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Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Investigating the Protective Role of Rhodanese Enzyme against Cyanide, the Cytotoxic by-product of Amygdalin, in HDF and L929 Cell Lines

Author(s): Ahmed Mohammed Alwan* and Jalil Tavakol Afshari*

Volume 20, Issue 9, 2023

Published on: 03 September, 2022

Page: [1295 - 1307] Pages: 13

DOI: 10.2174/1570180819666220610101055

Price: $65

Abstract

Introduction: Amygdalin (AMG) is a plant-based agent that has many therapeutic applications. Metabolism of this herbal remedy may cause cytotoxicity in cells.

Objective: In this study, the role of rhodanese (RH) enzyme against the cyanide of amygdalin has been investigated in human and mouse cell lines in vitro.

Methods: We analyzed the cytotoxicity, morphologic changes, apoptotic effects, and gene expression alterations resulting from treatment with AMG and AMG combined with RH (AMG-RH) in mouse fibroblasts (L929) and human dermal fibroblasts (HDF) cell lines.

Results: The lowest half-maximal inhibitory concentration (IC50) values were 87.95±3.63 mg/ml and 80.82±2.13 mg/ml at 72 h in both cell lines. Cell viability of both cell lines was significantly decreased after AMG treatment; however, it increased following treatment with AMG-RH for 24, 48, and 72 h. Morphological changes were observed in both cell lines after AMG treatment for 72 h. AMG-RH combination did not cause any significant morphological alterations in either cell line.

Conclusion: The apoptosis rates were increased in both cell lines treated with AMG and decreased in AMG-RH treatment for 72 h. BAX, CASP-3, BCL-2, and TST genes were upregulated after treatment with AMG for 72 h in both cell lines. BCL-2 and TST genes were upregulated, while BAX and CASP3 were downregulated after treatment with AMG-RH for 72 h. The findings of this study indicate the IC50 dose of AMG could cause cytotoxicity in HDF and L929 cell lines. Furthermore, it was found that the RH enzyme could decrease AMG cytotoxicity and might have a protective role against AMG.

Keywords: Amygdalin, rhodanese, apoptosis, cytotoxicity, detoxification, cancer.

