Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Anticancer Activity of Platinum (II) Complex with 2-Benzoylpyridine by Induction of DNA Damage, S-Phase Arrest, and Apoptosis

Author(s): Yu-Lan Li, Xin-Li Gan, Rong-Ping Zhu, Xuehong Wang, Duan-Fang Liao, Junfei Jin* and Zhaoquan Huang*

Volume 20, Issue 4, 2020

Page: [504 - 517] Pages: 14

DOI: 10.2174/1871520619666191112114340

Price: $65

Abstract

Objective: To overcome the disadvantages of cisplatin, numerous platinum (Pt) complexes have been prepared. However, the anticancer activity and mechanism of Pt(II) complexed with 2-benzoylpyridine [Pt(II)- Bpy]: [PtCl2(DMSO)L] (DMSO = dimethyl sulfoxide, L = 2-benzoylpyridine) in cancer cells remain unknown.

Methods: Pt(II)-Bpy was synthesized and characterized by spectrum analysis. Its anticancer activity and underlying mechanisms were demonstrated at the cellular, molecular, and in vivo levels.

Results: Pt(II)-Bpy inhibited tumor cell growth, especially HepG2 human liver cancer cells, with a halfmaximal inhibitory concentration of 9.8±0.5μM, but with low toxicity in HL-7702 normal liver cells. Pt(II)- Bpy induced DNA damage, which was demonstrated through a marked increase in the expression of cleavedpoly (ADP ribose) polymerase (PARP) and gamma-H2A histone family member X and a decrease in PARP expression. The interaction of Pt(II)-Bpy with DNA at the molecular level was most likely through an intercalation mechanism, which might be evidence of DNA damage. Pt(II)-Bpy initiated cell cycle arrest at the S phase in HepG2 cells. It also caused severe loss of the mitochondrial membrane potential; a decrease in the expression of caspase-9 and caspase-3; an increase in reactive oxygen species levels; the release of cytochrome c and apoptotic protease activation factor; and the activation of caspase-9 and caspase-3 in HepG2 cells, which in turn resulted in apoptosis. Meanwhile, changes in p53 and related proteins were observed including the upregulation of p53, the phosphorylation of p53, p21, B-cell lymphoma-2-associated X protein, and NOXA; and the downregulation of B-cell lymphoma 2. Moreover, Pt(II)-Bpy displayed marked inhibitory effects on tumor growth in the HepG2 nude mouse model.

Conclusion: Pt(II)-Bpy is a potential candidate for cancer chemotherapy.

Keywords: Pt(II)-Bpy, anticancer activity, apoptosis, DNA damage, S-phase arrest, HepG2.

