Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Research Article

In Vitro Anticancer Effects of Stilbene Derivatives: Mechanistic Studies on HeLa and MCF-7 Cells

Author(s): Faisal Rashid, Aamer Saeed and Jamshed Iqbal*

Volume 21 , Issue 6 , 2021

Published on: 11 August, 2020

Page: [793 - 802] Pages: 10

DOI: 10.2174/1871520620666200811123230

Price: $65

Abstract

Background and Objective: The growing prevalence of cancer and the resulting chemoresistance exert a huge burden on healthcare systems and impose a great challenge to public health around the world. In efforts to develop new chemotherapeutic agents for cancer treatment, a class of heterocyclic compounds i.e. triazine-based molecules were investigated as anticancer agents.

Materials and Methods: New triazine hybrids of stilbene were synthesized and evaluated as anticancer agents for cervical (HeLa) and breast (MCF-7) carcinoma cells. The compound (7e), sodium (E)-6,6'-(ethene-1,2- diyl)bis(3-((4-chloro-6-((3-luorophenyl)amino)-1,3,5-triazin-2-yl)amino)benzenesulfonate) was found to be most potent among synthesized derivatives and was explored further for detailed mechanistic studies.

Results: In a set comprised of twelve derivatives, compound 7e, sodium (E)-6,6'-(ethene-1,2-diyl)bis(3-((4- chloro-6-((3-luorophenyl)amino)-1,3,5-triazin-2-yl)amino)benzenesulfonate) was found most potent inhibitor for HeLa and MCF-7 cells.

Discussion: The present study has revealed that compound 7e may activate mitochondrial pathway of apoptosis in HeLa and MCF-7 cells which was assessed by DNA binding studies, estimation of the release of Lactate Dehydrogenase (LDH), fluorescence imaging, production of Reactive Oxygen Species (ROS) in cancer cells, analysis of cell cycle by flow cytometry, change in Mitochondrial Membrane Potential (MMP) and activation of caspase-9 and caspase-3.

Conclusion: Compound 7e may serve as a lead in designing new anticancer compounds based on stilbene scaffold.

Keywords: Stilbene derivatives, cell cycle analysis, DNA binding studies, lactate dehydrogenase release, reactive oxygen species, mitochondrial membrane potential, caspase-9, caspase-3.