[1]
Torre, L.A.; Siegel, R.L.; Ward, E.M.; Jemal, A. Global cancer incidence and mortality rates and trends—an update. Cancer Epidemiol. Biomarkers Prev., 2016, 25(1), 16-27.
[http://dx.doi.org/10.1158/1055-9965.EPI-15-0578] [PMID: 26667886]
[2]
Alwan, A.M.; Afzaljavan, F.; Tavakol Afshari, J.; Homaei Shandiz, F.; Barati Bagherabad, M.; Vahednia, E.; Kheradmand, N.; Pasdar, A. The impact of CYP19A1 variants and haplotypes on breast cancer risk, clinicopathological features and prognosis. Mol. Genet. Genomic Med., 2021, 9(7), e1705.
[http://dx.doi.org/10.1002/mgg3.1705] [PMID: 34014013]
[3]
Rayan, A.; Raiyn, J.; Falah, M. Nature is the best source of anticancer drugs: Indexing natural products for their anticancer bioactivity. PLoS One, 2017, 12(11), e0187925.
[http://dx.doi.org/10.1371/journal.pone.0187925] [PMID: 29121120]
[4]
Mohammed Alwan, A.; Tavakol Afshari, J.; Afzaljavan, F. The significance of estrogen hormone and SNPs in the progression of breast cancer among females. Arch. Razi Inst., 2022, 77, 943-958.
[http://dx.doi.org/10.22092/ari.2022.357629.2077]
[5]
Jaswal, V.; Palanivelu, J. C, R. Effects of the Gut microbiota on Amygdalin and its use as an anti-cancer therapy: Substantial review on the key components involved in altering dose efficacy and toxicity. Biochem. Biophys. Rep., 2018, 14, 125-132.
[http://dx.doi.org/10.1016/j.bbrep.2018.04.008] [PMID: 29872744]
[6]
Qadir, M.; Fatima, K. Review on Pharmacological Activity of Amygdalin. Arch. Cancer Res., 2017, 05(04), 10-12.
[http://dx.doi.org/10.21767/2254-6081.100160]
[7]
Luo, H.; Zhao, F.; Zhang, F.; Liu, N. Influence of amygdalin on PDG, IGF and PDGFR expression in HSC-T6 cells. Exp. Ther. Med., 2018, 15(4), 3693-3698.
[http://dx.doi.org/10.3892/etm.2018.5886] [PMID: 29556259]
[8]
Sohail, R.; Abbas, S.R. Evaluation of amygdalin-loaded alginate-chitosan nanoparticles as biocompatible drug delivery carriers for anticancerous efficacy. Int. J. Biol. Macromol., 2020, 153, 36-45.
[http://dx.doi.org/10.1016/j.ijbiomac.2020.02.191] [PMID: 32097740]
[9]
Albogami, S.; Hassan, A.; Ahmed, N.; Alnefaie, A.; Alattas, A.; Alquthami, L.; Alharbi, A. Evaluation of the effective dose of amygdalin for the improvement of antioxidant gene expression and suppression of oxidative damage in mice. PeerJ, 2020, 8, e9232.
[http://dx.doi.org/10.7717/peerj.9232] [PMID: 32509470]
[10]
Kalaiyarasan, G.; Veerapandian, M. JebaMercy, G.; Balamurugan, K.; Joseph, J. Amygdalin-functionalized carbon quantum dots for probing β-glucosidase activity for cancer diagnosis and therapeutics. ACS Biomater. Sci. Eng., 2019, 5(6), 3089-3099.
[http://dx.doi.org/10.1021/acsbiomaterials.9b00394] [PMID: 33405541]
[11]
Song, Z.; Xu, X. Advanced research on anti-tumor effects of amygdalin. J. Cancer Res. Ther., 2014, 10(5)(Suppl. 1), 3-7.
[http://dx.doi.org/10.4103/0973-1482.139743] [PMID: 25207888]
[12]
Blaheta, R.A.; Nelson, K.; Haferkamp, A.; Juengel, E. Amygdalin, quackery or cure? Phytomedicine, 2016, 23(4), 367-376.
[http://dx.doi.org/10.1016/j.phymed.2016.02.004]
[13]
Boehm, S.M.E.L.; Milazzo, S.; Horneber, M.; Ernst, E. Br. Biomed. Bull., 2017, 5(4), 296.
