Suppressive oligodeoxynucleotides synergistically enhance antiproliferative effects of anticancer drugs in A549 human lung cancer cells

Takahashi,Ryohei; Sato,Takashi; Klinman,Dennis   M.; Shimosato,Takeshi; Kaneko,Takeshi; Ishigatsubo,Yoshiaki

doi:10.3892/ijo.2012.1755

Suppressive oligodeoxynucleotides synergistically enhance antiproliferative effects of anticancer drugs in A549 human lung cancer cells

Authors:
- Ryohei Takahashi
- Takashi Sato
- Dennis M. Klinman
- Takeshi Shimosato
- Takeshi Kaneko
- Yoshiaki Ishigatsubo
View Affiliations

Affiliations: Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236‑0004, Japan, Center for Cancer Research, Cancer and Inflammation Program, National Cancer Institute at Frederick, Frederick, MD 21702, USA, Graduate School of Agriculture, Shinshu University, Nagano 399-4598, Japan
Published online on: December 28, 2012 https://doi.org/10.3892/ijo.2012.1755
Pages: 429-436
Copyright: © Takahashi et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Immunosuppressive oligodeoxynucleotides (Sup ODNs) containing repetitive TTAGGG motifs reduce inflammation and, thus, may have an impact on inflammation‑related tumor growth. In this study, we found a significant antiproliferative effect of Sup ODNs on the A549 non‑small cell lung cancer (NSCLC) cell line compared to those treated with control ODNs (p<0.05). Sup-ODN-mediated G1 phase cell cycle arrest was achieved via inhibition of Akt and extracellular signal-regulated kinase 1/2 phosphorylation and the p15INK4b and p27KIP1/retinoblastoma protein pathway. In addition, Sup ODNs induced apoptosis and enhanced apoptosis when combined with vinorelbine. In a setting similar to clinical use of multidrug chemotherapy for advanced NSCLC, these effects were investigated by using Sup ODNs in combination with conventional anticancer drugs. Sup ODNs had a significant synergistic effect with 5-fluorouracil, vinorelbine, gemcitabine, paclitaxel and irinotecan, with a mean combination index of 0.43-0.78 (<1.0 indicates synergism) in the A549 NSCLC cell line. In conclusion, our results showed that Sup ODNs have an anticancer effect and increase the sensitivity of NSCLC cells to conventional anticancer drugs by modifying Akt and the extracellular signal-regulated kinase 1/2 pathway. Thus, Sup ODNs may serve as a novel therapeutic strategy for NSCLC patients.

