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Cancer Chemotherapy and Pharmacology

Published in:

01-05-2012 | Original Article

Pingyangmycin downregulates the expression of EGFR and enhances the effects of cetuximab on esophageal cancer cells and the xenograft in athymic mice

Authors: Jian-hua Gong, Xiu-jun Liu, Yi Li, Yong-su Zhen

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2012

Abstract

Purpose

As reported, epidermal growth factor receptor (EGFR) is over expressed in a variety of cancers including esophageal squamous cell carcinoma. Therefore, it becomes one of the potential targets for treating esophageal cancer. Pingyangmycin (PYM), a single A5 component of bleomycin, is currently used for the treatment of different types of cancers of epidermal origin, especially for head and neck cancers. In this report, the effect of PYM on EGFR expression in human esophageal cancer cells and the therapeutic efficacy of the combination of PYM and cetuximab on esophageal cancer xenograft were investigated.

Methods

The effects of PYM, cetuximab and the combination on EGFR signaling, proliferation, cell cycle, apoptosis were evaluated by using MTT, Western blotting, RT-PCR assays and flow cytometry assays, respectively, in vitro and the therapeutic efficacy by a xenograft model in athymic mice.

Results

Cell volume and nucleus were enlarged after PYM treatment. PYM showed potent cytotoxicity in both cell lines of Kyse-150 and Eca-109 in time and dosage-depended manner in MTT assay. PYM treatment induced G₂/M phase arrest and apoptosis. Notably, the expression of EGFR was down-regulated by PYM in EGFR highly expression esophageal cancer cells. PYM plus cetuximab resulted in a potentiation of antiproliferative activity. PYM combined with cetuximab displayed a much higher therapeutic effect than that of the single agent on esophageal cancer xenograft in athymic mice.

Conclusions

PYM could down-regulate the expression of EGFR in esophageal cancer cells and potentiate the effects of cetuximab on esophageal cancer xenograft in nude mice. The combination of PYM and cetuximab, the EGFR-targeted combination of a chemotherapeutic agent and an antibody-based drug, might be useful in cancer therapy.

Zhen YS, Li DD, Li Q et al (1981) Studies on antitumor effect and pharmacology of pingyangmycin. Topics on cancer chemotherapy. In: Proceedings of international symposium on adriamycin and other drugs in antitumor chemotherapy, China Academic Publishers, pp 211–224

Zhen YS, Li DD (2009) Antitumor antibiotic pingyangmycin: research and clinical use for 40 years. Chin J Antibiot 34:577–580

Byrnes RW, Templin J, Sem D, Lyman S, Petering DH (1990) Intracellular DNA strand scission and growth inhibition of Ehrlich ascites tumor cells by bleomycins. Cancer Res 50:5275–5286PubMed

Chen J, Stubbe J (2005) Bleomycins: towards better therapeutics. Nat Rev Cancer 5:102–112PubMedCrossRef

Williams ED, Merrick MV, Lavender JP (1975) The distribution and dosimetry of ¹¹¹In-Bleomycin in man. Br J Radiol 48:275–278PubMedCrossRef

Homs MY, Voest EE, Siersema PD (2009) Emerging drugs for esophageal cancer. Expert Opin Emerg Drugs 14:329–339PubMedCrossRef

Mariette C, Piessen G, Triboulet JP (2007) Therapeutic strategies in esophageal carcinoma: role of surgery and other modalities. Lancet Oncol 8:545–553PubMedCrossRef

Gebski V, Burmeister B, Smithers BM, Foo K, Zalcberg J, Simes J (2007) Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in esophageal carcinoma: a metaanalysis. Lancet Oncol 8:226–234PubMedCrossRef

Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103:211–225PubMedCrossRef

10.

Gibault L, Metges JP, Conan-Charlet V, Lozac’h P, Robaszkiewicz M, Bessaguet C, Lagarde N, Volant A (2005) Diffuse EGFR staining is associated with reduced overall survival in locally advanced oesophageal squamous cell cancer. Br J Cancer 93:107–115PubMedCrossRef

11.

Itakura Y, Sasano H, Shiga C, Furukawa Y, Shiga K, Mori S, Nagura H (1994) Epidermal growth factor receptor overexpression in esophageal carcinoma. An immunohistochemical study correlated with clinicopathologic findings and DNA amplification. Cancer 74:795–804PubMedCrossRef

12.

Yano H, Shiozaki H, Kobayashi K, Yano T, Tahara H, Tamura S, Mori T (1991) Immunohistologic detection of the epidermal growth factor receptor in human esophageal squamous cell carcinoma. Cancer 67:91–98PubMedCrossRef

13.

Hanawa M, Suzuki S, Dobashi Y, Yamane T, Kono K, Enomoto N, Ooi A (2006) EGFRprotein overexpression and gene amplification in squamous cell carcinomas of the esophagus. Int J Cancer 118:1173–1180PubMedCrossRef

14.

Miyawaki M, Hijiya N, Tsukamoto Y, Nakada C, Kawahara K, Moriyama M (2008) Enhanced phosphorylation of the epidermal growth factor receptor at the site of tyrosine 992 in esophageal carcinomas. APMIS 116:1097–1106PubMedCrossRef

15.

Carneiro A, Isinger A, Karlsson A, Johansson J, Jönsson G, Bendahl PO, Falkenback D, Halvarsson B, Nilbert M (2008) Prognostic impact of array-based genomic profiles in esophageal squamous cell cancer. BMC Cancer 11:98–106CrossRef

16.

Boone J, van Hillegersberg R, Offerhaus GJ, van Diest PJ, Borel Rinkes IH, Ten Kate FJ (2009) Targets for molecular therapy in esophageal squamous cell carcinoma: an immunohistochemical analysis. Dis Esophagus 22:496–504PubMedCrossRef

17.

Cao SS, Zhen YS (1989) Potentiation of antimetabolite: antitumor activity in vivo by dipyridamole and amphotericin B. Cancer Chemother Pharmacol 24:181–186PubMedCrossRef

18.

Zhen YS, Taniki T, Weber G (1992) Azidothymidine and dipyridamole as biochemical response modifiers: synergism with methotrexate and 5-fluorouracil in human colon and pancreatic carcinoma cells. Oncol Res 4:73–88PubMed

19.

Matar P, Rojo F, Cassia R, Moreno-Bueno G, Di Cosimo S, Tabernero J, Guzmán M, Rodriguez S, Arribas J, Palacios J, Baselga J (2004) Combined epidermal growth factor receptor targeting with the tyrosine kinase inhibitor gefitinib (ZD1839) and the monoclonal antibody cetuximab (IMC-C225): superiority over single-agent receptor targeting. Clin Cancer Res 10:6487–6501PubMedCrossRef

20.

Yokoyama Y, Dhanabal M, Griffioen AW, Sukhatme VP, Ramakrishnan S (2000) Synergy between angiostatin and endostatin: inhibition of ovarian cancer growth. Cancer Res 60:2190–2196PubMed

21.

Wei Q, Chen L, Sheng L, Nordgren H, Wester K, Carlsson J (2007) EGFR, HER2 and HER3 expression in esophageal primary tumours and corresponding metastases. Int J Oncol 31:493–499PubMed

22.

Langer R, Von Rahden BH, Nahrig J, Von Weyhern C, Reiter R, Feith M, Stein HJ, Siewert JR, Höfler H, Sarbia M (2006) Prognostic significance of expression patterns of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor in oesophageal adenocarcinoma: a tissue microarray study. J Clin Pathol 59:631–634PubMedCrossRef

23.

Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567–578PubMedCrossRef

24.

Safran H, Suntharalingam M, Dipetrillo T, Ng T, Doyle LA, Krasna M, Plette A, Evans D, Wanebo H, Akerman P, Spector J, Kennedy N, Kennedy T (2008) Cetuximab with concurrent chemoradiation for esophagogastric cancer: assessment of toxicity. Int J Radiat Oncol Biol Phys 70:391–395PubMedCrossRef

25.

Gold PJ, Goldman B, Iqbal S, Leichman LP, Lenz HJ, Blanke CD (2010) Cetuximab as second-line therapy in patients with metastatic esophageal cancer: a phase II Southwest Oncology Group Study. J Thorac Oncol 5:1472–1476PubMedCrossRef

26.

Ku GY, Shah MA, Tang LH, Miron B, Kelsen DP, Ilson DH (2008) Cetuximab (C225) plus irinotecan/cisplatin (CPT/Cis) for CPT/Cis-refractory esophageal cancer. J Clin Oncol 26(Supplement; ASCO Meeting Abstracts):15580

27.

Hollstein MC, Smits AM, Galiana C, Yamasaki H, Bos JL, Mandard A, Partensky C, Montesano R (1988) Amplification of epidermal growth factor receptor gene but no evidence of ras mutations in primary human esophageal cancers. Cancer Res 48:5119–5123PubMed

28.

Hollstein MC, Peri L, Mandard AM, Welsh JA, Montesano R, Metcalf RA, Bak M, Harris CC (1991) Genetic analysis of human esophageal tumors from two high incidence geographic areas: frequent p53 base substitutions and absence of ras mutations. Cancer Res 51:4102–4106PubMed

29.

Lyronis ID, Baritaki S, Bizakis I, Krambovitis E, Spandidos DA (2008) K-ras mutation, HPV infection and smoking or alcohol abuse positively correlate with esophageal squamous carcinoma. Pathol Oncol Res 14:267–273PubMedCrossRef

30.

Nakayama Y, Igarashi A, Kikuchi I, Obata Y, Fukumoto Y, Yamaguchi N (2009) Bleomycin-induced over-replication involves sustained inhibition of mitotic entry through the ATM/ATR pathway. Exp Cell Res 315:2515–2528PubMedCrossRef

31.

Zhou BB, Elledge SJ (2000) The DNA damage response: putting checkpoints in perspective. Nature 408:433–439PubMedCrossRef

32.

Benhar M, Engelberg D, Levitzki A (2002) ROS, stress-activated kinases and stress signaling in cancer. EMBO Rep 3:420–425PubMedCrossRef

33.

Oliveras-Ferraros C, Vazquez-Martin A, López-Bonet E, Martín-Castillo B, Del Barco S, Brunet J, Menendez JA (2008) Growth and molecular interactions of the anti-EGFR antibody cetuximab and the DNA cross-linking agent cisplatin in gefitinib-resistant MDA-MB-468 cells: new prospects in the treatment of triple-negative/basal-like breast cancer. Int J Oncol 33:1165–1176PubMed

Title: Pingyangmycin downregulates the expression of EGFR and enhances the effects of cetuximab on esophageal cancer cells and the xenograft in athymic mice
Authors: Jian-hua Gong
Xiu-jun Liu
Yi Li
Yong-su Zhen
Publication date: 01-05-2012
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2012
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-012-1827-9

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Abstract

Purpose

Methods

Results

Conclusions

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