S-Phase Kinase-Associated Protein-2 and Nuclear Factor-kappa Beta as Molecular Targets of Oral Burkitt’s Lymphoma Cell Induced by Quinolinone Derivate-Vesnarinone

Author(s): Supriatno*

Journal Name: Current Signal Transduction Therapy

Volume 15 , Issue 2 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: 3,4-Dihydro-6-[4-{3,4-dimethoxybenzoyl}-1-piperazinyl]-2(1H)-quinolinone (vesnarinone), a novel inotropic drug with unique and complex mechanisms of action, is known to show antitumor activity against several human malignancies. In the present study, vesnarinone-induced signal transduction of S-phase kinase-associated protein 2 (Skp2) and Nuclear Factor-kappa Beta (NF-κB) as molecular targets of oral malignant Burkitt’s lymphoma (Raji cells) was evaluated.

Materials and Methods: Raji cells were incubated with vesnarinone at concentrations of 0, 1.25x10-2, 2.50x10-2, or 5.0x10-2 Molar. After 24 h, chemotactic cell migration was examined by a Boyden chamber kit. Apoptosis induction was observed by caspase-9 colorimetric assay. To evaluate levels of Skp2, NF-kB, and α-tubulin, Western blot analysis was performed.

Results: Vesnarinone markedly suppressed chemotactic cell migration and significantly induced apoptosis by increasing the caspase-9 activity of Raji cells through down regulation of Skp2 and NF-κB.

Conclusion: Vesnarinone decreased the expression of Skp2 and NF-κB indicating these molecules may be targeted for the treatment of oral malignant Burkitt’s lymphoma (BL). The results of this work offer a promising therapeutic approach for BL tumors.

Keywords: Vesnarinone, chemotactic migration, apoptosis, Burkitt's lymphoma cell, Skp-2, NF-kB.

