Cytotoxicity Evaluation of Dimethoxy and Trimethoxy Indanonic Spiroisoxazolines Against Cancerous Liver Cells

Author(s): Ahmad Abolhasani, Fatemeh Heidari, Somayeh Noori, Shokoufeh Mousavi, Hoda Abolhasani*

Journal Name: Current Chemical Biology

Volume 14 , Issue 1 , 2020


DOI : 10.2174/2212796813666190926112807

  Journal Home
Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: 3'-(3,4-dimethoxyphenyl)-4'-(4-(methylsulfonyl)phenyl)-4'H-spiro [indene-2,5'-isoxazol]-1(3H)-one and 4'-(4-(methylsulfonyl)phenyl)-3'-(3,4,5-trimethoxyphenyl)- 4'H-spiro[indene-2,5'-isoxazol]-1(3H)-one compounds containing indanonic spiroisoxazoline core are widely known for their antiproliferative activities and investigation of tubulin binding modes.

Objective: To evaluate the cytotoxicity effect of Dimethoxy and Trimethoxy Indanonic Spiroisoxazolines against HepG2 cancerous liver cell line and to perform a comparison with other known anti-liver cancer drugs.

Methods: The evaluation of cytotoxicity of dimethoxy and trimethoxy indanonic spiroisoxazoline compounds, Oxaliplatin, Doxorubicin, 5-fluorouracil and Cisplatin against HepG2 (hepatocellular liver carcinoma) cell line has been performed using MTT assay and analyzed by GraphPad PRISM software (version 8.0.2).

Results: Potent cytotoxicity effects against HepG2 cell line, comparable to Cisplatin (IC50= 0.047±0.0045 µM), Oxaliplatin (IC50= 0.0051µM), Doxorubicin (IC50= 0.0014µM) and 5- fluorouracil (IC50= 0.0089 µM), were shown by both dimethoxy (IC50= 0.059±0.012 µM) and trimethoxy (IC50= 0.086±0.019 µM) indanonic spiroisoxazoline compounds.

Conclusion: In vitro biological evaluations revealed that dimethoxy and trimethoxy indanonic spiroisoxazoline compounds are good candidates for the development of new anti-liver cancer agents.

Keywords: Anticancer, indanonic spiroisoxazoline, HepG2, antitubulin, selective COX-2 inhibitor, cancerous liver cells.