« Previous
Graphical Abstract

[1]
Rosenberg, B.; Loretta, V.C.; Thomas, K. Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode. Nature, 1965, 205, 698-699.
[http://dx.doi.org/10.1038/205698a0] [PMID: 14287410]
[2]
Jamieson, E.R.; Lippard, S.J. Structure, recognition, and processing of cisplatin-DNA adducts. Chem. Rev., 1999, 99(9), 2467-2498.
[http://dx.doi.org/10.1021/cr980421n] [PMID: 11749487]
[3]
Wong, E.; Giandomenico, C.M. Current status of platinum-based antitumor drugs. Chem. Rev., 1999, 99(9), 2451-2466.
[http://dx.doi.org/10.1021/cr980420v] [PMID: 11749486]
[4]
Reedijk, J. Why does Cisplatin reach Guanine-n7 with competing s-donor ligands available in the cell? Chem. Rev., 1999, 99(9), 2499-2510.
[http://dx.doi.org/10.1021/cr980422f] [PMID: 11749488]
[5]
Todd, R.C.; Lippard, S.J. Inhibition of transcription by platinum antitumor compounds. Metallomics, 2009, 1(4), 280-291.
[http://dx.doi.org/10.1039/b907567d] [PMID: 20046924]
[6]
Farrell, P.N. Platinum formulations as anticancer drugs clinical and pre-clinical studies. Curr. Top. Med. Chem., 2011, 11(21), 2623-2631.
[http://dx.doi.org/10.2174/156802611798040714] [PMID: 22039867]
[7]
Hambley, T.W. Platinum binding to DNA: Structural controls and consequences. J. Chem. Soc., Dalton Trans., 2001, 19, 2711-2718.
[http://dx.doi.org/10.1039/b105406f]
[8]
Fricker, S.P. Metal based drugs: from serendipity to design. Dalton Trans., 2007, 43, 4903-4917.
[http://dx.doi.org/10.1039/b705551j] [PMID: 17992275]
[9]
Klein, A.V.; Hambley, T.W. Platinum drug distribution in cancer cells and tumors. Chem. Rev., 2009, 109(10), 4911-4920.
[http://dx.doi.org/10.1021/cr9001066] [PMID: 19711978]
[10]
Rosenberg, B.; Camp, L.V.; Trosko, J.E.; Mansour, V.H. Platinum compounds: a new class of potent antitumour agents. Nature, 1969, 222, 385-386.
[http://dx.doi.org/10.1038/222385a0] [PMID: 5782119]
[11]
Bruijnincx, P.C.; Sadler, P.J. New trends for metal complexes with anticancer activity. Curr. Opin. Chem. Biol., 2008, 12(2), 197-206.
[http://dx.doi.org/10.1016/j.cbpa.2007.11.013] [PMID: 18155674]
[12]
Raymond, E.; Chaney, S.G.; Taamma, A.; Cvitkovic, E. Oxaliplatin: a review of preclinical and clinical studies. Ann. Oncol., 1998, 9(10), 1053-1071.
[http://dx.doi.org/10.1023/A:1008213732429] [PMID: 9834817]
[13]
O’Dwyer, P.J.; Stevenson, J.P.; Johnson, S.W. Clinical pharmacokinetics and administration of established platinum drugs. Drugs, 2000, 59(Suppl. 4), 19-27.
[http://dx.doi.org/10.2165/00003495-200059004-00003] [PMID: 10864227]
[14]
Wexselblatt, E.; Gibson, D. What do we know about the reduction of Pt(IV) pro-drugs? J. Inorg. Biochem., 2012, 117, 220-229.
[http://dx.doi.org/10.1016/j.jinorgbio.2012.06.013] [PMID: 22877926]
[15]
Dey, S.; Sarkar, S.; Zangrando, E.; Evans, H.S.; Sutter, J-P.; Chattopadhyay, P. 2-Benzoylpyridine and copper(II) ion in basic medium: Hydroxide nucleophilic addition stabilized by metal complexation, reactivity, crystal structure, DNA binding study and magnetic behavior. Inorg. Chim. Acta, 2011, 367, 1-8.
[http://dx.doi.org/10.1016/j.ica.2010.11.012]
[16]
Reis, D.C.; Pinto, M.C.; Souza-Fagundes, E.M.; Wardell, S.M.; Wardell, J.L.; Beraldo, H. Antimony(III) complexes with 2-benzoylpyridine-derived thiosemicarbazones: cytotoxicity against human leukemia cell lines. Eur. J. Med. Chem., 2010, 45(9), 3904-3910.
[http://dx.doi.org/10.1016/j.ejmech.2010.05.044] [PMID: 20576328]
[17]
Ferraz, K.S.O.; Ferandes, L.; Carrilho, D.; Pinto, M.C.X.; Leite, M.F.; Souza-Fagundes, E.M.; Speziali, N.L.; Mendes, I.C.; Beraldo, H. 2-Benzoylpyridine-N(4)-tolyl thiosemicarbazones and their palladium(II) complexes: cytotoxicity against leukemia cells. Bioorg. Med. Chem., 2009, 17(20), 7138-7144.
[http://dx.doi.org/10.1016/j.bmc.2009.08.063] [PMID: 19773176]
[18]
Wang, X.; Li, Y.; Lin, M.; Jin, J.; Huang, Z. Rhodium (II) complex with 2-benzoylpyridine, a novel potential chemotherapeutic drug, induces cell cycle arrest and apoptosis in HepG2 cells. Biometals, 2017, 30(6), 903-915.
[http://dx.doi.org/10.1007/s10534-017-0056-4] [PMID: 28993927]
[19]
Sheldrick, G.M. SHELXL-97, Program for structure refinement; University of Göttingen, 1997.
[20]
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]
[21]
Olive, P.L.; Banáth, J.P.; Durand, R.E. Heterogeneity in radiation-induced DNA damage and repair in tumor and normal cells measured using the “comet” assay. Radiat. Res., 1990, 122(1), 86-94.
[http://dx.doi.org/10.2307/3577587] [PMID: 2320728]
[22]
Sathiyaraj, S.; Sampath, K.; Butcher, R.J.; Pallepogu, R.; Jayabalakrishnan, C. Designing, structural elucidation, comparison of DNA binding, cleavage, radical scavenging activity and anticancer activity of copper(I) complex with 5-dimethyl-2-phenyl-4-[(pyridin-2-ylmethylene)-amino]-1,2-dihydro-pyrazol-3-one Schiff base ligand. Eur. J. Med. Chem., 2013, 64, 81-89.
[http://dx.doi.org/10.1016/j.ejmech.2013.03.047] [PMID: 23644191]
[23]
Liu, Y-C.; Chen, Z-F.; Song, X-Y.; Peng, Y.; Qin, Q-P.; Liang, H. Synthesis, crystal structure, cytotoxicity and DNA interaction of 5,7-dibromo-8-quinolinolato-lanthanides. Eur. J. Med. Chem., 2013, 59, 168-175.
[http://dx.doi.org/10.1016/j.ejmech.2012.11.001] [PMID: 23220645]
[24]
Olmsted, J., III; Kearns, D.R. Mechanism of ethidium bromide fluorescence enhancement on binding to nucleic acids. Biochemistry, 1977, 16(16), 3647-3654.
[http://dx.doi.org/10.1021/bi00635a022] [PMID: 889813]
[25]
Li, Y.L.; Qin, Q.P.; Liu, Y.C.; Chen, Z.F.; Liang, H. A platinum(II) complex of liriodenine from traditional Chinese medicine (TCM): Cell cycle arrest, cell apoptosis induction and telomerase inhibition activity via G-quadruplex DNA stabilization. J. Inorg. Biochem., 2014, 137, 12-21.
[http://dx.doi.org/10.1016/j.jinorgbio.2014.04.001] [PMID: 24798373]
[26]
Chen, Z.F.; Qin, Q.P.; Qin, J.L.; Liu, Y.C.; Huang, K.B.; Li, Y.L.; Meng, T.; Zhang, G.H.; Peng, Y.; Luo, X.J.; Liang, H. Stabilization of G-quadruplex DNA, inhibition of telomerase activity, and tumor cell apoptosis by organoplatinum(II) complexes with oxoisoaporphine. J. Med. Chem., 2015, 58(5), 2159-2179.
[http://dx.doi.org/10.1021/jm5012484] [PMID: 25650792]
[27]
Palchaudhuri, R.; Hergenrother, P.J. DNA as a target for anticancer compounds: methods to determine the mode of binding and the mechanism of action. Curr. Opin. Biotechnol., 2007, 18(6), 497-503.
[http://dx.doi.org/10.1016/j.copbio.2007.09.006] [PMID: 17988854]
[28]
Liu, H.K.; Sadler, P.J. Metal complexes as DNA intercalators. Acc. Chem. Res., 2011, 44(5), 349-359.
