Cetuximab-Triptolide Conjugate Suppresses the Growth of EGFR-Overexpressing Lung Cancers through Targeting RNA Polymerase II
To overcome poor pharmacokinetics and toxicity of triptolide (TPL), a natural compound that exhibits potent anticancer activities, we developed a novel antibody-drug conjugate (ADC) to specifically deliver TPL to epidermal growth factor receptor (EGFR)-overexpressing non-small cell lung cancer (NSCL...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-09-01
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| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770520301054 |
| _version_ | 1818772589125828608 |
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| author | Keqiang Zhang Yuelong Ma Yuming Guo Ting Sun Jun Wu Rajendra P. Pangeni Min Lin Wendong Li David Horne Dan J. Raz |
| author_facet | Keqiang Zhang Yuelong Ma Yuming Guo Ting Sun Jun Wu Rajendra P. Pangeni Min Lin Wendong Li David Horne Dan J. Raz |
| author_sort | Keqiang Zhang |
| collection | DOAJ |
| description | To overcome poor pharmacokinetics and toxicity of triptolide (TPL), a natural compound that exhibits potent anticancer activities, we developed a novel antibody-drug conjugate (ADC) to specifically deliver TPL to epidermal growth factor receptor (EGFR)-overexpressing non-small cell lung cancer (NSCLC) and others. The ADC (Cet-TPL) is made by conjugation of TPL to lysine residues of cetuximab (Cet), a clinically available anti-EGFR monoclonal antibody. Studies of antitumor efficacy demonstrated that Cet-TPL drastically suppressed in vitro proliferation and in vivo growth of these EGFR-overexpressing cancers, including NSCLC A549 and H1299 cells and two patient-derived xenografts, and head and neck squamous carcinoma UM-SCC6 cell, while it did not inhibit the proliferation and growth of NSCLC H520 that rarely expresses EGFR. Furthermore, immunofluorescence analysis revealed that Cet-TPL was effectively internalized and transported into lysosomes of EGFR-overexpressing cells. Cet-TPL effectively led to degradation of RNA polymerase II (Pol II) and demethylation of histone H3 lysines, and significantly induced apoptosis in these EGFR-overexpressing cancers. Compared with TPL, Cet, or their combination, Cet-TPL displayed higher target-specific cytotoxicity against EGFR-expressing cancers and much lower in vivo toxicity. In addition, Cet-TPL efficiently suppressed the activated EGFR pathway in UM-SCC6 cancer cells. Taken together, Cet-TPL represents a potent targeting therapeutic agent against EGFR-overexpressing NSCLC and others. |
| first_indexed | 2024-12-18T10:11:45Z |
| format | Article |
| id | doaj.art-39c1e2d20ed54675bd83dba83c5ca446 |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-12-18T10:11:45Z |
| publishDate | 2020-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-39c1e2d20ed54675bd83dba83c5ca4462022-12-21T21:11:24ZengElsevierMolecular Therapy: Oncolytics2372-77052020-09-0118304316Cetuximab-Triptolide Conjugate Suppresses the Growth of EGFR-Overexpressing Lung Cancers through Targeting RNA Polymerase IIKeqiang Zhang0Yuelong Ma1Yuming Guo2Ting Sun3Jun Wu4Rajendra P. Pangeni5Min Lin6Wendong Li7David Horne8Dan J. Raz9Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA, USADepartment of Molecular Medicine, City of Hope National Medical Center, Duarte, CA, USADivision of Comparative Medicine, City of Hope National Medical Center, Duarte, CA, USADivision of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA, USADivision of Comparative Medicine, City of Hope National Medical Center, Duarte, CA, USADivision of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA, USADepartment of Molecular Medicine, City of Hope National Medical Center, Duarte, CA, USADivision of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA, USADepartment of Molecular Medicine, City of Hope National Medical Center, Duarte, CA, USA; Corresponding author: David Horne, PhD, Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA, USA.Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA, USA; Corresponding author: Dan J. Raz, MD, MS, Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA, USA.To overcome poor pharmacokinetics and toxicity of triptolide (TPL), a natural compound that exhibits potent anticancer activities, we developed a novel antibody-drug conjugate (ADC) to specifically deliver TPL to epidermal growth factor receptor (EGFR)-overexpressing non-small cell lung cancer (NSCLC) and others. The ADC (Cet-TPL) is made by conjugation of TPL to lysine residues of cetuximab (Cet), a clinically available anti-EGFR monoclonal antibody. Studies of antitumor efficacy demonstrated that Cet-TPL drastically suppressed in vitro proliferation and in vivo growth of these EGFR-overexpressing cancers, including NSCLC A549 and H1299 cells and two patient-derived xenografts, and head and neck squamous carcinoma UM-SCC6 cell, while it did not inhibit the proliferation and growth of NSCLC H520 that rarely expresses EGFR. Furthermore, immunofluorescence analysis revealed that Cet-TPL was effectively internalized and transported into lysosomes of EGFR-overexpressing cells. Cet-TPL effectively led to degradation of RNA polymerase II (Pol II) and demethylation of histone H3 lysines, and significantly induced apoptosis in these EGFR-overexpressing cancers. Compared with TPL, Cet, or their combination, Cet-TPL displayed higher target-specific cytotoxicity against EGFR-expressing cancers and much lower in vivo toxicity. In addition, Cet-TPL efficiently suppressed the activated EGFR pathway in UM-SCC6 cancer cells. Taken together, Cet-TPL represents a potent targeting therapeutic agent against EGFR-overexpressing NSCLC and others.http://www.sciencedirect.com/science/article/pii/S2372770520301054antibody-drug conjugatetargeted therapytriptolidecetuximabEGFRNSCLC |
| spellingShingle | Keqiang Zhang Yuelong Ma Yuming Guo Ting Sun Jun Wu Rajendra P. Pangeni Min Lin Wendong Li David Horne Dan J. Raz Cetuximab-Triptolide Conjugate Suppresses the Growth of EGFR-Overexpressing Lung Cancers through Targeting RNA Polymerase II Molecular Therapy: Oncolytics antibody-drug conjugate targeted therapy triptolide cetuximab EGFR NSCLC |
| title | Cetuximab-Triptolide Conjugate Suppresses the Growth of EGFR-Overexpressing Lung Cancers through Targeting RNA Polymerase II |
| title_full | Cetuximab-Triptolide Conjugate Suppresses the Growth of EGFR-Overexpressing Lung Cancers through Targeting RNA Polymerase II |
| title_fullStr | Cetuximab-Triptolide Conjugate Suppresses the Growth of EGFR-Overexpressing Lung Cancers through Targeting RNA Polymerase II |
| title_full_unstemmed | Cetuximab-Triptolide Conjugate Suppresses the Growth of EGFR-Overexpressing Lung Cancers through Targeting RNA Polymerase II |
| title_short | Cetuximab-Triptolide Conjugate Suppresses the Growth of EGFR-Overexpressing Lung Cancers through Targeting RNA Polymerase II |
| title_sort | cetuximab triptolide conjugate suppresses the growth of egfr overexpressing lung cancers through targeting rna polymerase ii |
| topic | antibody-drug conjugate targeted therapy triptolide cetuximab EGFR NSCLC |
| url | http://www.sciencedirect.com/science/article/pii/S2372770520301054 |
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