[1]
Mukherjee AK, Basu S, Sarkar N, Ghosh AC. Advances in cancer therapy with plant based natural products. Curr Med Chem 2001; 8(12): 1467-86.
[http://dx.doi.org/10.2174/0929867013372094] [PMID: 11562277]
[2]
Bridges JF, Joy SM, Gallego G, et al. Needs for hepatocellular carcinoma control policy in the Asia-Pacific region. Asian Pac J Cancer Prev 2011; 12(10): 2585-91.
[PMID: 22320959]
[3]
El-Serag HB. Hepatocellular carcinoma: an epidemiologic view. J Clin Gastroenterol 2002; 35(5)(Suppl. 2): S72-8.
[http://dx.doi.org/10.1097/00004836-200211002-00002] [PMID: 12394209]
[4]
Bydder S, Spry NA, Christie DR, et al. A prospective trial of short-fractionation radiotherapy for the palliation of liver metastases. Australas Radiol 2003; 47(3): 284-8.
[http://dx.doi.org/10.1046/j.1440-1673.2003.01177.x] [PMID: 12890250]
[5]
Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014; 74(11): 2913-21.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-0155] [PMID: 24840647]
[6]
Chen CJ, Wang LY, Yu MW. Epidemiology of hepatitis B virus infection in the Asia-Pacific region. J Gastroenterol Hepatol 2000; 15(Suppl.): E3-6.
[http://dx.doi.org/10.1046/j.1440-1746.2000.02124.x] [PMID: 10921373]
[7]
Venook AP, Papandreou C, Furuse J, de Guevara LL. The incidence and epidemiology of hepatocellular carcinoma: a global and regional perspective. Oncologist 2010; 15(Suppl. 4): 5-13.
[http://dx.doi.org/10.1634/theoncologist.2010-S4-05] [PMID: 21115576]
[8]
Forner A, Reig ME, de Lope CR, Bruix J. Current strategy for staging and treatment: the BCLC update and future prospects. Semin Liver Dis 2010; 30(1): 61-74.
[http://dx.doi.org/10.1055/s-0030-1247133] [PMID: 20175034]
[9]
Weiss L, Grundmann E, Torhorst J, et al. Haematogenous metastatic patterns in colonic carcinoma: an analysis of 1541 necropsies. J Pathol 1986; 150(3): 195-203.
[http://dx.doi.org/10.1002/path.1711500308] [PMID: 3806280]
[10]
Borrell B. How accurate are cancer cell lines? Nature 2010; 463(7283): 858.
[http://dx.doi.org/10.1038/463858a] [PMID: 20164888]
[11]
Gillet JP, Varma S, Gottesman MM. The clinical relevance of cancer cell lines. J Natl Cancer Inst 2013; 105(7): 452-8.
[http://dx.doi.org/10.1093/jnci/djt007] [PMID: 23434901]
[12]
Wilding JL, Bodmer WF. Cancer cell lines for drug discovery and development. Cancer Res 2014; 74(9): 2377-84.
[http://dx.doi.org/10.1158/0008-5472.CAN-13-2971] [PMID: 24717177]
[13]
Xin H, Wang K, Hu G, et al. Establishment and characterization of 7 novel hepatocellular carcinoma cell lines from patient-derived tumor xenografts. PLoS One 2014; 9(1): e85308
[http://dx.doi.org/10.1371/journal.pone.0085308] [PMID: 24416385]
[14]
Chen B, Sirota M, Fan-Minogue H, Hadley D, Butte AJ. Relating hepatocellular carcinoma tumor samples and cell lines using gene expression data in translational research. BMC Med Genomics 2015; 8(Suppl. 2): S5.
[http://dx.doi.org/10.1186/1755-8794-8-S2-S5] [PMID: 26043652]
[15]
Puntambekar DS, Giridhar R, Yadav MR. Insights into the structural requirements of farnesyltransferase inhibitors as potential anti-tumor agents based on 3D-QSAR CoMFA and CoMSIA models. Eur J Med Chem 2008; 43(1): 142-54.
[http://dx.doi.org/10.1016/j.ejmech.2007.02.003] [PMID: 17448576]
[16]
Chinigo GM, Paige M, Grindrod S, et al. Asymmetric synthesis of 2,3-dihydro-2-arylquinazolin-4-ones: methodology and application to a potent fluorescent tubulin inhibitor with anticancer activity. J Med Chem 2008; 51(15): 4620-31.
[http://dx.doi.org/10.1021/jm800271c] [PMID: 18610995]
[17]
Hamel E. Antimitotic natural products and their interactions with tubulin. Med Res Rev 1996; 16(2): 207-31.