[http://dx.doi.org/10.1021/ar100140e] [PMID: 21446672]
[29]
Govender, P.; Renfrew, A.K.; Clavel, C.M.; Dyson, P.J.; Therrien, B.; Smith, G.S. Antiproliferative activity of chelating N,O- and N,N-ruthenium(II) arene functionalised poly(propyleneimine) dendrimer scaffolds. Dalton Trans. (Cambridge, England: 2003), 2011, 40, 1158-1167.
[http://dx.doi.org/10.1039/c0dt00761g] [PMID: 21165516]
[30]
Novakova, O.; Malina, J.; Suchankova, T.; Kasparkova, J.; Bugarcic, T.; Sadler, P.J.; Brabec, V. Energetics, conformation, and recognition of DNA duplexes modified by monodentate Ru(II) complexes containing terphenyl arenes. Chemistry, 2010, 16(19), 5744-5754.
[http://dx.doi.org/10.1002/chem.200903078] [PMID: 20376825]
[31]
Fairbairn, D.W.; Olive, P.L.; O’Neill, K.L. The comet assay: a comprehensive review. Mutat. Res., 1995, 339(1), 37-59.
[http://dx.doi.org/10.1016/0165-1110(94)00013-3] [PMID: 7877644]
[32]
Pages, B.J.; Ang, D.L.; Wright, E.P.; Aldrich-Wright, J.R. Metal complex interactions with DNA. Dalton Trans. (Cambridge, England: 2003), 2015, 44, 3505-3526.
[http://dx.doi.org/10.1039/ C4DT02700K] [PMID: 25427534]
[33]
Xu, H.; Zheng, K.C.; Chen, Y.; Li, Y.Z.; Lin, L.J.; Li, H.; Zhang, P.X.; Ji, L.N. Effects of ligand planarity on the interaction of polypyridyl Ru(II) complexes with DNA. Dalton Trans., 2003, 11, 2260-2268.
[http://dx.doi.org/10.1039/b300353a]
[34]
Chen, Z.F.; Liu, Y.C.; Liu, L.M.; Wang, H.S.; Qin, S.H.; Wang, B.L.; Bian, H.D.; Yang, B.; Fun, H.K.; Liu, H.G.; Liang, H.; Orvig, C. Potential new inorganic antitumour agents from combining the anticancer traditional Chinese medicine (TCM) liriodenine with metal ions, and DNA binding studies. Dalton Trans., 2009, 2, 262-272.
[http://dx.doi.org/10.1039/B813363H] [PMID: 19089006]
[35]
Ramachandran, E.; Raja, D.S.; Mike, J.L.; Wagner, T.R.
Zeller, M.; Natarajan, K. Evaluation on the role of terminal N-substitution in 6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde thiosemicarbazones on the biological properties of new water-soluble nickel (ii) complexes. RSC Advances, 2012, 2, 8515-8525.
[http://dx.doi.org/10.1039/c2ra21199h]
[36]
Chaney, S.G.; Campbell, S.L.; Bassett, E.; Wu, Y. Recognition and processing of cisplatin- and oxaliplatin-DNA adducts. Crit. Rev. Oncol. Hematol., 2005, 53(1), 3-11.
[http://dx.doi.org/10.1016/j.critrevonc.2004.08.008] [PMID: 15607931]
[37]
Lerman, L.S. Structural considerations in the interaction of DNA and acridines. J. Mol. Biol., 1961, 3, 18-30.
[http://dx.doi.org/10.1016/S0022-2836(61)80004-1] [PMID: 13761054]
[38]
Pauty, J.; Côté, M.F.; Rodrigue, A.; Velic, D.; Masson, J.Y.; Fortin, S. Investigation of the DNA damage response to SFOM-0046, a new small-molecule drug inducing DNA double-strand breaks. Sci. Rep., 2016, 6, 23302.
[http://dx.doi.org/10.1038/srep23302] [PMID: 27001483]
[39]
Roos, W.P.; Kaina, B. DNA damage-induced cell death by apoptosis. Trends Mol. Med., 2006, 12(9), 440-450.
[http://dx.doi.org/10.1016/j.molmed.2006.07.007] [PMID: 16899408]
[40]
Kaina, B. DNA damage-triggered apoptosis: critical role of DNA repair, double-strand breaks, cell proliferation and signaling. Biochem. Pharmacol., 2003, 66(8), 1547-1554.
[http://dx.doi.org/10.1016/S0006-2952(03)00510-0] [PMID: 14555233]
[41]