Graphical Abstract
[1]
(a) Pedersen, J.W.; Wandall, H.H Autoantibodies as biomarkers in cancer. Lab. Med., 2016, 42(10), 623-628.
[http://dx.doi.org/10.1309/LM2T3OU3RZRTHKSN]
(b) Henry, N.L; Hayes, D.F Cancer biomarkers. Mol. Oncol., 2012, 6(2), 140-146.
[http://dx.doi.org/10.1016/j.molonc.2012.01.010] [PMID: 22356776]
(c) Goossens, N.; Nakagawa, S.; Sun, X.; Hoshida, Y. Cancer biomarker discovery and validation. Transl. Cancer Res., 2015, 4(4), 256-269.
[PMID: 26213686]
(d) Goswami, S.; Sharma, P. Genetic biomarker for cancer immunotherapyScience; , 2017, 357, pp. (6349)358-358.
[http://dx.doi.org/10.1126/science.aao1894] [PMID: 28751597]
(e) Perez-Gracia, J.L.; Sanmamed, M.F.; Bosch, A.; Patiño-Garcia, A.; Schalper, K.A.; Segura, V.; Bellmunt, J.; Tabernero, J.; Sweeney, C.J.; Choueiri, T.K.; Martín, M.; Fusco, J.P.; RodriguezRuiz, M.E.; Calvo, A.; Prior, C.; Paz-Ares, L.; Pio, R.; GonzalezBillalabeitia, E.; Gonzalez Hernandez, A.; Páez, D.; Piulats, J.M.; Gurpide, A.; Andueza, M.; de Velasco, G.; Pazo, R.; Grande, E.; Nicolas, P.; Abad-Santos, F.; Garcia-Donas, J.; Castellano, D.; Pajares, M.J.; Suarez, C.; Colomer, R.; Montuenga, L.M.; Melero, I. Strategies to design clinical studies to identify predictive biomarkers in cancer research.Cancer Treat. Rev; , 2017, 53, pp. 79-97.
[http://dx.doi.org/10.1016/j.ctrv.2016.12.005] [PMID: 28088073]
[2]
Podolskiy, D.I.; Gladyshev, V.N. Intrinsic versus extrinsic cancer risk factors and aging. Trends Mol. Med., 2016, 22(10), 833-834.
[http://dx.doi.org/10.1016/j.molmed.2016.08.001] [PMID: 27544777]
[3]
(a) Kim, Y.J.; Siegler, E.L.; Siriwon, N.; Wang, P. Therapeutic strategies for targeting cancer stem cells. J. Cancer Metastasis Treat., 2016, 2, 233-242.
[http://dx.doi.org/10.20517/2394-4722.2016.26]
(b) Kuroki, M.; Shirasu, N. Novel treatment strategies for cancer and their tumor-targeting approaches using antibodies against tumor-associated antigens. Anticancer Res., 2014, 34(8), 4481-4488.
[PMID: 25075090]
(c) Yeang, C-H.; Beckman, R.A. Long range personalized cancer treatment strategies incorporating evolutionary dynamics. Biol. Direct, 2016, 11(1), 56.
[http://dx.doi.org/10.1186/s13062-016-0153-2] [PMID: 27770811]
(d) Yildizhan, H.; Barkan, N.P.; Turan, S.K.; Demiralp, Ö.; Demiralp, F.D.Ö.; Uslu, B.; Ōzkan, S.A. Treatment strategies in cancer from past to present. In:Drug Targeting and Stimuli Sensitive Drug Delivery Systems; Grumezescu, A.M., Ed.; William Andrew: New York, 2018, pp. 1-37.
[http://dx.doi.org/10.1016/B978-0-12-813689-8.00001-X]
[4]
(a) Oun, R.; Moussa, Y.E.; Wheate, N.J. The side effects of platinum-based chemotherapy drugs: A review for chemists. Dalton Trans., 2018, 47(19), 6645-6653.
[http://dx.doi.org/10.1039/C8DT00838H] [PMID: 29632935]
(b) Pearce, A.; Haas, M.; Viney, R.; Pearson, S-A.; Haywood, P.; Brown, C.; Ward, R. Incidence and severity of self-reported chemotherapy side effects in routine care: A prospective cohort study. PLoS One, 2017, 12(10)e0184360
[http://dx.doi.org/10.1371/journal.pone.0184360] [PMID: 29016607]
[5]
(a) DeVita, V.T., Jr; Chu, E. A history of cancer chemotherapy. Cancer Res., 2008, 68(21), 8643-8653.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-6611] [PMID: 18974103]
(b) Harrington, S.E.; Smith, T.J. The role of chemotherapy at the end of life: “When is enough, enough? JAMA, 2008, 299(22), 2667-2678.
[http://dx.doi.org/10.1001/jama.299.22.2667] [PMID: 18544726]
(c) Buiting, H.M.; Terpstra, W.; Dalhuisen, F.; Gunnink-Boonstra, N.; Sonke, G.S.; den Hartogh, G. The facilitating role of chemotherapy in the palliative phase of cancer: Qualitative interviews with advanced cancer patients. PLoS One, 2013, 8(11)e77959