[http://dx.doi.org/10.1002/(SICI)1098-1128(199603)16:2<207:AID-MED4>3.0.CO;2-4] [PMID: 8656780]
[18]
Romagnoli R, Baraldi PG, Carrion MD, et al. 2-Arylamino-4-amino-5-aroylthiazoles. “One-pot” synthesis and biological evaluation of a new class of inhibitors of tubulin polymerization. J Med Chem 2009; 52(17): 5551-5.
[http://dx.doi.org/10.1021/jm9001692] [PMID: 19663386]
[19]
Kim DY, Kim KH, Kim ND, et al. Design and biological evaluation of novel tubulin inhibitors as antimitotic agents using a pharmacophore binding model with tubulin. J Med Chem 2006; 49(19): 5664-70.
[http://dx.doi.org/10.1021/jm050761i] [PMID: 16970393]
[20]
Chaplin DJ, Hill SA. The development of combretastatin A4 phosphate as a vascular targeting agent. Int J Radiat Oncol Biol Phys 2002; 54(5): 1491-6.
[http://dx.doi.org/10.1016/S0360-3016(02)03924-X] [PMID: 12459376]
[21]
Ludford RJ. Colchicine in the experimental chemotherapy of cancer. J Natl Cancer Inst 1945; 6(2): 89-101.
[http://dx.doi.org/10.1093/jnci/6.2.89]
[22]
Lin CM, Ho HH, Pettit GR, Hamel E. Antimitotic natural products combretastatin A-4 and combretastatin A-2: studies on the mechanism of their inhibition of the binding of colchicine to tubulin. Biochemistry 1989; 28(17): 6984-91.
[http://dx.doi.org/10.1021/bi00443a031] [PMID: 2819042]
[23]
Pettit GR, Singh SB, Hamel E, Lin CM, Alberts DS, Garcia-Kendall D. Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4. Experientia 1989; 45(2): 209-11.
[http://dx.doi.org/10.1007/BF01954881] [PMID: 2920809]
[24]
Cushman M, Nagarathnam D, Gopal D, Chakraborti AK, Lin CM, Hamel E. Synthesis and evaluation of stilbene and dihydrostilbene derivatives as potential anticancer agents that inhibit tubulin polymerization. J Med Chem 1991; 34(8): 2579-88.
[http://dx.doi.org/10.1021/jm00112a036] [PMID: 1875350]
[25]
Ohsumi K, Hatanaka T, Fujita K, et al. Syntheses and antitumor activity of cis-restricted combretastatins: 5-membered heterocyclic analogues. Bioorg Med Chem Lett 1998; 8(22): 3153-8.
[http://dx.doi.org/10.1016/S0960-894X(98)00579-4] [PMID: 9873694]
[26]
Pettit GR, Rhodes MR, Herald DL, Hamel E, Schmidt JM, Pettit RK. Antineoplastic agents. 445. Synthesis and evaluation of structural modifications of (Z)- and (E)-combretastatin A-41. J Med Chem 2005; 48(12): 4087-99.
[http://dx.doi.org/10.1021/jm0205797] [PMID: 15943482]
[27]
Hsieh HP, Liou JP, Mahindroo N. Pharmaceutical design of antimitotic agents based on combretastatins. Curr Pharm Des 2005; 11(13): 1655-77.
[http://dx.doi.org/10.2174/1381612053764751] [PMID: 15892667]
[28]
Nam NH. Combretastatin A-4 analogues as antimitotic antitumor agents. Curr Med Chem 2003; 10(17): 1697-722.
[http://dx.doi.org/10.2174/0929867033457151] [PMID: 12871118]
[29]
Tron GC, Pirali T, Sorba G, Pagliai F, Busacca S, Genazzani AA. Medicinal chemistry of combretastatin A4: present and future directions. J Med Chem 2006; 49(11): 3033-44.
[http://dx.doi.org/10.1021/jm0512903] [PMID: 16722619]
[30]
Pinney KG, Jelinek C, Edvardsen K, Chaplin DJ, Pettit GR. The discovery and development of combretastatins.In: Gordon M. Cragg, David G.I. Kingston,David J. Newman, Eds. . Anticancer agents from natural products. UK: Taylor & francis 2005; pp. 23-46.
[31]
Alazard J-P, Millet-Paillusson C, Boyé O, et al. Synthesis of tricyclic phenylpyrrole lactams, new models of antitubulin agents. Bioorg Med Chem Lett 1991; 1(12): 725-8.
[http://dx.doi.org/10.1016/S0960-894X(01)81056-8]
[32]
Massarotti A, Theeramunkong S, Mesenzani O, Caldarelli A, Genazzani AA, Tron GC. Identification of novel antitubulin agents by using a virtual screening approach based on a 7-point pharmacophore model of the tubulin colchi-site. Chem Biol Drug Des 2011; 78(6): 913-22.