[http://dx.doi.org/10.1002/14651858.CD005476.pub4]
[14]
Hwang, H.J.; Kim, P.; Kim, C.J.; Lee, H.J.; Shim, I.; Yin, C.S.; Yang, Y.; Hahm, D.H. Antinociceptive effect of amygdalin isolated from Prunus armeniaca on formalin-induced pain in rats. Biol. Pharm. Bull., 2008, 31(8), 1559-1564.
[http://dx.doi.org/10.1248/bpb.31.1559] [PMID: 18670089]
[15]
Chang, H-K.; Shin, M.S.; Yang, H.Y.; Lee, J.W.; Kim, Y.S.; Lee, M.H.; Kim, J.; Kim, K.H.; Kim, C.J. Amygdalin induces apoptosis through regulation of Bax and Bcl-2 expressions in human DU145 and LNCaP prostate cancer cells. Biol. Pharm. Bull., 2006, 29(8), 1597-1602.
[http://dx.doi.org/10.1248/bpb.29.1597] [PMID: 16880611]
[16]
Liczbiński, P.; Bukowska, B. Molecular mechanism of amygdalin action in vitro: Review of the latest research. Immunopharmacol. Immunotoxicol., 2018, 40(3), 212-218.
[http://dx.doi.org/10.1080/08923973.2018.1441301] [PMID: 29486614]
[17]
Dang, T.; Nguyen, C.; Tran, P.N. Physician beware: Severe cyanide toxicity from amygdalin tablets ingestion. Case Rep. Emerg. Med., 2017, 2017, 4289527.
[http://dx.doi.org/10.1155/2017/4289527] [PMID: 28912981]
[18]
Newton, G.W.; Schmidt, E.S.; Lewis, J.P.; Lawrence, R.; Conn, E. Amygdalin toxicity studies in rats predict chronic cyanide poisoning in humans. West. J. Med., 1981, 134(2), 97.
[PMID: 7222669]
[19]
Arshi, A.; Hosseini, S.M.; Hosseini, F.S.K.; Amiri, Z.Y.; Hosseini, F.S.; Sheikholia Lavasani, M.; Kerdarian, H.; Dehkordi, M.S. The anti-cancer effect of amygdalin on human cancer cell lines. Mol. Biol. Rep., 2019, 46(2), 2059-2066.
[http://dx.doi.org/10.1007/s11033-019-04656-3] [PMID: 30725348]
[20]
Ayaz, Z.; Zainab, B.; Khan, S.; Abbasi, A.M.; Elshikh, M.S.; Munir, A.; Al-Ghamdi, A.A.; Alajmi, A.H.; Alsubaie, Q.D.; Mustafa, A.E.M.A. In silico authentication of amygdalin as a potent anticancer compound in the bitter kernels of family Rosaceae. Saudi J. Biol. Sci., 2020, 27(9), 2444-2451.
[http://dx.doi.org/10.1016/j.sjbs.2020.06.041] [PMID: 32884428]
[21]
He, X-Y.; Wu, L-J.; Wang, W-X.; Xie, P-J.; Chen, Y-H.; Wang, F. Amygdalin - A pharmacological and toxicological review. J. Ethnopharmacol., 2020, 254, 112717.
[http://dx.doi.org/10.1016/j.jep.2020.112717] [PMID: 32114166]
[22]
Li, Y.L.; Li, Q.X.; Liu, R.J.; Shen, X.Q. Chinese medicine Amygdalin and β-glucosidase combined with antibody enzymatic prodrug system as a feasible antitumor therapy. Chin. J. Integr. Med., 2018, 24(3), 237-240.
[http://dx.doi.org/10.1007/s11655-015-2154-x] [PMID: 26272547]
[23]
Zhou, J.; Hou, J.; Rao, J.; Zhou, C.; Liu, Y.; Gao, W. Magnetically directed enzyme/prodrug prostate cancer therapy based on β-glucosidase/amygdalin. Int. J. Nanomedicine, 2020, 15, 4639-4657.
[http://dx.doi.org/10.2147/IJN.S242359] [PMID: 32636623]
[24]
Shim, S.M.; Kwon, H. Metabolites of amygdalin under simulated human digestive fluids. Int. J. Food Sci. Nutr., 2010, 61(8), 770-779.
[http://dx.doi.org/10.3109/09637481003796314] [PMID: 20528582]
[25]
Mani, J.; Rutz, J.; Maxeiner, S.; Juengel, E.; Bon, D.; Roos, F.; Chun, F.K.; Blaheta, R.A. Cyanide and lactate levels in patients during chronic oral amygdalin intake followed by intravenous amygdalin administration. Complement. Ther. Med., 2019, 43, 295-299.
