Tumor-penetration and antitumor efficacy of cetuximab are enhanced by co-administered iRGD in a murine model of human NSCLC

Zhang,Yang; Yang,Jie; Ding,Manhua; Li,Liantao; Lu,Zheng; Zhang,Qing; Zheng,Junnian

doi:10.3892/ol.2016.5081

Tumor-penetration and antitumor efficacy of cetuximab are enhanced by co-administered iRGD in a murine model of human NSCLC

Authors:
- Yang Zhang
- Jie Yang
- Manhua Ding
- Liantao Li
- Zheng Lu
- Qing Zhang
- Junnian Zheng
View Affiliations

Affiliations: Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu 221002, P.R. China, Department of Oncology, Xuzhou Tumor Hospital, Xuzhou, Jiangsu 221005, P.R. China
Published online on: September 2, 2016 https://doi.org/10.3892/ol.2016.5081
Pages: 3241-3249
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Lung cancer is the leading cause of cancer‑associated mortality, worldwide. For this reason, novel therapies are required for the treatment of this devastating disease. Cetuximab is a monoclonal antibody against epidermal growth factor receptor (EGFR), which is overexpressed in a variety of solid tumors, including non‑small cell lung cancer (NSCLC). The therapeutic efficacy of cetuximab for NSCLC is limited to use as a monotherapy or in combination with chemotherapy. The objective of the present study was to develop a novel strategy to enhance the therapeutic efficacy of cetuximab for NSCLC by a co‑administration with the tumor‑penetrating internalizing RGD peptide (iRGD). Human NSCLC subcutaneous xenograft models established with the A549 cell line in nude mice were treated with 30 mg/kg cetuximab, 4 mg/kg iRGD, cetuximab plus iRGD or phosphate‑buffered saline. The tumor‑penetration, in vivo therapeutic efficacy and involved mechanism were evaluated. The present study showed that the A549 xenograft model is sensitive to the co-administration of cetuximab and iRGD. Treatment with cetuximab plus iRGD resulted in a significant increase in the tumor‑penetration of cetuximab and tumor reduction compared with cetuximab monotherapy. In conclusion, iRGD enhances the effects of co‑administered cetuximab in an NSCLC model. The combined application of cetuximab and iRGD may be a novel strategy to enhance the clinical therapeutic efficacy of cetuximab for the treatment of NSCLC.