[http://dx.doi.org/10.1111/j.1747-0285.2011.01245.x] [PMID: 22039890]
[33]
Pellegrini F, Budman DR. Review: tubulin function, action of antitubulin drugs, and new drug development. Cancer Invest 2005; 23(3): 264-73.
[http://dx.doi.org/10.1081/CNV-200055970] [PMID: 15948296]
[34]
Yang XH, Wen Q, Zhao TT, et al. Synthesis, biological evaluation, and molecular docking studies of cinnamic acyl 1,3,4-thiadiazole amide derivatives as novel antitubulin agents. Bioorg Med Chem 2012; 20(3): 1181-7.
[http://dx.doi.org/10.1016/j.bmc.2011.12.057] [PMID: 22261027]
[35]
Abolhasani H, Zarghi A, Hamzeh-Mivehroud M, Alizadeh AA, Shahbazi Mojarrad J, Dastmalchi S. In-silico investigation of tubulin binding modes of a series of novel antiproliferative spiroisoxazoline compounds using docking studies. Iran J Pharm Res 2015; 14(1): 141-7.
[PMID: 25561920]
[36]
Amir M, Agarwal HK. Role of COX-2 selective inhibitors for prevention and treatment of cancer. Pharmazie 2005; 60(8): 563-70.
[PMID: 16124396]
[37]
Fu SL, Wu YL, Zhang YP, Qiao MM, Chen Y. Anti-cancer effects of COX-2 inhibitors and their correlation with angiogenesis and invasion in gastric cancer. World J Gastroenterol 2004; 10(13): 1971-4.
[http://dx.doi.org/10.3748/wjg.v10.i13.1971] [PMID: 15222049]
[38]
Mandal PK, Freiter EM, Bagsby AL, Robertson FM, McMurray JS. Efficient synthesis of apricoxib, CS-706, a selective cyclooxygenase-2 inhibitor, and evaluation of inhibition of prostaglandin E2 production in inflammatory breast cancer cells. Bioorg Med Chem Lett 2011; 21(20): 6071-3.
[http://dx.doi.org/10.1016/j.bmcl.2011.08.050] [PMID: 21903394]
[39]
Sobolewski C, Cerella C, Dicato M, Ghibelli L, Diederich M. The role of cyclooxygenase-2 in cell proliferation and cell death in human malignancies. International journal of cell biology 2010; 2010
[http://dx.doi.org/10.1155/2010/215158]
[40]
Xu L, Stevens J, Hilton MB, et al. COX-2 inhibition potentiates antiangiogenic cancer therapy and prevents metastasis in preclinical models. Sci Transl Med 2014; 6(242), 242ra84
[http://dx.doi.org/10.1126/scitranslmed.3008455] [PMID: 24964992]
[41]
Abolhasani H, Zarghi A, Abolhasani A. Design, synthesis and biological evaluation of new analogues of phenyl ethyl and phenoxy methyl oxadiazol as selective inhibitors of cyclooxygenase-2 enzyme. Eur J Pharm Sci 2009; 38(1)(Suppl.): 203-4.
[http://dx.doi.org/10.1016/j.ejps.2009.09.015]
[42]
Turini ME, DuBois RN. Cyclooxygenase-2: a therapeutic target. Annu Rev Med 2002; 53: 35-57.
[http://dx.doi.org/10.1146/annurev.med.53.082901.103952] [PMID: 11818462]
[43]
Koga H, Sakisaka S, Ohishi M, et al. Expression of cyclooxygenase-2 in human hepatocellular carcinoma: relevance to tumor dedifferentiation. Hepatology 1999; 29(3): 688-96.
[http://dx.doi.org/10.1002/hep.510290355] [PMID: 10051469]
[44]
Yao M, Lam EC, Kelly CR, Zhou W, Wolfe MM. Cyclooxygenase-2 selective inhibition with NS-398 suppresses proliferation and invasiveness and delays liver metastasis in colorectal cancer. Br J Cancer 2004; 90(3): 712-9.
[http://dx.doi.org/10.1038/sj.bjc.6601489] [PMID: 14760389]
[45]
Chen H, Cai W, Chu ESH, et al. Hepatic cyclooxygenase-2 overexpression induced spontaneous hepatocellular carcinoma formation in mice. Oncogene 2017; 36(31): 4415-26.
[http://dx.doi.org/10.1038/onc.2017.73] [PMID: 28346420]
[46]
Casado M, Mollá B, Roy R, et al. Protection against Fas-induced liver apoptosis in transgenic mice expressing cyclooxygenase 2 in hepatocytes. Hepatology 2007; 45(3): 631-8.
[http://dx.doi.org/10.1002/hep.21556] [PMID: 17326157]
[47]
Koki AT, Masferrer JL. Celecoxib: a specific COX-2 inhibitor with anticancer properties. Cancer Contr 2002; 9(2)(Suppl.): 28-35.
