentially successful strategy to overcome tumor plasticity in melanoma.
Method: We conducted the present in vitro study to investigate antiproliferative and apoptotic effects of Nic-ALA, as a new compound, on A375 melanoma cell line using MTT assay and flow cytometry, respectively. The gene expression profiles of the cancer cells were obtained for Bcl-2 and BAX as the main genes of the apoptosis signaling pathway and WIF1 and beta-catenin genes from the WNT signaling pathway with qRT-PCR.
Results: Nic-ALA’s cytotoxicity on A375 melanoma cell line from MTT assay was obtained with IC50 166.7, 144.2, and 146.1μM. This novel derivative induced 11.3, 46.1, and 85.7% of apoptosis in 24, 48, and 72h time points, respectively. In the treated cells, the expression of BAX, beta-catenin, and WIF1 genes increased, while the expression of Bcl-2 decreased significantly at 200μM concentration and the treated times of 48 and 72h.
Conclusion: The antiproliferation of Nic-ALA at a lower value than what we found in nicotinic acid alone represented the higher bioavailability and transport efficiency of this novel derivative through A375 melanoma cell line. Its antipoetic effects were obtained by increasing the apoptosis rate and expression of the Bax gene and reducing Bcl-2 gene expression. Upregulation of WIF1 and beta-catenin in the WNT signaling pathway emphasized Nic-ALA’s anticancer effect on A375 melanoma cell line.
Keywords
How to cite this article:
Malikhan H, Siasi Torbati E, Majd A, Gheibi N. Anti-cancer properties of Nicotinic Cid-alpha linolenic acid derivative on A375 melanoma cell line: Assessment of apoptosis and WNT signaling pathways. Middle East J Cancer. 2022;13(4):593-606. doi: 10.30476/mejc.2021.89494.1530.
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4.Erdmann F, Lortet-Tieulent J, Sch¸z J, Zeeb H, Greinert R, Breitbart EW, et al. International trends in the incidence of malignant melanoma 1953-2008--are recent generations at higher or lower risk? Int J Cancer. 2013;132(2):385-400. doi: 10.1002/ijc.27616.
5.Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-16. doi: 10.1056/NEJMoa1103782.
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8.Arendse, Lyle. The modulating effect of conjugated linoleic acid (CLA) on cancer cell survival in vitro. [dissertation] Cape Town: University of the Western Cape; 2014. 158 p.
9.Asghari H, Chegini KG, Amini A, Gheibi N. Effect of poly and mono-unsaturated fatty acids on stability and structure of recombinant S100A8/A9. Int J Biol Macromol. 2016;84(2):35-42. doi: 10.1016/j.ijbiomac. 2015.11.065.
10.Zajdel A, Wilczok A, Tarkowski M. Toxic effects of n-3 polyunsaturated fatty acids in human lung A549 cells. Toxicol In Vitro. 2015;30(1):486-91. doi: 10.1016/j.tiv.2015.09.013.
11.Das UN. Essential fatty acids: biochemistry, physiology and pathology. Biotechnol J. 2006;1(4):420-39. doi: 10.1002/biot.200600012.
12.Hussain G, Schmitt F, Loeffler JP, Gonzalez De Aguilar J. Fatting the brain: a brief of recent research. Front Cell Neurosci. 2013;7:144. doi: 10.3389/fncel. 2013.00144.
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14.Ljungblad LM, Johnsen JI, Wickström M, Kogner P, Gleissman H. Abstract 3275: A novel approach to treat medulloblastoma: The omega-3 fatty acids DHA and EPA reduce medulloblastoma tumor growth in vitro and in vivo. Cancer Res. 2015;75(15):3275. doi:10.1158/1538-7445.AM2015-3275.
15.Das UJ. Tumoricidal action of cis-unsaturated fatty acids and their relationship to free radicals and lipid peroxidation. Cancer Lett. 1991;56(3):235-43. doi: 10.1016/0304-3835(91)90008-6.
16.Moniri NH, Farah Q. Short-chain free-fatty acid G protein-coupled receptors in colon cancer. Bioch Pharmacol. 2021;186:114483. doi: 10.1016/j.bcp. 2021.114483.
17.Bogan KL, Brenner C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu Rev Nutr. 2008;28(3):115-30. doi: 10.1146/annurev. nutr.28.061807.155443.
18.Pan L, Yu G, Chen X, Li X. Nicotinic acid inhibits angiogenesis likely through cytoskeleton remodeling. Organogenesis. 2017;13(4):183-91. doi: 10.1080/ 15476278.2017.1364829.
19.Dubrall D, Pflock R, Kosinska J, Schmid M, Bleich M, Himmerkus N, et al. Do dimethyl fumarate and nicotinic acid elicit common, potentially HCA2 -mediated adverse reactions? A combined epidemiological-experimental approach. Br J Clin Pharmacol. 2021. doi: 10.1111/bcp.14787.
20.Norbury CJ, Hickson ID. Cellular responses to DNA damage. Annu Rev Pharmacol Toxicol. 2001;41(1) :367-401. doi: 10.1146/annurev.pharmtox. 41.1.367.
21.Berke GJC. The CTL's kiss of death. Cell. 1995;81(1):9-12. doi: 10.1016/0092-8674(95)90365-8.
22.Trisciuoglio D, Del Bufalo D. New insights into the roles of antiapoptotic members of the Bcl-2 family in melanoma progression and therapy. Drug Discov Today. 2021;S1359-6446(21)00059-3. doi: 10.1016/j.drudis.2021.01.027.
23.Tessoulin B, Papin A, Gomez-Bougie P, Bellanger C, Amiot M, Pellat-Deceunynck C, et al. BCL2-family dysregulation in B-cell malignancies: From gene expression regulation to a targeted therapy biomarker. Front Oncol. 2019;8:645. doi: 10.3389/fonc.2018.00645.
24.Liu YL, Yang HP, Gong L, Tang CL, Wang HJ. Hypomethylation effects of curcumin, demethoxycurcumin and bisdemethoxycurcumin on WIF-1 promoter in non-small cell lung cancer cell lines. Mol Med Rep. 2011;4(4):675-9. doi:10.3892/mmr.2011.473.
25.Paul S, Dey AJN. Wnt signaling and cancer development: therapeutic implication Minireview. Neoplasma. 2008;55(3):165-76.
26.Xiong X, Xu W, Gong J, Wang L, Dai M, Chen G, et al. miR-937-5p targets SOX17 to modulate breast cancer cell cycle and cell proliferation through the Wnt signaling pathway. Cell Signal. 2021;77:109818. doi:10.1016/j.cellsig.2020.109818.
27.Hsieh JC, Kodjabachian L, Rebbert ML, Rattner A, Smallwood PM, Samos CH, et al. A new secreted protein that binds to Wnt proteins and inhibits their activites. Nature. 1999;398(6726):431-6. doi:10.1038/18899.
28.Mazieres J, He B, You L, Xu Z, Lee AY, Mikami I, et al. Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer. Cancer Res. 2004;64(14):4717-20. doi: 10.1158/0008-5472.CAN-04-1389.
29.Jalilvand A, Soltanpour MS. Promoter hypermethylation of Wnt/β-catenin signaling pathway inhibitor WIF-1 gene and its association with MTHFR C677T polymorphism in patients with colorectal cancer. Oman Med J. 2020;35(3):e131. doi: 10.5001/omj.2020.49.
30.Freitas RD, Campos MM. Protective effects of omega-3 fatty acids in cancer-related complications. Nutrients. 2019;11(5):945. doi:10.3390/nu11050945.
31.Ma Y, Wang J, Li Q, Cao B. The Effect of omega-3 polyunsaturated fatty acid supplementations on anti-tumor drugs in triple negative breast cancer. Nut. Cancer. 2021;73(2):196-205. doi:10.1080/01635581. 2020.1743873.
32.Jing K, Song KS, Shin S, Kim N, Jeong S, Oh HR, et al. Docosahexaenoic acid induces autophagy through p53/AMPK/mTOR signaling and promotes apoptosis in human cancer cells harboring wild-type p53. Autophagy. 2011;7(11):1348-58. doi:10.1080/ 01635581.2020.1743873.
33.Jamali Z, Rezaei Behbehani G, Zare K, Gheibi N. Effect of chrysin omega-3 and 6 fatty acid esters on mushroom tyrosinase activity, stability, and structure. J Food Biochem. 2019;43(3):e12728. doi: 10.1111/ jfbc.12728.
34.Gheibi N, Taherkhani N, Ahmadi A, Haghbeen K, Ilghari D. Characterization of inhibitory effects of the potential therapeutic inhibitors, benzoic acid and pyridine derivatives, on the monophenolase and diphenolase activities of tyrosinase. Iran J Basic Med Sci. 2015;18(2):122-9.
35.Kiesewetter B, Mayerhoefer ME, Lukas J, Zielinski CC, M¸llauer L, Raderer M. Rituximab plus bendamustine is active in pretreated patients with extragastric marginal zone B cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma). Ann Hematol. 2014;93(2):249-53. doi:10.1007/s00277-013-1865-3.
36.He YC, He L, Khoshaba R, Lu FG, Cai C, Zhou FL, et al. Curcumin nicotinate selectively induces cancer cell apoptosis and cycle arrest through a P53-mediated mechanism. Molecules. 2019;24(22):4179. doi: 10.3390/molecules24224179.
37.Hu Jn, Zou Xg, He Y, Chen F, Deng ZY. Esterification of quercetin increases its transport across human Caco-2 cells. J Food Sci. 2016;81(7):H1825-H1832. doi: 10.1111/1750-3841.13366.
38.Benavente CA, Jacobson MK, Jacobson EL. NAD in skin: therapeutic approaches for niacin. Curr Pharm Des. 2009;15(1):29-38. doi: 10.2174/1381612 09787185760.
39.Luo H, Rankin GO, Li Z, DePriest L, Chen YC. Kaempferol induces apoptosis in ovarian cancer cells through activating p53 in the intrinsic pathway. Food Chem. 2011;128(2):513-9. doi: 10.1016/j.foodchem. 2011.03.073.
40.Mou S, Zhou Z, He Y, Liu F, Gong L. Curcumin inhibits cell proliferation and promotes apoptosis of laryngeal cancer cells through Bcl-2 and PI3K/Akt, and by upregulating miR-15a. Oncol Lett. 2017;14(4):4937-42. doi: 10.3892/ol.2017.6739.
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