Hotta K, Nashimoto A, Yasumura E, et al. Vesnarinone suppresses TNFα mRNA expression by inhibiting valosin-containing protein. Mol Pharmacol 2013; 83(5): 930-8.
[http://dx.doi.org/10.1124/mol.112.081935] [PMID: 23393163]
Harada K. Supriatno , Kawaguchi S, et al High antitumor activity using intratumoral injection of plasmid DNA with mutant-type p27Kip1 gene following in vivo electroporation. Oncol Rep 2005; 13(2): 201-6.
[PMID: 15645112]
Inage M, Nakamura H, Saito H, et al. Vesnarinone represses the fibrotic changes in murine lung injury induced by bleomycin Int J Biol Sci https://www.ncbi.nlm.nih.gov/pubmed/?term=Inage+2009; 5(4): 304-10.
Uchida D, Onoue T, Begum NM, et al. Vesnarinone downregulates CXCR4 expression via upregulation of Krüppel-like factor 2 in oral cancer cells. Mol Cancer 2009; 8(8): 62-6.
[http://dx.doi.org/10.1186/1476-4598-8-62] [PMID: 19671192]
Masuoka H, Ito M, Sugioka M, et al. Two isoforms of cGMPinhibited cyclic nucleotide phosphodiesterases in human tissues distinguished by their responses to vesnarinone, a new cardiotonic agent. Biochem Biophys Res Commun 1993; 190(2): 412-7.
[http://dx.doi.org/10.1006/bbrc.1993.1063] [PMID: 8381275]
Yokozaki H, Ito R, Ono S, et al. Effet of 3,4-dihydro-6-[4-3,4-dimethoxybenzoyl-1-piperazinyl]-2(1H)-quinolinone (vesnarinone) on the growth of gastric cancer cell lines. Cancer Lett 1999; 140: 121-8.
[http://dx.doi.org/10.1016/S0304-3835(99)00061-0] [PMID: 10403550]
Honma Y, Yamamoto-Yamaguchi Y, Kanatani Y. Vesnarinone and glucocorticoids cooperatively induce G1 arrest and have an antitumour effect on human non-small cell lung carcinoma cells grown in nude mice. Br J Cancer 1999; 80(1-2): 96-103.
[http://dx.doi.org/10.1038/sj.bjc.6690327] [PMID: 10389984]
Kubo K, Matsuzaki Y, Kato A, Terai S, Okita K. Antitumor effect of vesnarinone on human hepatocellular carcinoma cell lines. Int J Oncol 1999; 14(1): 41-6.
[http://dx.doi.org/10.3892/ijo.14.1.41] [PMID: 9863007]
Yoneda K, Yamamoto T, Ueta E, Osaki T. Induction of cyclin-dependent kinase inhibitor p21 in vesnarinoneinduced differentiation of squamous cell carcinoma cells. Cancer Lett 1998; 133(1): 35-45.
[http://dx.doi.org/10.1016/S0304-3835(98)00187-6] [PMID: 9929158]
Nara N, Kurokawa H, Tohda S, Tomiyama J, Nagata K, Tanikawa S. Effect of vesnarinone, a quinolinone derivative, on the growth of leukemic blasts in acute myelogenous leukemia. Exp Hematol 1997; 25(3): 199-204.
[PMID: 9091294]
Nio Y, Ohmori H, Minari Y, et al. A quinolinone derivative, vesnarinone (OPC-8212), significantly inhibits the in vitro and in vivo growth of human pancreatic cancer cell lines. Anticancer Drugs 1997; 8(7): 686-95.
[http://dx.doi.org/10.1097/00001813-199708000-00007] [PMID: 9311445]
Tewfik TL, Bond M, al-Ghamdi K, Bernard C. Burkitt’s lymphoma of the tonsil in children. J Otolaryngol 1996; 25(3): 205-8.
[PMID: 8783089]
Carbone A, Canzonieri V, Gloghini A, Rinaldo A, Gaidano G, Ferlito A. Burkitt’s lymphoma: historical background and recent insights into classification and pathogenesis. Ann Otol Rhinol Laryngol 2000; 109(7): 693-702.
[http://dx.doi.org/10.1177/000348940010900716] [PMID: 10903055]
Salamon D, Adori M, He M, et al. Type I interferons directly down-regulate BCL-6 in primary and transformed germinal center B cells: differential regulation in B cell lines derived from endemic or sporadic Burkitt’s lymphoma. Cytokine 2012; 57(3): 360-71.
[http://dx.doi.org/10.1016/j.cyto.2011.12.001] [PMID: 22204827]
Zhang H, Kobayashi R, Galaktionov K, Beach D. p19Skp1 and p45Skp2 are essential elements of the cyclin A-CDK2 S phase kinase. Cell 1995; 82(6): 915-25.
[http://dx.doi.org/10.1016/0092-8674(95)90271-6] [PMID: 7553852]
Yokoi S, Yasui K, Iizasa T, Takahashi T, Fujisawa T, Inazawa J. Down-regulation of SKP2 induces apoptosis in lung-cancer cells. Cancer Sci 2003; 94(4): 344-9.
[http://dx.doi.org/10.1111/j.1349-7006.2003.tb01444.x] [PMID: 12824902]
Supriatno HK, Harada K, Yoshida H, Sato M. Basic investigation on the development of molecular targeting therapy against cyclindependent kinase inhibitor p27Kip1 in head and neck cancer cells. Int J Oncol 2005; 27(3): 627-35.
[PMID: 16077910]
Nakayama K, Nagahama H, Minamishima YA, et al. Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication. EMBO J 2000; 19(9): 2069-81.
[http://dx.doi.org/10.1093/emboj/19.9.2069] [PMID: 10790373]
Marti A, Wirbelauer C, Scheffner M, Krek W. Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation. Nat Cell Biol 1999; 1(1): 14-9.
[http://dx.doi.org/10.1038/8984] [PMID: 10559858]
Méndez J, Zou-Yang XH, Kim SY, Hidaka M, Tansey WP, Stillman B. Human origin recognition complex large subunit is degraded by ubiquitin-mediated proteolysis after initiation of DNA replication. Mol Cell 2002; 9(3): 481-91.
[http://dx.doi.org/10.1016/S1097-2765(02)00467-7] [PMID: 11931757]
Hershko D, Bornstein G, Ben-Izhak O, et al. Inverse relation between levels of p27(Kip1) and of its ubiquitin ligase subunit Skp2 in colorectal carcinomas. Cancer 2001; 91(9): 1745-51.
[http://dx.doi.org/10.1002/1097-0142(20010501)91:9<1745::AIDCNCR1193>3.0.CO;2-H] [PMID: 11335900]
Chiarle R, Fan Y, Piva R, et al. S-phase kinase-associated protein 2 expression in non-Hodgkin’s lymphoma inversely correlates with p27 expression and defines cells in S phase. Am J Pathol 2002; 160(4): 1457-66.
[http://dx.doi.org/10.1016/S0002-9440(10)62571-0] [PMID: 11943729]
Lawrence T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 2009; 1(6) a001651
[http://dx.doi.org/10.1101/cshperspect.a001651] [PMID: 20457564]
Hoesel B, Schmid JA. The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer 2013; 12: 86-92.
[http://dx.doi.org/10.1186/1476-4598-12-86] [PMID: 23915189]
Manna SK, Aggarwal BB, Aggarwal A. Vesnarinone suppresses TNF-induced activation of NF-kappa B, c-Jun kinase, and apoptosis. J Immunol 2000; 164(11): 5815-25.
[http://dx.doi.org/10.4049/jimmunol.164.11.5815] [PMID: 10820260]
Sato M, Harada K, Bando T, et al. Characteristic of antitumor activity of vesnarinone against a human adenoid squamous carcinoma-forming cell line grown in athymic nude mice. Cancer Lett 1995; 91: 1-9.
[http://dx.doi.org/10.1016/0304-3835(95)03713-7] [PMID: 7750082]
Sato S, Tomoyasu S, Okabe-Kado J, et al. Induction of differentiation and enhancement of vincristine sensitivity of human erythroleukemia HEL cells by vesnarinone, a positive inotropic agent. Exp Hematol 1996; 24(1): 37-42.
[PMID: 8536790]
Kawai K, Konishi Y, Izumi K, Sato M, Adachi M, Hozumi M. Enhancement of anticancer effects of radiation and conventional anticancer agents by a quinolinone derivative, vesnarinone: studies on human gastric cancer tissue xenografts in nude mice. Anticancer Res 1998; 18(1A): 405-12.
[PMID: 9568110]
Supriatno HK, Harada K, Kawaguchi S, Yoshida H, Sato M. Effect of p27Kip1 on the ability of invasion and metastasis of an oral cancer cell line. Oncol Rep 2003; 10(3): 527-32.
[PMID: 12684618]
Harada K. Supriatno , Yoshida H, Sato M. Low p27Kip1 expression is associated with poor prognosis in oral squamous cell carcinoma. Anticancer Res 2002; 22(5): 2985-9.
[PMID: 8783089]

open access plus

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Page: [88 - 93]
Pages: 6
DOI: 10.2174/1574362413666180912113856

Article Metrics

PDF: 34