Antitumor activity of a 2-pyridinecarboxaldehyde 2-pyridinecarboxylic acid hydrazone copper complex and the related mechanism

Yang,Yingli; Huang,Tengfei; Zhou,Sufeng; Fu,Yun; Liu,Youxun; Yuan,Yanbin; Zhang,Qiongqing; Li,Shaoshan; Li,Changzheng

doi:10.3892/or.2015.4087

Antitumor activity of a 2-pyridinecarboxaldehyde 2-pyridinecarboxylic acid hydrazone copper complex and the related mechanism

Authors:
- Yingli Yang
- Tengfei Huang
- Sufeng Zhou
- Yun Fu
- Youxun Liu
- Yanbin Yuan
- Qiongqing Zhang
- Shaoshan Li
- Changzheng Li
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Affiliations: Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, Henan, P.R. China, Clinical Skill Training Center, Xinxiang Medical University, Xinxiang, Henan, P.R. China, Department of Surgery, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, P.R. China
Published online on: June 26, 2015 https://doi.org/10.3892/or.2015.4087
Pages: 1311-1318

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Abstract

In the present study, 2-pyridinecarboxaldehyde 2-pyridinecarboxylic acid hydrazone (PPAH) was prepared and its antitumor activity was evaluated. The inhibition of proliferation of PPAH against the HepG2 and HCT-116 cell lines was less effective, yet in the presence of copper ions, the mixture demonstrated excellent antitumor activity (IC50 at 2.75±0.30 µM for the HepG2 cell line, and 1.90±0.20 µM for the HCT-116 cell line, respectively) and the new active species was confirmed to be a PPAH copper complex with a 1:1 ratio by spectral analysis. The excellent antitumor activity of the copper complex prompted us to investigate the underlying mechanism. RT-PCR was performed to detect the changes in the expression of apoptotic genes induced by PPAH and its copper complex. However, no changes were observed when the cells were treated by the agents for 24 or 48 h, indicating that ROS were unlikely involved. Cell cycle analysis showed that both PPAH and its copper complex led to S phase arrest of the cells. The sDNA relaxation assay revealed that the PPAH-copper complex displayed dual topoisomerase inhibition for type I and II. The data suggest that the inhibition of proliferation exhibited by the PPAH copper complex may stem from its dual topoisomerase inhibition, which is rarely observed for a metal complex.