[http://dx.doi.org/10.1371/journal.pone.0077959] [PMID: 24223130]
[6]
(a) Farzaei, M.H.; Bahramsoltani, R.; Rahimi, R. Phytochemicals as adjunctive with conventional anticancer therapies. Curr. Pharm. Des., 2016, 22(27), 4201-4218.
[http://dx.doi.org/10.2174/1381612822666160601100823] [PMID: 27262332]
(b) Faustino, C.; Francisco, A.P.; Isca, V.M.S.; Duarte, N. Cytotoxic stilbenes and derivatives as promising antimitotic leads for cancer therapy. Curr. Pharm. Des., 2018, 24(36), 4270-4311.
[http://dx.doi.org/10.2174/1381612825666190111123959] [PMID: 30636588]
(c) Marrelli, M.; Conforti, F.; Statti, G.A.; Cachet, X.; Michel, S.; Tillequin, F.; Menichini, F. Biological potential and structure-activity relationships of most recently developed vascular disrupting agents: an overview of new derivatives of natural combretastatin a-4. Curr. Med. Chem., 2011, 18(20), 3035-3081.
[http://dx.doi.org/10.2174/092986711796391642] [PMID: 21651481]
[7]
Mahbub, A.A.; Le Maitre, C.L.; Haywood-Small, S.L.; McDougall, G.J.; Cross, N.A.; Jordan-Mahy, N. Differential effects of polyphenols on proliferation and apoptosis in human myeloid and lymphoid leukemia cell lines. Anticancer. Agents Med. Chem., 2013, 13(10), 1601-1613.
[http://dx.doi.org/10.2174/18715206113139990303] [PMID: 23796248]
[8]
(a) Giacomini, E.; Rupiani, S.; Guidotti, L.; Recanatini, M.; Roberti, M. The use of stilbene scaffold in medicinal chemistry and multi-target drug design. Curr. Med. Chem., 2016, 23(23), 2439-2489.
[http://dx.doi.org/10.2174/0929867323666160517121629] [PMID: 27183980]
(b) Reinheimer, C.; Büttner, D.; Proschak, E.; Bode, H.B.; Kempf, V.A.J.; Wichelhaus, T.A. Anti-tubercular activity of a natural stilbene and its synthetic derivatives. GMS Infect. Dis., 2018, 6, Doc01.
[PMID: 30671332]
(c) Geldenhuys, W.J.; Van der Schyf, C.J. Rationally designed multi-targeted agents against neurodegenerative diseases. Curr. Med. Chem., 2013, 20(13), 1662-1672.
[http://dx.doi.org/10.2174/09298673113209990112] [PMID: 23410161]
(d) Amoroso, R.; Leporini, L.; Cacciatore, I.; Marinelli, L.; Ammazzalorso, A.; Bruno, I.; Filippis, B.D. Synthesis, characterization and evaluation of gemfibrozil-stilbene hybrid as antioxidant agent. Lett. Drug Des. Discov., 2018, 15(11), 1230-1238.
[http://dx.doi.org/10.2174/1570180815666180321163246]
(e) Garbicz, D.; Mielecki, D.; Wrzesinski, M.; Pilzys, T.; Marcinkowski, M.; Piwowarski, J.; Debski, J.; Palak, E.; Szczecinski, P.; Krawczyk, H.; Grzesiuk, E. Evaluation of anti-cancer Activity of stilbene and methoxydibenzo[b,f] oxepin derivatives. Curr. Cancer Drug Targets, 2018, 18(7), 706-717.
[http://dx.doi.org/10.2174/1568009617666170623120742] [PMID: 28669347]
[9]
Cagir, A.; Odaci, B.; Varol, M.; Akcok, I.; Okur, O.; Koparal, A.T. Evaluation of multifunctional hybrid analogs for stilbenes, chalcones and flavanones. Anticancer. Agents Med. Chem., 2018, 17(14), 1915-1923.
[http://dx.doi.org/10.2174/1871520617666170530091223] [PMID: 28554313]
[10]
Simoni, D.; Roberti, M.; Invidiata, F.P.; Aiello, E.; Aiello, S.; Marchetti, P.; Baruchello, R.; Eleopra, M.; Di Cristina, A.; Grimaudo, S.; Gebbia, N.; Crosta, L.; Dieli, F.; Tolomeo, M. Stilbene-based anticancer agents: Resveratrol analogues active toward HL60 leukemic cells with a non-specific phase mechanism. Bioorg. Med. Chem. Lett., 2006, 16(12), 3245-3248.
[http://dx.doi.org/10.1016/j.bmcl.2006.03.028] [PMID: 16580204]
[11]
Madadi, N.R.; Penthala, N.R.; Ketkar, A.; Eoff, R.L.; Trujullo-Alonso, V.; Guzman, M.L.; Crooks, P.A. Synthesis and evaluation of 2-naphthaleno trans-stilbenes and cyanostilbenes as anticancer agents. Anticancer. Agents Med. Chem., 2018, 18(4), 556-564.
