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Cetuximab Enhances the Anti-Proliferative Effect of Trastuzumab in ERBB2 Over-Expressing Breast Cancer Cells – Preliminary Study

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Cetuximab Enhances the Anti-Proliferative Effect of Trastuzumab in ERBB2 Over-Expressing Breast Cancer Cells – Preliminary Study OriginaL PaPER Cetuximab Enhances the Anti-proliferative Effect of Trastuzumab in ERBB2 Over-expressing Breast Cancer Cells – Preliminary Study Cetuximab zvyšuje antiproliferativní účinek trastuzumabu u buněk karcinomu prsu s nadměrnou expresí ERBB2 – předběžná studie Überall I.1,2, Křížová K.1,2, Steigerová J.1,2 1 Institute of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic 2 Institute of Molecular and Translational Medicine (IMTM), Faculty of Medicine and Dentristry, Palacky University, Olomouc summary Background: The tyrosine kinase receptor comprises a subclass of cell surface growth factor This publication was supported by a grant receptors. Inhibition of certain members of the Epidermal Growth Factor Receptor (EGFR) of the Czech Ministry of Education MSM 6198959216, grant of Palacky University family is an effective treatment approach in some cancers. The anti-tumor effects are greater when LF_2011_009 and the Biomedicine for regional this approach is combined with inhibition of the ERBB2 receptors. These studies provide novel development and human resources project experimental data demonstrating a significant augmentation of the anti-proliferative effects of (BIOMEDREG) C.1.05/2.1.00/01.0030. monoclonal antibodies (cetuximab and trastuzumab) on human breast carcinoma cell lines with Tato práce byla podpořena grantem MŠMT different level of ERBB receptor expression. Materials and Methods: Three breast cancer cell lines, ČR MsM 6198959216, grantem Univerzity MCF-7, BT-474, and SK-BR-3 were used. These are characterised by different levels of EGFR and/or Palackého LF_2011_009 a biomedicína pro other ERBB family members. Inhibition of cell growth in response to cetuximab, trastuzumab or regionální rozvoj a lidské zdroje (bIOMEDREG) their combination was assessed by MTT assay. Results: The breast cancer cell lines differed in their C.1.05/2.1.00/01.0030. sensitivity to TZ, CTX and their combination. The SK-BR-3 cancer cell line was sensitive to TZ. On the Autoři deklarují, že v souvislosti s předmětem other hand, CTX had no effect on BT-474 or on SK-BR-3 that expressed low levels of EGFR and high studie nemají žádné komerční zájmy. levels of ERBB2. Conclusion: Our new experimental data show that the combination of anti-EGF The authors declare they have no potential receptor and anti-ERBB2 mAb may inhibit cancer cells expressing both EGF and ERBB2 receptors. conflicts of interest concerning drugs, products, or services used in the study. Redakční rada potvrzuje, že rukopis práce Key words splnil ICMJE kritéria pro publikace zasílané do ERBB receptors – dual inhibition – trastuzumab – cetuximab – breast cancer bi omedicínských časopisů. The Editorial board declares that the manuscript souhrn met the ICMJE “uniform requirements” for Východiska: Receptorové tyrozinkinázy představují podtřídu transmemránových receptorů. biomedical papers. Inhibice členů rodiny receptorů pro epidermální růstové faktory je efektivní pro léčbu někte- rých typů nádorů. V kombinaci s inhibicí ERBB2 receptorů je protinádorový efekt výraznější. Tato studie předkládá nová experimentální data, která prokazují zesílení anti-proliferačního Ing. Bc. Ivo Überall, Ph.D. účinku monoklonálních protilátek (cetuximab a trastuzumab) na nádorové linie odvozené Institute of Clinical and Molecular z karcinomu prsu, které se liší rozdílnou expresí ERBB receptorů. Materiál a metody: Tato studie Pathology se věnuje kombinovanému účinku souběžné inhibice dvou členů rodiny ERBB, receptorů EGFR Faculty of Medicine and Dentistry a ERBB2 pomocí monoklonálních protilátek trastuzumab (Herceptin, TZ) a cetuximab (Erbitux/ Palacky University C225, CTX). V rámci studie byly testovány tři buněčné linie odvozené z karcinomu prsu (MCF-7, Hněvotínská 3 BT-474 a SK-BR-3). Tyto linie se liší různou expresí EGFR a ERB2. Inhibice buněčného růstu byla 775 15 Olomouc sledována využitím metody MTT assay. Rovněž byly pomocí Western blotu analyzovány změny e-mail: [email protected] v expresi EGFR, ERBB2 a klíčových regulátorů buněčného cyklu. Výsledky: Prsní nádorové linie vykazovaly rozdílnou citlivost k působení TZ a CTX a jejich kombinací. Linie SK-BR-3 byla citlivá k působení TZ. Naopak CTX neměl vliv na linii BT-474 a na SK-BR-3, které exprimují nízkou hla- Obdrženo/submitted: 8. 9. 2010 dinu EGFR a vysokou hladinu ERBB2. Závěr: Získané výsledky potvrzují hypotézu o vzájemném Přijato/accepted: 7. 12. 2010 zesilujícím anti-proliferačním efektu současné inhibice obou receptorů. Klíčová slova ERBB receptory – duální inhibice – trastuzumab – cetuximab – karcinom prsu 356 Klin Onkol 2011; 24(5): 356– 360 Klin Onkol 2011; 24(5): 356– 360 Cetuximab ENhances ThE Anti-proliferative Effect of TRastuzumab in ERBB2 Over-expressing BreasT Cancer Cells Introduction and signal transduction in breast can- they were maintained for additional 72 The family of ERBB receptors inclu- cer cell lines, expressing various levels of hours in the absence (control) or pre- des the epidermal growth factor recep- EGFR and ERBB2 receptors. sence of cetuximab (20 μg/mL) or trastu- tors, ERBB-1/EGFR/HER1, ERBB2/HER2, zumab (20 μg/mL). Treatment was termi- ERBB-3/HER3, and ERBB-4/HER4. These Materials and Methods nated by adding a lysis buffer NP40 with are transmembrane receptors with ty- Cell Lines protease and phosphatase inhibitors. rosine kinase activity and they are fre- Three breast cancer cell lines, MCF-7, The lysate was incubated for 30 minutes quently implicated in the development BT-474, and SK-BR-3 obtained from the at 4 °C and then centrifuged at 15,000 g and progression of epithelial cell neopla- American Type Culture Collection (Rock- for 30 minutes at 4 °C. The superna- sias both in animals and humans [1–3]. ville, MD) were used. These are charac- tant was used for Western blot analy- EGFR and ERBB2 play the key role. [4]. terized by different levels of EGFR and/ sis after determination of protein con- ERBB receptor activation occurs via li- or other ERBB family members. BT-474 centration by the Bradford method [16]. gand binding and dimerization initia- and SK-BR-3 breast cancer cell lines exhi- Aliquots containing 50 μg of protein ted by molecular signals that promote bit ERBB2 gene amplification and over- were separated on 10% SDS-PAGE and tumorigenesis [5]. Clinical studies show expression of EGFR is 3-fold higher in then electroblotted to a nitrocelulose that over-expression of EGFR and/or SK-BR-3 than BT-474 [13]. MCF-7 cell line membrane. The membrane was bloc- ERBB2, common in human cancers, cor- had normal EGFR and ERBB2 expres- ked 2 hours with 5% skimmed dried relates with poor prognosis [6]. sion and was used as a control [14]. They milk in TBS-T buffer (20 mmol/L TRIS Trastuzumab (Herceptin) and cetuxi- were maintained in DMEM medium sup- (pH 7.5), 100 mmol/L NaCl, 0.1% Tween mab (Erbitux/C225) are currently being plemented with 10% fetal bovine serum, 20, followed by overnight incubation investigated in clinical trials for their an- 100 units/mL streptomycin-penicillin, with the primary antibodies in TBS-T ti-tumor activity. These anti-EGFR and and incubated at 37 °C in an atmosphere buffer containing 5% skimmed dried ERBB2 monoclonal antibodies have of 95% air and 5% CO2. Trastuzumab and milk at 4°C (anti-mouse mcm7-1 : 2,000 been approved by the FDA for treating cetuximab were applied in concentra- Santa Cruz, anti-mouse EGFR-1 : 250 tumors that express high levels of EGFR tions of 0.2, 2, 20 and 200 μg/mL. Neomarkers, anti-mouse ERBB2-1 : 250 and ERBB2. Although some patients be- (IC50, was achieved at a concentration Dako, anti-mouse-p27-1 : 250 Dako, nefit from Erbitux and Herceptin treat- (200 μg/mL TZ and 200 μg/mL CTX). anti-mouse cyclinA-1 : 250 Novocastra, ment, failure may result, among other anti-mouse cyclin B1 1 : 250 Novo- reasons, from a different expression/ Growth Inhibition Assay castra, anti-mouse-cyclin-D1-1 : 250 changed function of the multiple ERBB Inhibition of cell growth in response to Cell Signaling, anti-mouse Bcl-2 1 : 500, receptor family members leading to dis- cetuximab, trastuzumab or their com- Biogenes). After washing three times harmony in receptor interaction. Can- bination was assessed by 2-(4,5-di- with TBS-T buffer, the membranes were cers that co-express EGFR and ERBB2 methylthiazol-2-yl)-2,5-diphenyltet- incubated with horseradish peroxidase- have a poorer outcome than those that razolium bromide assay as previously conjugated secondary antibodies for over-express either of the receptors described [15]. Briefly, aliquots of cells 2 hours at room temperature. Proteins alone. There is increasing evidence that (2 × 104 cells/mL) in DMEM/10% fetal were visualized using an enzyme-linked pathways mediated by these receptors bovine serum were plated in a 96-well enhanced chemiluminiscence detection are being bypassed. A number of in vitro culture plate with four replicates per system (ECL, Amersham, Arlington He- and in vivo studies suggest that dual in- treatment. After 24 hours of plating, ights, IL). The membranes were then re- hibition of these receptors would be cells were incubated at 37°C in the ab- probed with mcm-7 antibodies as an in- fruit ful [7–11]. sence (control) or presence of cetuxi- ternal control. Signals on the blots were Ye et al (1999a) described the addi- mab and/or trastuzumab for 72 hours as visualized by autoradiography. tive anti-proliferative effects of cetuxi- stated in the legends to figures. All incu- mab (CTX) and trastuzumab (TZ) in the bations were terminated by addition of Results treatment of ovarian cancer cells [7]. 10 μl of 0.5 g/mL stock 2-(4,5-dimethyl- Fig. 1 shows the concentration-depen- Brockhoff et al (2004) investigated the thiazol-2-yl)-2,5-diphenyltetrazolium dent growth inhibition measured in % different impact monoclonal inhibitors bromide to each well. The reaction was of viable cells, of breast carcinoma cell Cetuximab, Trastuzumab and Pertuzu- allowed to proceed for 4 hours at 37 °C.
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