Hengartner, M.O. The biochemistry of apoptosis. Nature, 2000, 407(6805), 770-776.
[http://dx.doi.org/10.1038/35037710] [PMID: 11048727]
[42]
Wang, X.H.; Jia, D.Z.; Liang, Y.J.; Yan, S.L.; Ding, Y.; Chen, L.M.; Shi, Z.; Zeng, M.S.; Liu, G.F.; Fu, L.W. Lgf-YL-9 induces apoptosis in human epidermoid carcinoma KB cells and multidrug resistant KBv200 cells via reactive oxygen species-independent mitochondrial pathway. Cancer Lett., 2007, 249(2), 256-270.
[http://dx.doi.org/10.1016/j.canlet.2006.09.008] [PMID: 17055640]
[43]
Zhao, J.; Zhang, L.; Li, J.; Wu, T.; Wang, M.; Xu, G.; Zhang, F.; Liu, L.; Yang, J.; Sun, S. A novel pyrazolone-based derivative induces apoptosis in human esophageal cells via reactive oxygen species (ROS) generation and caspase-dependent mitochondria-mediated pathway. Chem. Biol. Interact., 2015, 231, 1-9.
[http://dx.doi.org/10.1016/j.cbi.2015.02.004] [PMID: 25684395]
[44]
Yao, G.; Ling, L.; Luan, J.; Ye, D.; Zhu, P. Nonylphenol induces apoptosis of Jurkat cells by a caspase-8 dependent mechanism. Int. Immunopharmacol., 2007, 7(4), 444-453.
[http://dx.doi.org/10.1016/j.intimp.2006.11.013] [PMID: 17321467]
[45]
Fulda, S. Targeting apoptosis for anticancer therapy. Semin. Cancer Biol., 2015, 31, 84-88.
[http://dx.doi.org/10.1016/j.semcancer.2014.05.002] [PMID: 24859747]
[46]
Fulda, S.; Vucic, D. Targeting IAP proteins for therapeutic intervention in cancer. Nat. Rev. Drug Discov., 2012, 11(2), 109-124.
[http://dx.doi.org/10.1038/nrd3627] [PMID: 22293567]
[47]
Zou, H.; Yang, R.; Hao, J.; Wang, J.; Sun, C.; Fesik, S.W.; Wu, J.C.; Tomaselli, K.J.; Armstrong, R.C. Regulation of the Apaf-1/caspase-9 apoptosome by caspase-3 and XIAP. J. Biol. Chem., 2003, 278(10), 8091-8098.
[http://dx.doi.org/10.1074/jbc.M204783200] [PMID: 12506111]
[48]
Harris, C.C. p53 tumor suppressor gene: from the basic research laboratory to the clinic--an abridged historical perspective. Carcinogenesis, 1996, 17(6), 1187-1198.
[http://dx.doi.org/10.1093/carcin/17.6.1187] [PMID: 8681432]
[49]
Green, D.R.; Kroemer, G. Cytoplasmic functions of the tumour suppressor p53. Nature, 2009, 458(7242), 1127-1130.
[http://dx.doi.org/10.1038/nature07986] [PMID: 19407794]
[50]
Oren, M. Regulation of the p53 tumor suppressor protein. J. Biol. Chem., 1999, 274(51), 36031-36034.
[http://dx.doi.org/10.1074/jbc.274.51.36031] [PMID: 10593882]
[51]
Hofseth, L.J.; Hussain, S.P.; Harris, C.C. p53: 25 years after its discovery. Trends Pharmacol. Sci., 2004, 25(4), 177-181.
[http://dx.doi.org/10.1016/j.tips.2004.02.009] [PMID: 15116721]
[52]
Takahashi, P.; Polson, A.; Reisman, D. Elevated transcription of the p53 gene in early S-phase leads to a rapid DNA-damage response during S-phase of the cell cycle. Apoptosis, 2011, 16(9), 950-958.
[http://dx.doi.org/10.1007/s10495-011-0623-z] [PMID: 21710255]
[53]
Neidle, S.; Thurston, D.E. Chemical approaches to the discovery and development of cancer therapies. Nat. Rev. Cancer, 2005, 5(4), 285-296.
[http://dx.doi.org/10.1038/nrc1587] [PMID: 15803155]
[54]
Adjei, A.A.; Rowinsky, E.K. Novel anticancer agents in clinical development. Cancer Biol. Ther., 2003, 2(4)(Suppl. 1), S5-S15.
[PMID: 14508076]

Rights & Permissions Print Cite
Article Metrics
29
1
© 2024 Bentham Science Publishers | Privacy Policy