[http://dx.doi.org/10.2174/1871521409666170412115703] [PMID: 28403783]
[12]
Belluti, F.; Fontana, G.; Dal Bo, L.; Carenini, N.; Giommarelli, C.; Zunino, F. Design, synthesis and anticancer activities of stilbene-coumarin hybrid compounds: Identification of novel proapoptotic agents. Bioorg. Med. Chem., 2010, 18(10), 3543-3550.
[http://dx.doi.org/10.1016/j.bmc.2010.03.069] [PMID: 20409723]
[13]
Saeed, A.; Shabir, G.; Batool, I. Novel stilbene-triazine symmetrical optical brighteners: Synthesis and applications. J. Fluoresc., 2014, 24(4), 1119-1127.
[http://dx.doi.org/10.1007/s10895-014-1392-1] [PMID: 24859631]
[14]
Sarwar, M.R.; Saqib, A. Cancer prevalence, incidence and mortality rates in Pakistan in 2012. Cogent Med., 2017, 4(1)1288773
[http://dx.doi.org/10.1080/2331205X.2017.1288773]
[15]
Sirajuddin, M.; Ali, S.; McKee, V.; Zaib, S.; Iqbal, J. Organotin (IV) carboxylate derivatives as a new addition to anticancer and antileishmanial agents: design, physicochemical characterization and interaction with Salmon sperm DNA. RSC Adv., 2014, 4(101), 57505-57521.
[http://dx.doi.org/10.1039/C4RA10487K]
[16]
(a) Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
(b) Niks, M.; Otto, M. Towards an optimized MTT assay. J. Immunol. Methods, 1990, 130(1), 149-151.
[http://dx.doi.org/10.1016/0022-1759(90)90309-J] [PMID: 2358686]
[17]
Scifo, C.; Cardile, V.; Russo, A.; Consoli, R.; Vancheri, C.; Capasso, F.; Vanella, A.; Renis, M. Resveratrol and propolis as necrosis or apoptosis inducers in human prostate carcinoma cells. Oncol. Res., 2004, 14(9), 415-426.
[http://dx.doi.org/10.3727/0965040041791437] [PMID: 15490973]
[18]
Lin, G-J.; Jiang, G-B.; Xie, Y-Y.; Huang, H-L.; Liang, Z-H.; Liu, Y-J. Cytotoxicity, apoptosis, cell cycle arrest, reactive oxygen species, mitochondrial membrane potential, and Western blotting analysis of ruthenium(II) complexes. J. Biol. Inorg. Chem., 2013, 18(8), 873-882.
[http://dx.doi.org/10.1007/s00775-013-1032-2] [PMID: 23989405]
[19]
Rastogi, R.P.; Singh, S.P.; Häder, D-P.; Sinha, R.P. Detection of Reactive Oxygen Species (ROS) by the oxidant-sensing probe 2′,7′-dichlorodihydrofluorescein diacetate in the cyanobacterium Anabaena variabilis PCC 7937. Biochem. Biophys. Res. Commun., 2010, 397(3), 603-607.
[http://dx.doi.org/10.1016/j.bbrc.2010.06.006] [PMID: 20570649]
[20]
Saito, Y.; Uchida, N.; Tanaka, S.; Suzuki, N.; Tomizawa-Murasawa, M.; Sone, A.; Najima, Y.; Takagi, S.; Aoki, Y.; Wake, A.; Taniguchi, S.; Shultz, L.D.; Ishikawa, F. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat. Biotechnol., 2010, 28(3), 275-280.
[http://dx.doi.org/10.1038/nbt.1607] [PMID: 20160717]
[21]
Uddin, N.; Rashid, F.; Ali, S.; Tirmizi, S.A.; Ahmad, I.; Zaib, S.; Zubair, M.; Diaconescu, P.L.; Tahir, M.N.; Iqbal, J.; Haider, A. Synthesis, characterization, and anticancer activity of Schiff bases. J. Biomol. Struct. Dyn., 2019, 38(11), 1-14.
[http://dx.doi.org/10.1080/07391102.2019.1654924] [PMID: 31411114]
[22]
Al-Anbaky, Q.; Al-Karakooly, Z.; Kilaparty, S.P.; Agrawal, M.; Albkuri, Y.M. RanguMagar, A.B.; Ghosh, A.; Ali, N.; Rangu Magar, A.B.; Ghosh, A.; Ali, N. Cytotoxicity of Manganese (III) complex in human breast adenocarcinoma cell line is mediated by the generation of reactive oxygen species followed by mitochondrial damage. Int. J. Toxicol., 2016, 35(6), 672-682.
[http://dx.doi.org/10.1177/1091581816659661] [PMID: 27461214]
[23]
(a) Lin, S-F.; Lin, J-D.; Hsueh, C.; Chou, T-C.; Wong, R.J. Activity of roniciclib in medullary thyroid cancer. Oncotarget, 2018, 9(46), 28030-28041.
[http://dx.doi.org/10.18632/oncotarget.25555] [PMID: 29963260]
