Paclitaxel in combination with cetuximab exerts antitumor effect by suppressing NF-κB activity in human oral squamous cell carcinoma cell lines

Harada,Koji; Ferdous,Tarannum; Kobayashi,Hiroaki; Ueyama,Yoshiya

doi:10.3892/ijo.2014.2655

Paclitaxel in combination with cetuximab exerts antitumor effect by suppressing NF-κB activity in human oral squamous cell carcinoma cell lines

Authors:
- Koji Harada
- Tarannum Ferdous
- Hiroaki Kobayashi
- Yoshiya Ueyama
View Affiliations

Affiliations: Department of Oral and Maxillofacial Surgery, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan
Published online on: September 17, 2014 https://doi.org/10.3892/ijo.2014.2655
Pages: 2439-2445

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

In the present study, we examined the antitumor effect of paclitaxel (PTX) in combination with cetuximab in oral squamous cell carcinoma (OSCC) and the mechanism of its enhanced antitumor activity. Treatment of OSCC (HSC2, HSC3 and HSC4) cells with PTX (0.02 µg/ml) and cetuximab (1 µg/ml) combination resulted in a significant inhibition of cell growth in vitro compared to either agent alone. Moreover, it was found by Hoechst 33258 staining that DNA fragmentation markedly occurred in OSCC cells treated with PTX and cetuximab combination treatment. Furthermore, PTX and cetuximab combination treatment reduced the expression of p65 (NF-κB) protein in OSCC cells. In our in vivo experiment, HSC2 tumor-bearing nude mice were treated with PTX (20 mg/kg/day, twice/week, 3 weeks) and/or cetuximab (20 mg/kg/day, twice/week, 3 weeks). Tumor growth was significantly suppressed by PTX and cetuximab combined treatment when compared to PTX or cetuximab alone, or the untreated control. TUNEL-positive cells were upregulated in HSC2 tumors treated with PTX and cetuximab. In addition, immunohistochemical staining revealed that expression of p65 was downregulated in HSC2 tumors treated with PTX and cetuximab. Our results indicate that cetuximab may enhance the effect of PTX in OSCC through the downregulation of PTX induced p65 expression. Therefore, the combination of PTX and cetuximab might be a promising option for OSCC treatment.

View Figures

View References

1	Exarchos KP, Goletsis Y and Fotiadis DI: A multiscale and multiparametric approach for modeling the progression of oral cancer. BMC Med Inform Decis Mak. 12:1362012. View Article : Google Scholar : PubMed/NCBI
2	Parkin DM, Bray F, Ferlay J and Pisani P: Global Cancer Statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar
3	Tanaka T, Tanaka M and Tanaka T: Oral carcinogenesis and oral cancer chemoprevention (review). Patholog Res Int. 2011:4312462011.PubMed/NCBI
4	Inagi K, Takahashi H, Okamoto M, Nakayama M, Makoshi T and Nagai H: Treatment effects in patients with squamous cell carcinoma of the oral cavity. Acta Otolaryngol (Suppl). 547:25–29. 2002. View Article : Google Scholar : PubMed/NCBI
5	Shingaki S, Takada M, Sasai K, Bibi R, Kobayashi T, Nomura T and Saito C: Impact of lymph node metastasis on the pattern of failure and survival in oral carcinomas. Am J Surg. 185:278–284. 2003. View Article : Google Scholar : PubMed/NCBI
6	Wise-Draper TM, Draper DJ, Gutkind JS, Molinolo AA, Wikenheiser-Brokamp KA and Wells SI: Future directions and treatment strategies for head and neck squamous cell carcinomas. Transl Res. 160:167–177. 2012. View Article : Google Scholar : PubMed/NCBI
7	Russell JS and Colevas AD: The use of epidermal growth factor receptor monoclonal antibodies in squamous cell carcinoma of the head and neck. Chemother Res Pract. 2012:7615182012.PubMed/NCBI
8	Vincenzi B, Zoccoli A, Pantano F, Venditti O and Galluzzo S: Cetuximab: from bench to bedside. Curr Cancer Drug Targets. 10:80–95. 2010. View Article : Google Scholar : PubMed/NCBI
9	Peng D, Fan Z, Lu Y, DeBlasio T, Scher H and Mendelsohn J: Anti-epidermal growth factor receptor monoclonal antibody 225 upregulates p27^KIP1 and induces G1 arrest in prostatic cancer cell line DU145. Cancer Res. 56:3666–3669. 1996.PubMed/NCBI
10	Wani MC, Taylor HL, Wall ME, Coggon P and McPhail AT: Plant antitumor agents. VI The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc. 93:2325–2327. 1971. View Article : Google Scholar : PubMed/NCBI
11	Rowinsky EK, Donehower RC, Jones RJ and Tucker RW: Microtubule changes and cytotoxicity in leukemic cell lines treated with taxol. Cancer Res. 48:4093–4100. 1988.PubMed/NCBI
12	Schiff PB, Fant J and Horwitz SB: Promotion of microtubule assembly in vitro by taxol. Nature. 277:665–667. 1979. View Article : Google Scholar : PubMed/NCBI
13	Langer CJ, Lee JW, Patel UA, Shin DM, Argiris AE, Quon H, Ridge JA and Forastiere AA: Concurrent radiation (RT), cisplatin (DDP) and cetuximab (C) in unresectable, locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN). J Clin Oncol. 26:20(abst 6006). 2008.PubMed/NCBI
14	Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK and Ang KK: Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 11:21–28. 2010.PubMed/NCBI
15	Sosa AE, Grau JJ, Feliz L, Pereira V, Alcaraz D, Muñoz-García C and Caballero M: Outcome of patients treated with palliative weekly paclitaxel plus cetuximab in recurrent head and neck cancer after failure of platinum-based therapy. Eur Arch Otorhinolaryngol. 271:373–378. 2014. View Article : Google Scholar : PubMed/NCBI
16	Jiménez B, Trigo JM, Pajares BI, Sáez MI, Quero C, Navarro V, Llácer C, Medina L, Rueda A and Alba E: Efficacy and safety of weekly paclitaxel combined with cetuximab in the treatment of pretreated recurrent/metastatic head and neck cancer patients. Oral Oncol. 49:182–185. 2013.PubMed/NCBI
17	Hitt R, Irigoyen A, Cortes-Funes H, Grau JJ, García-Sáenz JA and Cruz-Hernandez JJ; Spanish Head and Neck Cancer Cooperative Group (TTCC). Phase II study of the combination of cetuximab and weekly paclitaxel in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head and neck. Ann Oncol. 23:1016–1022. 2012. View Article : Google Scholar : PubMed/NCBI
18	Wong YN, Litwin S, Vaughn D, Cohen S, Plimack ER, Lee J, Song W, Dabrow M, Brody M, Tuttle H and Hudes G: Phase II trial of cetuximab with or without paclitaxel in patients with advanced urothelial tract carcinoma. J Clin Oncol. 30:3545–3551. 2012. View Article : Google Scholar
19	Mecca C, Ponzetti A, Caliendo V, Ciuffreda L and Lista P: Complete response of metastatic cutaneous squamous cell carcinoma to cetuximab plus paclitaxel. Eur J Dermatol. 22:758–761. 2012.PubMed/NCBI
20	Beg AA, Sha WC, Bronson RT, Ghosh S and Baltimore D: Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB. Nature. 376:167–170. 1995.PubMed/NCBI
21	Cai Z, Korner M, Tarantino N and Chouaib S: IκB-α overexpression in human breast carcinoma MCF7 cells inhibits nuclear factor-κB activation but not tumor necrosis factor-α-induced apoptosis. J Biol Chem. 272:96–101. 1997.
22	Bargou RC, Emmerich F, Krappmann D, Bommert K, Mapara MY, Arnold W, Royer HD, Grinstein E, Greiner A, Scheidereit C and Dorken B: Constitutive nuclear factor-kappa B-RelA activation is required for proliferation and survival of Hodgkin’s disease tumor cells. J Clin Invest. 100:2961–2969. 1997.PubMed/NCBI
23	Sovak MA, Bellas RE, Kim DW, Zanieski GJ, Rogers AE, Traish AM and Sonenshein GE: Aberrant nuclear factor-κB/Rel expression and the pathogenesis of breast cancer. J Clin Invest. 100:2952–2960. 1997.
24	Shen HM and Tergaonkar V: NFkappaB signaling in carcinogenesis and as a potential molecular target for cancer therapy (review). Apoptosis. 14:348–363. 2009. View Article : Google Scholar : PubMed/NCBI
25	Beg AA and Baldwin AS Jr: The IκB proteins: multifunctional regulators of Rel/NF-κB transcription factors. Genes Dev. 7:2064–2070. 1993.
26	Duffey D, Chen Z, Dong G, Ondrey FG, Wolf JF, Brown K, Siebenlist U and Van Waes C: Expression of a dominant-negative mutant inhibitor-κBα of nuclear factor-κB in human head and neck squamous cell carcinoma inhibits survival, proinflammatory cytokine expression, and tumor growth in vivo. Cancer Res. 59:3468–3474. 1999.
27	Wang CY, Mayo MW and Baldwin AS Jr: TNF- and cancer therapy-induced apoptosis: Potentiation by inhibition of NF-κB. Science. 274:784–787. 1996.PubMed/NCBI
28	Wang CY, Mayo MW, Korneluk RG, Goeddel DV and Baldwin AS Jr: NF-κB antiapoptosis: Induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science. 281:1680–1683. 1998.
29	Das KC and White CW: Activation of NF-κB by antineoplastic agents. J Biol Chem. 272:14914–14920. 1997.
30	Spencer W, Kwon H, Crépieux P, Leclerc N, Lin R and Hiscott J: Taxol selectively blocks microtubule dependent NF-κB activation by phorbol ester via inhibition of IκB-α phosphorylation and degradation. Oncogene. 18:495–505. 1999.PubMed/NCBI
31	Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N and Hitt R: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 359:1116–1127. 2008. View Article : Google Scholar : PubMed/NCBI
32	Mesia R, Rivera F, Kawecki A, Rottey S, Hitt R, Kienzer H, Cupissol D, De Raucourt D, Benasso M, Koralewski P, Delord JP, Bokemeyer C, Curran D, Gross A and Vermorken JB: Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol. 21:1967–1973. 2010. View Article : Google Scholar : PubMed/NCBI
33	Leon X, Hitt R, Constenla M, Rocca A, Stupp R, Kovács AF, Amellal N, Bessa EH and Bourhis J: A retrospective analysis of the outcome of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck refractory to a platinum-based chemotherapy. Clin Oncol (R Coll Radiol). 17:418–424. 2005. View Article : Google Scholar : PubMed/NCBI
34	Janmaat ML, Kruyt FA, Rodriguez JA and Giaccone G: Response to epidermal growth factor receptor inhibitors in nonsmall cell lung cancer cells: limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways. Clin Cancer Res. 9:2316–2326. 2003.