View Figures

View References

1	Privitera G, Luca T, Musso N, Vancheri C, Crimi N, Barresi V, Condorelli D and Castorina S: In vitro antiproliferative effect of trastuzumab (Herceptin^®) combined with cetuximab (Erbitux^®) in a model of human non-small cell lung cancer expressing EGFR and HER2. Clin Exp Med. 2015.PubMed/NCBI
2	Patil N, Abba M and Allgayer H: Cetuximab and biomarkers in non-small-cell lung carcinoma. Biologics. 6:221–231. 2012.PubMed/NCBI
3	Pujol JL, Pirker R, Lynch TJ, Butts CA, Rosell R, Shepherd FA, Vansteenkiste J, O'Byrne KJ, de Blas B, Heighway J, et al: Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer. Lung Cancer. 83:211–218. 2014. View Article : Google Scholar : PubMed/NCBI
4	Kim SM, Kim JS, Kim JH, Yun CO, Kim EM, Kim HK, Solca F, Choi SY and Cho BC: Acquired resistance to cetuximab is mediated by increased PTEN instability and leads cross-resistance to gefitinib in HCC827 NSCLC cells. Cancer Lett. 296:150–159. 2010. View Article : Google Scholar : PubMed/NCBI
5	Pirker R, Pereira JR, von Pawel J, Krzakowski M, Ramlau R, Park K, de Marinis F, Eberhardt WE, Paz-Ares L, Störkel S, et al: EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: Analysis of data from the phase 3 FLEX study. Lancet Oncol. 13:33–42. 2012. View Article : Google Scholar : PubMed/NCBI
6	Douillard JY, Pirker R, O'Byrne KJ, Kerr KM, Störkel S, von Heydebreck A, Grote HJ, Celik I and Shepherd FA: Relationship between EGFR expression, EGFR mutation status and the efficacy of chemotherapy plus cetuximab in FLEX study patients with advanced non-small-cell lung cancer. J Thorac Oncol. 9:717–724. 2014. View Article : Google Scholar : PubMed/NCBI
7	van den Heuvel MM, Uyterlinde W, Vincent AD, de Jong J, Aerts J, Koppe F, Knegjens J, Codrington H, Kunst PW, Dieleman E, et al: Additional weekly Cetuximab to concurrent chemoradiotherapy in locally advanced non-small cell lung carcinoma: Efficacy and safety outcomes of a randomized, multi-center phase II study investigating. Radiother Oncol. 110:126–131. 2014. View Article : Google Scholar : PubMed/NCBI
8	Dubey S and Schiller JH: Three emerging new drugs for NSCLC: Pemetrexed, bortezomib and cetuximab. Oncologist. 10:282–291. 2005. View Article : Google Scholar : PubMed/NCBI
9	Wild R, Fager K, Flefleh C, Kan D, Inigo I, Castaneda S, Luo FR, Camuso A, McGlinchey K and Rose WC: Cetuximab preclinical antitumor activity (monotherapy and combination based) is not predicted by relative total or activated epidermal growth factor receptor tumor expression levels. Mol Cancer Ther. 5:104–113. 2006. View Article : Google Scholar : PubMed/NCBI
10	Yu T, Wang Z, Liu K, Wu Y, Fan J, Chen J, Li C, Zhu G and Li L: High interstitial fluid pressure promotes tumor progression through inducing lymphatic metastasis-related protein expressions in oral squamous cell carcinoma. Clin Transl Oncol. 16:539–547. 2014. View Article : Google Scholar : PubMed/NCBI
11	Milosevic MF, Pintilie M, Hedley DW, Bristow RG, Wouters BG, Oza AM, Laframboise S, Hill RP and Fyles AW: High tumor interstitial fluid pressure identifies cervical cancer patients with improved survival from radiotherapy plus cisplatin versus radiotherapy alone. Int J Cancer. 135:1692–1699. 2014. View Article : Google Scholar : PubMed/NCBI
12	Trédan O, Galmarini CM, Patel K and Tannock IF: Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst. 99:1441–1454. 2007. View Article : Google Scholar : PubMed/NCBI
13	Song W, Li M, Tang Z, Li Q, Yang Y, Liu H, Duan T, Hong H and Chen X: Methoxypoly (ethylene glycol)-block-poly (L-glutamic acid)-loaded cisplatin and a combination with iRGD for the treatment of non-small-cell lung cancers. Macromol Biosci. 12:1514–1523. 2012. View Article : Google Scholar : PubMed/NCBI
14	Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Girard OM, Hanahan D, Mattrey RF and Ruoslahti E: Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell. 16:510–520. 2009. View Article : Google Scholar : PubMed/NCBI
15	Su S, Wang H, Liu X, Wu Y and Nie G: iRGD-coupled responsive fluorescent nanogel for targeted drug delivery. Biomaterials. 34:3523–3533. 2013. View Article : Google Scholar : PubMed/NCBI
16	Alberici L, Roth L, Sugahara KN, Agemy L, Kotamraju VR, Teesalu T, Bordignon C, Traversari C, Rizzardi GP and Ruoslahti E: De novo design of a tumor-penetrating peptide. Cancer Res. 73:804–812. 2013. View Article : Google Scholar : PubMed/NCBI
17	Roth L, Agemy L, Kotamraju VR, Braun G, Teesalu T, Sugahara KN, Hamzah J and Ruoslahti E: Transtumoral targeting enabled by a novel neuropilin-binding peptide. Oncogene. 31:3754–3763. 2012. View Article : Google Scholar : PubMed/NCBI
18	Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Greenwald DR and Ruoslahti E: Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science. 328:1031–1035. 2010. View Article : Google Scholar : PubMed/NCBI
19	Zhang Q, Liu X, Xu S, Li C, Zhang Y, Yang J and Zheng J: Factor VII light chain-targeted lidamycin shows intensified therapeutic efficacy for liver cancer. Cancer Biother Radiopharm. 27:384–391. 2012. View Article : Google Scholar : PubMed/NCBI
20	Aizawa K, Liu C, Veeramachaneni S, Hu KQ, Smith DE and Wang XD: Development of ferret as a human lung cancer model by injecting 4-(Nmethyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Lung Cancer. 82:390–396. 2013. View Article : Google Scholar : PubMed/NCBI
21	Ning L, Li X, Ding X, Yin Y and Li G: An iRGD based strategy to study electrochemically the species inside a cell. Int J Mol Sci. 13:10424–10431. 2012. View Article : Google Scholar : PubMed/NCBI
22	Steiner P, Joynes C, Bassi R, Wang S, Tonra JR, Hadari YR and Hicklin DJ: Tumor growth inhibition with cetuximab and chemotherapy in non-small cell lung cancer xenografts expressing wild-type and mutated epidermal growth factor receptor. Clin Cancer Res. 13:1540–1551. 2007. View Article : Google Scholar : PubMed/NCBI
23	Xu F, Tian Y, Huang Y, Zhang LL, Guo ZZ, Huang JJ and Lin TY: EGFR inhibitors sensitize non-small cell lung cancer cells to TRAIL-induced apoptosis. Chin J Cancer. 30:701–711. 2011. View Article : Google Scholar : PubMed/NCBI
24	Akashi Y, Oda T, Ohara Y, Miyamoto R, Kurokawa T, Hashimoto S, Enomoto T, Yamada K, Satake M and Ohkohchi N: Anticancer effects of gemcitabine are enhanced by co-administered iRGD peptide in murine pancreatic cancer models that overexpressed neuropilin-1. Br J Cancer. 110:1481–1487. 2014. View Article : Google Scholar : PubMed/NCBI
25	Villanueva MT: Lung cancer: Cetuximab, you're fired. Nat Rev Clin Oncol. 11:32014. View Article : Google Scholar : PubMed/NCBI
26	Rasul KI and Kerr DJ: Targeted therapies: Cetuximab plus chemotherapy in patients with advanced NSCLC. Nat Rev Clin Oncol. 6:499–500. 2009. View Article : Google Scholar : PubMed/NCBI
27	Sanchez AJ, Vincent MJ, Erickson BR and Nichol ST: Crimean-congo hemorrhagic fever virus glycoprotein precursor is cleaved by Furin-like and SKI-1 proteases to generate a novel 38-kilodalton glycoprotein. J Virol. 80:514–525. 2006. View Article : Google Scholar : PubMed/NCBI
28	Wool-Lewis RJ and Bates P: Endoproteolytic processing of the ebola virus envelope glycoprotein: Cleavage is not required for function. J Virol. 73:1419–1426. 1999.PubMed/NCBI
29	Sjöberg M, Wallin M, Lindqvist B and Garoff H: Furin cleavage potentiates the membrane fusion-controlling intersubunit disulfide bond isomerization activity of leukemia virus Env. J Virol. 80:5540–5551. 2006. View Article : Google Scholar : PubMed/NCBI