(b) Pan, J.; Xu, G.; Yeung, S-C.J. Cytochrome c release is upstream to activation of caspase-9, caspase-8, and caspase-3 in the enhanced apoptosis of anaplastic thyroid cancer cells induced by manumycin and paclitaxel. J. Clin. Endocrinol. Metab., 2001, 86(10), 4731-4740.
[http://dx.doi.org/10.1210/jcem.86.10.7860] [PMID: 11600533]
[24]
Kwon, J-K.; Park, Y-S.; Park, B-K.; Kim, B-S.; Kim, S-K.; Jung, J-Y. Resveratrol induces apoptosis through PI3K/Akt and p53 signal pathway in MDA-MB-231 breast cancer cells. Korean J. Food Sci Technol, 2012, 44(4), 452-459.
[http://dx.doi.org/10.9721/KJFST.2012.44.4.452]
[25]
(a) Zhang, J.; Wang, X.; Vikash, V.; Ye, Q.; Wu, D.; Liu, Y.; Dong, W. ROS and ROS-mediated cellular signaling. Oxid. Med. Cell. Longev., 2016, 2016Article ID 4350965
(b) Finkel, T. Signal transduction by reactive oxygen species. J. Cell Biol., 2011, 194(1), 7-15.
[http://dx.doi.org/10.1083/jcb.201102095] [PMID: 21746850]
[26]
Perillo, B.; Di Donato, M.; Pezone, A.; Di Zazzo, E.; Giovannelli, P.; Galasso, G.; Castoria, G.; Migliaccio, A. ROS in cancer therapy: the bright side of the moon. Exp. Mol. Med., 2020, 52(2), 192-203.
[http://dx.doi.org/10.1038/s12276-020-0384-2] [PMID: 32060354]
[27]
Reczek, C.R.; Chandel, N.S. The two faces of reactive oxygen species in cancer. Ann. Rev. Cancer Biol., 2017, 1, 79-98.
[http://dx.doi.org/10.1146/annurev-cancerbio-041916-065808]
[28]
Kalyanaraman, B.; Darley-Usmar, V.; Davies, K.J.; Dennery, P.A.; Forman, H.J.; Grisham, M.B.; Mann, G.E.; Moore, K.; Roberts, L.J., II; Ischiropoulos, H. Measuring reactive oxygen and nitrogen species with fluorescent probes: Challenges and limitations. Free Radic. Biol. Med, 2012, 52(1), 1-6.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.09.030] [PMID: 22027063]
[29]
Circu, M.L.; Aw, T.Y. Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic. Biol. Med., 2010, 48(6), 749-762.
[http://dx.doi.org/10.1016/j.freeradbiomed.2009.12.022] [PMID: 20045723]
[30]
(a) Zielińska-Przyjemska, M.; Kaczmarek, M.; Krajka-Kuźniak, V.; Łuczak, M.; Baer-Dubowska, W. The effect of resveratrol, its naturally occurring derivatives and tannic acid on the induction of cell cycle arrest and apoptosis in rat C6 and human T98G glioma cell lines. Toxicol. In Vitro, 2017, 43, 69-75.
[http://dx.doi.org/10.1016/j.tiv.2017.06.004] [PMID: 28595835]
(b) Larrosa, M.; Tomás-Barberán, F.A.; Espín, J.C. Grape polyphenol resveratrol and the related molecule 4-hydroxystilbene induce growth inhibition, apoptosis, S-phase arrest, and upregulation of cyclins A, E, and B1 in human SK-Mel-28 melanoma cells. J. Agric. Food Chem., 2003, 51(16), 4576-4584.
[http://dx.doi.org/10.1021/jf030073c] [PMID: 14705880]
[31]
(a) Nikhil, K; Sharan, S; Singh, A.K; Chakraborty, A; Roy, P. Anticancer activities of pterostilbene-isothiocyanate conjugate in breast cancer cells: Involvement of PPARγ PLoS One, 2014, 9(8)e104592
[http://dx.doi.org/10.1371/journal.pone.0104592] [PMID: 25119466]
(b) Dhandayuthapani, S.; Marimuthu, P.; Hörmann, V.; KumiDiaka, J.; Rathinavelu, A. Induction of apoptosis in HeLa cells via caspase activation by resveratrol and genistein. J. Med. Food, 2013, 16(2), 139-146.
[http://dx.doi.org/10.1089/jmf.2012.0141] [PMID: 23356442]
(c) Parida, P.K; Mahata, B.; Santra, A; Chakraborty, S.; Ghosh, Z.; Raha, S.; Misra, A.K; Biswas, K; Jana, K Inhibition of cancer progression by a novel trans-stilbene derivative through disruption of microtubule dynamics, driving G2/M arrest, and p53-dependent apoptosis. Cell Death Dis., 2018, 9(5), 458.
[http://dx.doi.org/10.1038/s41419-018-0476-2] [PMID: 29670107]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy