Preferences help
enabled [disable] Abstract
Number of results
2017 | 64 | 1 | 41-48
Article title

Anticancer activity of new molecular hybrids combining 1,4-naphthalenedione motif with phosphonic acid moiety in hepatocellular carcinoma HepG2 cells

Title variants
Languages of publication
Structural motifs found in naturally occurring compounds are frequently used by researchers to develop novel synthetic drug candidates. Some of these new agents are hybrid molecules which are designed through a concept of combining more than one functional element. In this report, anticancer activity of new synthetic molecular hybrids, substituted 3-diethoxyphosphorylnaphtho[2,3-b]furan-4,9-diones and 3-diethoxyphosphorylbenzo[f]indole-4,9-diones, which integrate natural 1,4-naphtalenedione scaffold, present in several anticancer agents, with pharmacophoric phosphonate moiety, were tested against hepatocellular cell line HepG2. Cytotoxicity was examined using MTT assay. Two most potent compounds, furandione 8a and benzoindoldione 12a, which reduced the number of viable HepG2 cells with the IC50 values of 4.13 µM and 5.9 µM, respectively, were selected for further research. These compounds decreased the mRNA expression levels of several genes: Bcl-2, angiogenic vascular endothelial growth factor (VEGF), c-Fos, caspase-8 and increased the expression of Bax, caspase-3 and -9, c-Jun, p21, p53, as determined by quantitative real-time PCR. The ability of these compounds to induce apoptosis and DNA damage was studied by flow cytometry. The obtained data showed that the new compounds inhibited cell viability by increasing apoptosis and decreasing angiogenesis. Compound 8a was a much stronger apoptosis inducer as compared with 12a and strongly activated the intrinsic pathway of apoptosis, associated with the loss of mitochondrial membrane potential and changes in Bax/Bcl-2 ratio. These findings show that the synthetic hybrids combining 1,4-naphthalenedione system and phosphonic acid moiety display potential to be further explored in the development of new anticancer agents.
Physical description
  • Department of Biomolecular Chemistry, Faculty of Medicine, Medicinal University of Lodz, Łódź, Poland
  • Department of Biomolecular Chemistry, Faculty of Medicine, Medicinal University of Lodz, Łódź, Poland
  • Central Scientific Laboratory, Division of Public Health, Faculty of Health Sciences, Medical University of Lodz, Łódź, Poland
  • Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Łódź, Poland
  • Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Łódź, Poland
  • Department of Biomolecular Chemistry, Faculty of Medicine, Medicinal University of Lodz, Łódź, Poland
  • Abbas T, Dutta A (2009) p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 9: 400-414. doi: 10.1038/nrc2657.
  • Adams JM, Cory S (2007) The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26: 1324-1337. doi: 10.1038/sj.onc.1210220.
  • Ahn HJ, Kim KI, Kim G, Moon E, Yang SS, Lee JS (2011) Atmospheric-pressure plasma jet induces apoptosis involving mitochondria via generation of free radicals. PLoS One 6: e28154. doi: 10.1371/journal.pone.0028154.
  • Bruix J, Sherman M (2011) American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 53: 1020-1022. doi: 10.1002/hep.24199.
  • Buschmann T, Yin Z, Bhoumik A, Ronai Z (2000) Amino-terminal-derived JNK fragment alters expression and activity of c-Jun, ATF2, and p53 and increases H2O2-induced cell death. J Biol Chem 275: 16590-16596. doi: 0.1074/jbc.M910045199.
  • Cheng WH, Zheng X, Quimby FR, Roneker CA, Lei XG (2003) Low levels of glutathione per-oxidase 1 activity in selenium-deficient mouse liver affect c-Jun N-terminal kinase activa-tion and p53 phosphorylation on Ser-15 in pro-oxidant-induced aponecrosis. Biochem J 370: 927-934. doi: 10.1042/bj20021870.
  • Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156-159. doi: 10.1016/0003-2697(87)90021-2.
  • Collado B, Sánchez MG, Díaz-Laviada I, Prieto JC, Carmena MJ (2005) Vasoactive intestinal peptide (VIP) induces c-fos expression in LNCaP prostate cancer cells through a mechanism that involves Ca2+ signalling. Implications in angiogenesis and neuroendocrine differentiation. Biochim Biophys Acta 1744: 224-233. doi: 10.1016/j.bbamcr.2005.04.009.
  • Cory S, Adams JM (2002) The Bcl2 family: Regulators of the cellular life-or-death switch. Nat Rev Cancer 2: 647-656. doi: 10.1038/nrc883.
  • Dehn PF, White CM, Conners DE, Shipkey G, Cumbo TA (2004) Characterization of the human hepatocellular carcinoma (hepg2) cell line as an in vitro model for cadmium toxicity studies. In Vitro Cell Dev Biol Anim 40: 172-182. doi: 10.1290%2F1543-706X(2004)40<172%3ACOTHHC>2.0.CO%3B2.
  • Dérijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M, Davis RJ (1994) JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76: 1025-1037. doi: 10.1016/0092-8674(94)90380-8.
  • Dhanasekaran DN, Reddy EP (2008) JNK signaling in apoptosis. Oncogene 27: 6245-6251. doi: 10.1038/onc.2008.301.
  • Elmore S (2007) Apoptosis: A review of programmed ell death. Toxicol Pathol 35: 495-516. doi: 10.1080/01926230701320337.
  • Gach K, Modranka J, Szymański J, Pomorska D, Krajewska U, Mirowski M, Janecki T, Janecka A (2016) Anticancer properties of new synthetic hybrid molecules combining naphtha[2,3-b]furan-4,9-dione or benzo[f]indole-4,9-dione motif with phosphonate subunit. Eur J Med Chem 120: 51-63. http://dx. doi: 10.1016/j.ejmech.2016.05.002.
  • Gurzov EN, Bakiri L, Alfaro JM, Wagner EF, Izquierdo M (2008) Targeting c-Jun and JunB proteins as potential anticancer. Oncogene 27: 641-652. doi: 10.1038/sj.onc.1210690.
  • Kharbanda S, Pandey P, Yamauchi T, Kumar S, Kaneki M, Kumar V (2000) Activation of MEK kinase 1 by the c-Abl protein tyrosine kinase in response to DNA damage. Mol Cell Biol 20: 4979-4989.
  • Kondoh K, Nishida E (2007) Regulation of MAP kinases by MAP ki­nase phosphatases. Biochim Biophys Acta 1773: 1227-1237. doi: 10.1016/j.bbamcr.2006.12.002.
  • Kyriakis JM, Banerjee P, Nikolakaki E, Dai T, Rubie EA, Ahmad MF, Avruch J, Woodgett JR (1994) The stress-activated protein kinase subfamily of c-Jun kinases. Nature 369: 156-160. doi: 10.1038/369156a0.
  • Llovet JM, Bruix J (2008) Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol 48 Suppl 1: S20-S37. doi: 10.1016/j.jhep.2008.01.022.
  • Llovet JM, Burroughs A, Bruix J (2003) Hepatocellular carcinoma. Lancet 362: 1907-1917. doi: 10.1016/S0140-6736(03)14964-1.
  • Matsuzawa A, Saegusa K, Noguchi T, Sadamitsu C, Nishitoh H, Nagai S (2005) ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity. Nat Immunol 6: 587-592. doi: 10.1038/ni1200.
  • Miyashita T, Kitada S, Krajewski S, Horne WA, Delia D, Reed JC (1995) Overexpression of the Bcl-2 protein increases the half-life of p21Bax. J Biol Chem 270: 26049-26052. doi: 10.1074/jbc.270.44.26049.
  • Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65: 55-63. doi: 10.1016/0022-1759(83)90303-4.
  • Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics. CA Cancer J Clin 55: 74-108. doi: 10.3322/canjclin.55.2.74.
  • Plotnikov A, Zehorai E, Procaccia S, Seger R (2011) The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim Biophys Acta 1813: 1619-1633. doi: 10.1016/j.bbamcr.2010.12.012.
  • Ramalingam S, Belani C (2008) Systemic chemotherapy for advanced non-small cell lung cancer: recent advances and future directions. Oncologist 13: 5-13. doi: 10.1634/theoncologist.13-S1-5.
  • Sanyal AJ, Yoon SK, Lencioni R (2010) The etiology of hepatocellular carcinoma and consequences for treatment. Oncologist 15 Suppl 4: 14-22. doi: 10.1634/theoncologist.2010-S4-14.
  • Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63: 11-30. doi: 10.3322/caac.21166.
  • Siegel RL, Fedewa SA, Miller KD, Goding-Sauer A, Pinheiro PS, Martinez-Tyson D, Jemal A (2015) Cancer statistics for Hispanics/Latinos, 2015. CA Cancer J Clin 65: 457-480. doi: 10.3322/caac.21314.
  • Simonetti RG, Liberati A, Angiolini C, Pagliaro L (1997) Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials. Ann. Oncol 8: 117-136. doi: 10.1023/A:1008285123736.
  • Takayama T, Makuuchi M, Hasegawa K (2010) Single HCC smaller than 2 cm: surgery or ablation?: surgeon's perspective. J. Hepatobiliary Pancreat Sci 17: 422-424. doi: 10.3748/wjg.v20.i29.10174.
  • Takeda K, Matsuzawa A, Nishitoh H, Tobiume K, Kishida S, Ninomiya-Tsuji J (2004) Involvement of ASK1 in Ca2+-induced p38 MAP kinase activation. EMBO Rep 5: 161-166. doi: 10.1038/sj.embor.7400072.
  • Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL (2000) Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102: 43-53. doi: 10.1016/S0092-8674(00)00009-X.
  • Waldman T, Kinzler KW, Vogelstein B (1995) p21 is necessary for the p53-mediated G1 arrest in human cancer cells. Cancer Res 55: 5187-5190.
  • Winer J, Jung CK, Shackel I, Williams PM (1999) Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro. Anal Biochem 270: 41-49. doi: 10.1006/abio.1999.4085.
  • Wisdom R, Johnson RS, Moore C (1999) c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms. EMBO J 18: 188-197. doi:
  • Yang SH, Sharrocks AD, Whitmarsh AJ (2013) MAP kinase signalling cascades and transcriptional regulation. Gene 513: 1-13. .
Document Type
Publication order reference
YADDA identifier
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.