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1	Chen Y and Hu L: Design of anticancer prodrugs for reductive activation. Med Res Rev. 29:29–64. 2009. View Article : Google Scholar
2	Chen Z, Zhang D, Yue F, Zheng M, Kovacevic Z and Richardson DR: The iron chelators Dp44mT and DFO inhibit TGF-β-induced epithelial-mesenchymal transition via up-regulation of N-Myc downstream-regulated gene 1 (NDRG1). J Biol Chem. 287:17016–17028. 2012. View Article : Google Scholar : PubMed/NCBI
3	Gupte A and Mumper RJ: Elevated copper and oxidative stress in cancer cells as a target for cancer treatment. Cancer Treat Rev. 35:32–46. 2009. View Article : Google Scholar
4	Pahl PM and Horwitz LD: Cell permeable iron chelators as potential cancer chemotherapeutic agents. Cancer Invest. 23:683–691. 2005. View Article : Google Scholar : PubMed/NCBI
5	Kalinowski DS, Sharpe PC, Bernhardt PV and Richardson DR: Structure-activity relationships of novel iron chelators for the treatment of iron overload disease: The methyl pyrazinylketone isonicotinoyl hydrazone series. J Med Chem. 51:331–344. 2008. View Article : Google Scholar
6	Chaston TB, Watts RN, Yuan J and Richardson DR: Potent antitumor activity of novel iron chelators derived from di-2-pyridylketone isonicotinoyl hydrazone involves Fenton-derived free radical generation. Clin Cancer Res. 10:7365–7374. 2004. View Article : Google Scholar : PubMed/NCBI
7	Filipović N, Borrmann H, Todorović T, Borna M, Spasojević V, Sladić D, Novaković I and Anđelković K: Copper(II) complexes of N-heteroaromatic hydrazones: Synthesis, X-ray structure, magnetic behavior, and antibacterial activity. Inorg Chim Acta. 362:1996–2000. 2009. View Article : Google Scholar
8	Hoyes KP, Hider RC and Porter JB: Cell cycle synchronization and growth inhibition by 3-hydroxypyridin-4-one iron chelators in leukemia cell lines. Cancer Res. 52:4591–4599. 1992.PubMed/NCBI
9	Chaston TB and Richardson DR: Interactions of the pyridine-2-carboxaldehyde isonicotinoyl hydrazone class of chelators with iron and DNA: Implications for toxicity in the treatment of iron overload disease. J Biol Inorg Chem. 8:427–438. 2003.PubMed/NCBI
10	Chaston TB, Lovejoy DB, Watts RN and Richardson DR: Examination of the antiproliferative activity of iron chelators: Multiple cellular targets and the different mechanism of action of triapine compared with desferrioxamine and the potent pyridoxal isonicotinoyl hydrazone analogue 311. Clin Cancer Res. 9:402–414. 2003.PubMed/NCBI
11	Turner J, Koumenis C, Kute TE, Planalp RP, Brechbiel MW, Beardsley D, Cody B, Brown KD, Torti FM and Torti SV: Tachpyridine, a metal chelator, induces G₂ cell-cycle arrest, activates checkpoint kinases, and sensitizes cells to ionizing radiation. Blood. 106:3191–3199. 2005. View Article : Google Scholar : PubMed/NCBI
12	Fu Y, Zhou S, Liu Y, Yang Y, Sun X and Li C: The cytotoxicity of benzaldehyde nitrogen mustard-2-pyridine carboxylic acid hydrazone being involved in topoisomerase IIα inhibition. BioMed Res Int. 2014:5270422014. View Article : Google Scholar
13	Zheng X, Zhao Y and Zhu BX: Coordination of the new Schiff base with copper(II) or Iron(III) in solution. Wuji Huaxue Xuebao. 27:1523–1528. 2011.In Chinese.
14	Singh NP, McCoy MT, Tice RR and Schneider EL: A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res. 175:184–191. 1988. View Article : Google Scholar : PubMed/NCBI
15	Fu Y, Zhang Y, Zhou SF, Liu Y, Wang J, Wang Y, Lu C and Li C: The effects of substitution of carboxyl with hydrazide group on position 3 of ciprofloxacin on its antimicrobial and antitumor activity. Int J Pharm. 9:416–429. 2013. View Article : Google Scholar
16	Banerjee S, Sen S, Basak S, Mitra S, Hughes DL and Desplanches C: Two new pseudohalide-bridged Cu(II) complexes with a hydrazone ligand: Syntheses, crystal structures and magnetic studies. Inorg Chim Acta. 361:2707–2714. 2008. View Article : Google Scholar
17	Buss JL, Neuzil J and Ponka P: Oxidative stress mediates toxicity of pyridoxal isonicotinoyl hydrazone analogs. Arch Biochem Biophys. 421:1–9. 2004. View Article : Google Scholar
18	Jansson PJ, Hawkins CL, Lovejoy DB and Richardson DR: The iron complex of Dp44mT is redox-active and induces hydroxyl radical formation: An EPR study. J Inorg Biochem. 104:1224–1228. 2010. View Article : Google Scholar : PubMed/NCBI
19	Becker E and Richardson DR: Development of novel aroylhydrazone ligands for iron chelation therapy: 2-pyridylcarboxaldehyde isonicotinoyl hydrazone analogs. J Lab Clin Med. 134:510–521. 1999. View Article : Google Scholar : PubMed/NCBI
20	Gillardon F, Wickert H and Zimmermann M: Up-regulation of bax and down-regulation of bcl-2 is associated with kainate-induced apoptosis in mouse brain. Neurosci Lett. 192:85–88. 1995. View Article : Google Scholar : PubMed/NCBI
21	Niu G, Yin S, Xie S, Li Y, Nie D, Ma L, Wang X and Wu Y: Quercetin induces apoptosis by activating caspase-3 and regulating Bcl-2 and cyclooxygenase-2 pathways in human HL-60 cells. Acta Biochim Biophys Sin. 43:30–37. 2011. View Article : Google Scholar
22	Turski ML and Thiele DJ: New roles for copper metabolism in cell proliferation, signaling, and disease. J Biol Chem. 284:717–721. 2009. View Article : Google Scholar :
23	Jain S, Cohen J, Ward MM, Kornhauser N, Chuang E, Cigler T, Moore A, Donovan D, Lam C, Cobham MV, et al: Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse. Ann Oncol. 24:1491–1498. 2013. View Article : Google Scholar : PubMed/NCBI
24	Tardito S and Marchiò L: Copper compounds in anticancer strategies. Curr Med Chem. 16:1325–1348. 2009. View Article : Google Scholar : PubMed/NCBI
25	Skrott Z and Cvek B: Diethyldithiocarbamate complex with copper: The mechanism of action in cancer cells. Mini Rev Med Chem. 12:1184–1192. 2012. View Article : Google Scholar : PubMed/NCBI
26	Zhou BB and Elledge SJ: The DNA damage response: Putting checkpoints in perspective. Nature. 408:433–439. 2000. View Article : Google Scholar : PubMed/NCBI
27	Ahmad M, Afzal M, Tabassum S, Kalińska B, Mrozinski J and Bharadwaj PK: Synthesis and structure elucidation of a cobalt(II) complex as topoisomerase I inhibitor: In vitro DNA binding, nuclease and RBC hemolysis. Eur J Med Chem. 74:683–693. 2014. View Article : Google Scholar
28	Katkar P, Coletta A, Castelli S, Sabino GL, Couto RA, Ferreira AM and Desideri A: Effect of oxindolimine copper(II) and zinc(II) complexes on human topoisomerase I activity. Metallomics. 6:117–125. 2014. View Article : Google Scholar
29	Wang P, Leung CH, Ma DL, Lu W and Che CM: Organoplatinum(II) complexes with nucleobase motifs as inhibitors of human topoisomerase II catalytic activity. Chem Asian J. 5:2271–2280. 2010. View Article : Google Scholar : PubMed/NCBI
30	Gao F, Chao H and Ji LN: DNA binding, photocleavage, and topoisomerase inhibition of functionalized ruthenium(II)-polypyridine complexes. Chem Biodivers. 5:1962–1979. 2008. View Article : Google Scholar : PubMed/NCBI
31	Kou JF, Qian C, Wang JQ, Chen X, Wang LL, Chao H and Ji LN: Chiral ruthenium(II) anthraquinone complexes as dual inhibitors of topoisomerases I and II. J Biol Inorg Chem. 17:81–96. 2012. View Article : Google Scholar
32	Lin RW, Yang CN, Ku S, Ho CJ, Huang SB, Yang MC, Chang HW, Lin CM, Hwang J, Chen YL, et al: CFS-1686 causes cell cycle arrest at intra-S phase by interference of interaction of topoisomerase 1 with DNA. PLoS One. 9:e1138322014. View Article : Google Scholar : PubMed/NCBI