[http://dx.doi.org/10.1016/j.ctim.2019.03.002] [PMID: 30935547]
[26]
Zagrobelny, M.; Bak, S.; Rasmussen, A.V.; Jørgensen, B.; Naumann, C.M.; Møller, B.L. Cyanogenic glucosides and plant-insect interactions. In: Phytochemistry; Elsevier, 2004; 65, pp. (3)293-306.
[http://dx.doi.org/10.1016/j.phytochem.2003.10.016]
[27]
Mosayyebi, B. An update on the toxicity of cyanogenic glycosides bioactive compounds: Possible clinical application in targeted cancer therapy. Mater. Chem. Phys., 2020, 246, 122841.
[http://dx.doi.org/10.1016/j.matchemphys.2020.122841]
[28]
Guo, J.Q.; Sheng, M.X.; Wang, L.J.; Tan, J.M.; Wu, W.Z.; Yang, S.L. Inhibitory effect of amygdalin on human renal fibroblast proliferation. J. Clin. Rehabil. Tissue Eng. Res., 2008, 12(18), 3575-3578.
[29]
Wang, R.; Zhang, D.; Tang, D.; Sun, K.; Peng, J.; Zhu, W.; Yin, S.; Wu, Y. Amygdalin inhibits TGFβ1-induced activation of hepatic stellate cells (HSCs) in vitro and CCl4-induced hepatic fibrosis in rats in vivo. Int. Immunopharmacol., 2021, 90, 107151.
[http://dx.doi.org/10.1016/j.intimp.2020.107151] [PMID: 33296784]
[30]
Chen, Y.; Ma, J.; Wang, F.; Hu, J.; Cui, A.; Wei, C.; Yang, Q.; Li, F. Amygdalin induces apoptosis in human cervical cancer cell line HeLa cells. Immunopharmacol. Immunotoxicol., 2013, 35(1), 43-51.
[http://dx.doi.org/10.3109/08923973.2012.738688] [PMID: 23137229]
[31]
Abboud, M.M.; Al Awaida, W.; Alkhateeb, H.H.; Abu-Ayyad, A.N. Antitumor action of amygdalin on human breast cancer cells by selective sensitization to oxidative stress. Nutr. Cancer, 2019, 71(3), 483-490.
[http://dx.doi.org/10.1080/01635581.2018.1508731] [PMID: 30407870]
[32]
Makarević, J.; Rutz, J.; Juengel, E.; Kaulfuss, S.; Reiter, M.; Tsaur, I.; Bartsch, G.; Haferkamp, A.; Blaheta, R.A. Amygdalin blocks bladder cancer cell growth in vitro by diminishing cyclin A and cdk2. PLoS One, 2014, 9(8), e105590.
[PMID: 25136960]
[33]
Makarević, J.; Tsaur, I.; Juengel, E.; Borgmann, H.; Nelson, K.; Thomas, C.; Bartsch, G.; Haferkamp, A.; Blaheta, R.A. Amygdalin delays cell cycle progression and blocks growth of prostate cancer cells in vitro. Life Sci., 2016, 147, 137-142.
[http://dx.doi.org/10.1016/j.lfs.2016.01.039] [PMID: 26827990]
[34]
Alwan, A.M.; Afshari, J.T. In vivo growth inhibition of human caucasian prostate adenocarcinoma in nude mice induced by amygdalin with metabolic enzyme combinations. BioMed Res. Int., 2022, 2022, 4767621.
[http://dx.doi.org/10.1155/2022/4767621]
[35]
Moon, J-Y.Y. Inhibition of cell growth and down-regulation of telomerase activity by amygdalin in human cancer cell lines. Animal Cells Syst. (Seoul), 2015, 19(5), 295-304.
[http://dx.doi.org/10.1080/19768354.2015.1060261]
[36]
Aminlari, M.; Malekhusseini, A.; Akrami, F.; Ebrahimnejad, H. Cyanide-metabolizing enzyme rhodanese in human tissues: Comparison with domestic animals. Comp. Clin. Pathol., 2007, 16(1), 47-51.
[http://dx.doi.org/10.1007/s00580-006-0647-x]
[37]
Cipollone, R.; Ascenzi, P.; Tomao, P.; Imperi, F.; Visca, P. Enzymatic detoxification of cyanide: Clues from Pseudomonas aeruginosa rhodanese. J. Mol. Microbiol. Biotechnol., 2008, 15(2-3), 199-211.
[http://dx.doi.org/10.1159/000121331] [PMID: 18685272]
[38]
Saidu, Y. Physicochemical features of rhodanese: A review. Afr. J. Biotechnol., 2004, 3(8), 370-374.
[http://dx.doi.org/10.5897/AJB2004.000-2071]
[39]
Westfall, B.B.; Peppers, E.V.; Evans, V.J.; Sanford, K.K.; Hawkins, N.M.; Fioramonti, M.C.; Kerr, H.A.; Hobbs, G.L.; Earle, W.R. The arginase and rhodanese activities of certain cell strains after long cultivation in vitro. J. Biophys. Biochem. Cytol., 1958, 4(5), 567-570.
[http://dx.doi.org/10.1083/jcb.4.5.567] [PMID: 13587550]
[40]
Cereda, A.; Carpen, A.; Picariello, G.; Iriti, M.; Faoro, F.; Ferranti, P.; Pagani, S. Effects of the deficiency of the rhodanese-like protein RhdA in Azotobacter vinelandii. FEBS Lett., 2007, 581(8), 1625-1630.
[http://dx.doi.org/10.1016/j.febslet.2007.03.028] [PMID: 17383639]
[41]
Moertel, C.G.; Ames, M.M.; Kovach, J.S.; Moyer, T.P.; Rubin, J.R.; Tinker, J.H. A pharmacologic and toxicological study of amygdalin. JAMA, 1981, 245(6), 591-594.
[http://dx.doi.org/10.1001/jama.1981.03310310033018] [PMID: 7005480]
[42]
Syrigos, K.N.; Rowlinson-Busza, G.; Epenetos, A.A.; Syrigos, K.N.; Rowlinson‐Busza, G.; Epenetos, A.A. In vitro cytotoxicity following specific activation of amygdalin by β-glucosidase conjugated to a bladder cancer-associated monoclonal antibody. Int. J. Cancer, 1998, 78(6), 712-719.
[http://dx.doi.org/10.1002/(SICI)1097-0215(19981209)78:6<712:AID-IJC8>3.0.CO;2-D] [PMID: 9833764]
[43]
Abdelkader, I.; Fahmi, A.A.; Nasraldin, K.M. Anticancer effect of amygdalin (Vitamin B-17) on hepatocellular carcinoma cell line (HepG2) in the presence and absence of zinc. Anticancer. Agents Med. Chem., 2020, 20(4), 486-494.
[44]
Kolesarova, A.; Baldovska, S.; Roychoudhury, S. Pharmaceuticals the multiple actions of amygdalin on cellular processes with an emphasis on female reproduction. Pharmaceuticals, 2021, 14(9), 881.
[http://dx.doi.org/10.3390/ph14090881]
[45]
Elbastawisy, Y.M.; Mohamed, H.A. Therapeutic effect of amygdalin on acetic acid-induced colitis in rats: Histopathological and immunohistochemical study. Egypt. Acad. J. Biol. Sci. D Histol. Histochem., 2022, 14(1), 27-41.
[http://dx.doi.org/10.21608/eajbsd.2022.216580]
[46]
Motawea, S.M.; Youssef, S.A-A.; Abdel-Aleem, G.A.; Mohamed, M.F.; Mostafa, M.S. Effect of amygdalin (Vitamin B17) on induced mammary tumor in virgin female albino rats: Histological and morphometric study. Egypt. J. Histol., 2022. Epub ahead of print
[http://dx.doi.org/10.21608/ejh.2022.119301.1637]
[47]
Al-Khafaji, K.; Taskin Tok, T. Understanding the mechanism of amygdalin’s multifunctional anti-cancer action using computational approach. J. Biomol. Struct. Dyn., 2021, 39(5), 1600-1610.
[http://dx.doi.org/10.1080/07391102.2020.1736159] [PMID: 32107968]
[48]
Kožich, V.; Ditrói, T.; Sokolová, J.; Křížková, M.; Krijt, J.; Ješina, P.; Nagy, P. Metabolism of sulfur compounds in homocystinurias. Br. J. Pharmacol., 2019, 176(4), 594-606.
[http://dx.doi.org/10.1111/bph.14523] [PMID: 30341787]

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