View Figures

View References

1.	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2.	Sandler AB, Nemunaitis J, Denham C, et al: Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 18:122–130. 2000.PubMed/NCBI
3.	Giancotti FG and Ruoslahti E: Integrin signaling. Science. 285:1028–1032. 1999. View Article : Google Scholar : PubMed/NCBI
4.	Okamura M, Yamaji S, Nagashima Y, et al: Prognostic value of integrin beta1-ILK-pAkt signaling pathway in non-small cell lung cancer. Hum Pathol. 38:1081–1091. 2007. View Article : Google Scholar : PubMed/NCBI
5.	Vicent S, Lopez-Picazo JM, Toledo G, et al: ERK1/2 is activated in non-small-cell lung cancer and associated with advanced tumours. Br J Cancer. 90:1047–1052. 2004. View Article : Google Scholar : PubMed/NCBI
6.	Roberts PJ and Der CJ: Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 26:3291–3310. 2007. View Article : Google Scholar
7.	Balkwill F and Mantovani A: Inflammation and cancer: back to Virchow? Lancet. 357:539–545. 2001. View Article : Google Scholar : PubMed/NCBI
8.	Coussens LM and Werb Z: Inflammation and cancer. Nature. 420:860–867. 2002. View Article : Google Scholar : PubMed/NCBI
9.	Dong L, Ito S, Ishii KJ and Klinman DM: Suppressive oligo-nucleotides protect against collagen-induced arthritis in mice. Arthritis Rheum. 50:1686–1689. 2004. View Article : Google Scholar : PubMed/NCBI
10.	Ikeuchi H, Kinjo T and Klinman DM: Effect of suppressive oligodeoxynucleotides on the development of inflammation-induced papillomas. Cancer Prev Res (Phila). 4:752–757. 2011. View Article : Google Scholar : PubMed/NCBI
11.	Zeuner RA, Ishii KJ, Lizak MJ, et al: Reduction of CpG-induced arthritis by suppressive oligodeoxynucleotides. Arthritis Rheum. 46:2219–2224. 2002. View Article : Google Scholar : PubMed/NCBI
12.	Zeuner RA, Verthelyi D, Gursel M, Ishii KJ and Klinman DM: Influence of stimulatory and suppressive DNA motifs on host susceptibility to inflammatory arthritis. Arthritis Rheum. 48:1701–1707. 2003. View Article : Google Scholar : PubMed/NCBI
13.	Shirota H, Gursel M and Klinman DM: Suppressive oligodeoxynucleotides inhibit Th1 differentiation by blocking IFN-gamma- and IL-12-mediated signaling. J Immunol. 173:5002–5007. 2004. View Article : Google Scholar : PubMed/NCBI
14.	Shirota H, Gursel I, Gursel M and Klinman DM: Suppressive oligodeoxynucleotides protect mice from lethal endotoxic shock. J Immunol. 174:4579–4583. 2005. View Article : Google Scholar : PubMed/NCBI
15.	Sato T, Shimosato T, Alvord WG and Klinman DM: Suppressive oligodeoxynucleotides inhibit silica-induced pulmonary inflammation. J Immunol. 180:7648–7654. 2008. View Article : Google Scholar : PubMed/NCBI
16.	Gursel I, Gursel M, Yamada H, Ishii KJ, Takeshita F and Klinman DM: Repetitive elements in mammalian telomeres suppress bacterial DNA-induced immune activation. J Immunol. 171:1393–1400. 2003. View Article : Google Scholar : PubMed/NCBI
17.	Park KH, Seol JY, Yoo CG, et al: Adenovirus expressing p27(Kip1) induces growth arrest of lung cancer cell lines and suppresses the growth of established lung cancer xenografts. Lung Cancer. 31:149–155. 2001. View Article : Google Scholar : PubMed/NCBI
18.	Sandor V, Senderowicz A, Mertins S, et al: P21-dependent g(1) arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228. Br J Cancer. 83:817–825. 2000. View Article : Google Scholar : PubMed/NCBI
19.	Weinberg RA: The retinoblastoma protein and cell cycle control. Cell. 81:323–330. 1995. View Article : Google Scholar : PubMed/NCBI
20.	Sherr CJ and Roberts JM: CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13:1501–1512. 1999. View Article : Google Scholar : PubMed/NCBI
21.	Chou TC and Talalay P: Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 22:27–55. 1984. View Article : Google Scholar : PubMed/NCBI
22.	Chou TC, Motzer RJ, Tong Y and Bosl GJ: Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design. J Natl Cancer Inst. 86:1517–1524. 1994. View Article : Google Scholar
23.	Li GZ, Eller MS, Hanna K and Gilchrest BA: Signaling pathway requirements for induction of senescence by telomere homolog oligonucleotides. Exp Cell Res. 301:189–200. 2004. View Article : Google Scholar : PubMed/NCBI
24.	Yaar M, Eller MS, Panova I, et al: Telomeric DNA induces apoptosis and senescence of human breast carcinoma cells. Breast Cancer Res. 9:R132007. View Article : Google Scholar : PubMed/NCBI
25.	Longe HO, Romesser PB, Rankin AM, et al: Telomere homolog oligonucleotides induce apoptosis in malignant but not in normal lymphoid cells: mechanism and therapeutic potential. Int J Cancer. 124:473–482. 2009. View Article : Google Scholar
26.	Guo XF and Cao EH: Telomeric plasmid induces human cancer cell dysfunction depending on ATM activity. Cell Biochem Funct. 28:381–386. 2010. View Article : Google Scholar : PubMed/NCBI
27.	Hall M and Peters G: Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv Cancer Res. 68:67–108. 1996. View Article : Google Scholar : PubMed/NCBI
28.	Toyoshima H and Hunter T: p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell. 78:67–74. 1994. View Article : Google Scholar : PubMed/NCBI
29.	DeCaprio JA, Ludlow JW, Lynch D, et al: The product of the retinoblastoma susceptibility gene has properties of a cell cycle regulatory element. Cell. 58:1085–1095. 1989. View Article : Google Scholar : PubMed/NCBI
30.	Vivanco I and Sawyers CL: The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2:489–501. 2002. View Article : Google Scholar : PubMed/NCBI
31.	Engelman JA: Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 9:550–562. 2009. View Article : Google Scholar : PubMed/NCBI
32.	Montagut C and Settleman J: Targeting the RAF-MEK-ERK pathway in cancer therapy. Cancer Lett. 283:125–134. 2009. View Article : Google Scholar : PubMed/NCBI
33.	Pujol JL, Barlesi F and Daures JP: Should chemotherapy combinations for advanced non-small cell lung cancer be platinum-based? A meta-analysis of phase III randomized trials. Lung Cancer. 51:335–345. 2006. View Article : Google Scholar : PubMed/NCBI
34.	Reck M, von Pawel J, Zatloukal P, et al: Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 27:1227–1234. 2009. View Article : Google Scholar : PubMed/NCBI
35.	Sandler A, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 355:2542–2550. 2006. View Article : Google Scholar : PubMed/NCBI
36.	Liu LF, Desai SD, Li TK, Mao Y, Sun M and Sim SP: Mechanism of action of camptothecin. Ann NY Acad Sci. 922:1–10. 2000. View Article : Google Scholar
37.	Longley DB, Harkin DP and Johnston PG: 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 3:330–338. 2003. View Article : Google Scholar : PubMed/NCBI
38.	Madrid LV, Wang CY, Guttridge DC, Schottelius AJ, Baldwin AS Jr and Mayo MW: Akt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NF-kappaB. Mol Cell Biol. 20:1626–1638. 2000. View Article : Google Scholar : PubMed/NCBI
39.	Zaludova R, Zakovska A, Kasparkova J, et al: DNA interactions of bifunctional dinuclear platinum(II) antitumor agents. Eur J Biochem. 246:508–517. 1997. View Article : Google Scholar : PubMed/NCBI
40.	Reeder F, Guo Z, Murdoch PD, et al: Platination of a GG site on single-stranded and double-stranded forms of a 14-base oligonucleotide with diaqua cisplatin followed by NMR and HPLC - influence of the platinum ligands and base sequence on 5′-G versus 3′-G platination selectivity. Eur J Biochem. 249:370–382. 1997.PubMed/NCBI
41.	Blommaert FA, van Dijk-Knijnenburg HC, Dijt FJ, et al: Formation of DNA adducts by the anticancer drug carboplatin: different nucleotide sequence preferences in vitro and in cells. Biochemistry. 34:8474–8480. 1995. View Article : Google Scholar : PubMed/NCBI
42.	Van Triest B, Pinedo HM, Giaccone G and Peters GJ: Downstream molecular determinants of response to 5-fluorouracil and anti-folate thymidylate synthase inhibitors. Ann Oncol. 11:385–391. 2000.PubMed/NCBI