[http://dx.doi.org/10.1177/107327480200902S04] [PMID: 11965228]
[48]
Li G, Wang X, Luo Q, Gan C. Identification of key genes and long non‑coding RNAs in celecoxib‑treated lung squamous cell carcinoma cell line by RNA‑sequencing. Mol Med Rep 2018; 17(5): 6456-64.
[http://dx.doi.org/10.3892/mmr.2018.8656] [PMID: 29512696]
[49]
Matbou Riahi M, Sahebkar A, Sadri K, Nikoofal-Sahlabadi S, Jaafari MR. Stable and sustained release liposomal formulations of celecoxib: In vitro and in vivo anti-tumor evaluation. Int J Pharm 2018; 540(1-2): 89-97.
[http://dx.doi.org/10.1016/j.ijpharm.2018.01.039] [PMID: 29371019]
[50]
DE Cremoux P, Hamy AS, Lehmann-Che J, et al. COX2/PTGS2 expression is predictive of response to neoadjuvant celecoxib in HER2-negative breast cancer patients. Anticancer Res 2018; 38(3): 1485-90.
[PMID: 29491076]
[51]
Singh S. Liposome encapsulation of doxorubicin and celecoxib in combination inhibits progression of human skin cancer cells. Int J Nanomedicine 2018; 13(T-NANO 2014 Abstracts): 11-3.
[http://dx.doi.org/10.2147/IJN.S124701] [PMID: 29593389]
[52]
Sui W, Zhang Y, Wang Z, et al. Antitumor effect of a selective COX-2 inhibitor, celecoxib, may be attributed to angiogenesis inhibition through modulating the PTEN/PI3K/Akt/HIF-1 pathway in an H22 murine hepatocarcinoma model. Oncol Rep 2014; 31(5): 2252-60.
[http://dx.doi.org/10.3892/or.2014.3093] [PMID: 24647425]
[53]
Abolhasani H, Zarghi A, Abolhasani A, et al. Design, synthesis and in vitro cytotoxicity evaluation of new 3′,4′-bis (3,4,5-trisubstituted)-4‘H-spiro[indene-2,5’-isoxazol]-1(3H)-one derivatives as promising anticancer agents. Lett Drug Des Discov 2014; 11(10): 1149-61.
[http://dx.doi.org/10.2174/1570180811666140704172442]
[54]
Das P, Omollo AO, Sitole LJ, et al. Synthesis and investigation of novel spiro-isoxazolines as anti-cancer agents. Tetrahedron Lett 2015; 56(14): 1794-7.
[http://dx.doi.org/10.1016/j.tetlet.2015.02.059] [PMID: 25821250]
[55]
Khazir J, Singh PP, Reddy DM, et al. Synthesis and anticancer activity of novel spiro-isoxazoline and spiro-isoxazolidine derivatives of α-santonin. Eur J Med Chem 2013; 63: 279-89.
[http://dx.doi.org/10.1016/j.ejmech.2013.01.003] [PMID: 23501113]
[56]
Najim N, Bathich Y, Zain MM, Hamzah AS, Shaameri Z. Evaluation of the bioactivity of novel spiroisoxazoline typecompounds against normal and cancer cell lines. Molecules 2010; 15(12): 9340-53.
[http://dx.doi.org/10.3390/molecules15129340] [PMID: 21169884]
[57]
Ribeiro CJA, Amaral JD, Rodrigues CMP, Moreira R, Santos MMM. Synthesis and evaluation of spiroisoxazoline oxindoles as anticancer agents. Bioorg Med Chem 2014; 22(1): 577-84.
[http://dx.doi.org/10.1016/j.bmc.2013.10.048] [PMID: 24268795]
[58]
Abolhasani H, Dastmalchi S, Hamzeh-Mivehroud M, Daraei B, Zarghi A. Design, synthesis and biological evaluation of new tricyclic spiroisoxazoline derivatives as selective COX-2 inhibitors and study of their COX-2 binding modes via docking studies. Med Chem Res 2016; 25(5): 858-69.
[http://dx.doi.org/10.1007/s00044-016-1534-x]
[59]
Abolhasani H, Zarghi A. Design & synthesis of novel 4′-(4-(methylsulfonyl) phenyl) 3′- psubstituted phenyl -4‘H-spiro [chroman-3, 5’-isoxazol]-4-one as selective COX-2 inhibitors. Res Pharm Sci 2012; 7(5): S525. Available from: . http: //rps.mui.ac.ir/index.php/jrps/article/view/1261/1245


open access plus

Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 14
ISSUE: 1
Year: 2020
Published on: 26 September, 2019
Page: [38 - 47]
Pages: 10
DOI: 10.2174/2212796813666190926112807

Article Metrics

PDF: 24
HTML: 5
EPUB: 1
PRC: 2



Related Article(s)