Therapeutic Effect of IL-4 Receptor-Targeting Pro-Apoptotic Peptide (AP1-ELP-KLAK) in Glioblastoma Tumor Model
Vijaya Sarangthem,1,2,* Aena Yi,1,* Yunjae Kim,1 Alnawaz Rehemtulla,3 Byung-Heon Lee,1 Young Hyun Jeon,4 Thoudam Debraj Singh,5 Rang-Woon Park1 1Department of Biochemistry and Cell Biology, School of Medicine, and Cell & Matrix Research Institute, Kyungpook National University, D...
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Dove Medical Press
2021
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oai:doaj.org-article:9d4825e0b44742ec9bf20b6a4ff607702021-12-02T16:51:17ZTherapeutic Effect of IL-4 Receptor-Targeting Pro-Apoptotic Peptide (AP1-ELP-KLAK) in Glioblastoma Tumor Model1178-2013https://doaj.org/article/9d4825e0b44742ec9bf20b6a4ff607702021-07-01T00:00:00Zhttps://www.dovepress.com/therapeutic-effect-of-il-4-receptor-targeting-pro-apoptotic-peptide-ap-peer-reviewed-fulltext-article-IJNhttps://doaj.org/toc/1178-2013Vijaya Sarangthem,1,2,* Aena Yi,1,* Yunjae Kim,1 Alnawaz Rehemtulla,3 Byung-Heon Lee,1 Young Hyun Jeon,4 Thoudam Debraj Singh,5 Rang-Woon Park1 1Department of Biochemistry and Cell Biology, School of Medicine, and Cell & Matrix Research Institute, Kyungpook National University, Daegu, 41944, Republic of Korea; 2Department of Pathology, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India; 3Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA; 4Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu, Republic of Korea; 5Department of Medical Oncology Laboratory, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India*These authors contributed equally to this workCorrespondence: Rang-Woon ParkDepartment of Biochemistry and Cell Biology, School of Medicine, and Cell & Matrix Research Institute, Kyungpook National University, Daegu, 41944, Republic of KoreaTel +82 53 420 4822Fax +82 53 422 1466Email nwpark@knu.ac.krThoudam Debraj SinghDepartment of Medical Oncology Laboratory, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, IndiaEmail debraj.thoudam@gmail.comBackground: Thermal-responsive self-assembled elastin-like polypeptide (ELP)-based nanoparticles are an emerging platform for controlled delivery of therapeutic peptides, proteins and small molecular drugs. The antitumor effect of bioengineered chimeric polypeptide AP1-ELP-KLAK containing an interleukin-4 receptor (IL-4R) targeting peptide and pro-apoptotic peptide (KLAKLAK) was evaluated in glioblastoma (GBM) in vitro and in vivo.Methods and Results: Herein, the therapeutic effect of AP1-ELP-KLAK was tested in advanced, and less curable glioblastoma cells with higher expression of IL-4R. Glioblastoma cell lines stably expressing different reporter systems i.e., caspase-3 sensor (surrogate marker for cellular apoptosis) or effluc/enhanced firefly luciferase (cellular viability) were established to measure cell death non-invasively. Bioluminescence imaging (BLI) of D54/effluc and U97MG/effluc treated with AP1-ELP-KLAK exhibited higher cell death up to 2∼ 3-fold than the control. Treatment with AP1-ELP-KLAK resulted in time-dependent increase of caspase-3 sensor BLI activity in D54/C cells and D54/C tumor-bearing mice. Intravenous injection of AP1-ELP-KLAK dramatically reduced tumor growth by inducing cellular apoptosis in D54/effluc tumor-bearing mice. Further, the immuno-histological examination of the excised tumor tissue confirmed the presence of apoptotic cells as well as caspase-3 activation.Conclusion: Collectively, AP1-ELP-KLAK effectively induced cellular apoptosis of glioblastoma cells and non-invasive imaging provides a window for real-time monitoring of anti-tumor effect with the provision of improving therapeutic efficacy in a glioblastoma mice model.Keywords: tumor targeting, ELP, caspase-sensor, apoptosis, IL-4 receptor, glioblastomaSarangthem VYi AKim YRehemtulla ALee BHJeon YHSingh TDPark RWDove Medical Pressarticletumor targetingelpcaspase-sensorapoptosisil-4 receptorglioblastomaMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 16, Pp 5039-5052 (2021) |
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DOAJ |
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EN |
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tumor targeting elp caspase-sensor apoptosis il-4 receptor glioblastoma Medicine (General) R5-920 |
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tumor targeting elp caspase-sensor apoptosis il-4 receptor glioblastoma Medicine (General) R5-920 Sarangthem V Yi A Kim Y Rehemtulla A Lee BH Jeon YH Singh TD Park RW Therapeutic Effect of IL-4 Receptor-Targeting Pro-Apoptotic Peptide (AP1-ELP-KLAK) in Glioblastoma Tumor Model |
| description |
Vijaya Sarangthem,1,2,* Aena Yi,1,* Yunjae Kim,1 Alnawaz Rehemtulla,3 Byung-Heon Lee,1 Young Hyun Jeon,4 Thoudam Debraj Singh,5 Rang-Woon Park1 1Department of Biochemistry and Cell Biology, School of Medicine, and Cell & Matrix Research Institute, Kyungpook National University, Daegu, 41944, Republic of Korea; 2Department of Pathology, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India; 3Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA; 4Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu, Republic of Korea; 5Department of Medical Oncology Laboratory, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India*These authors contributed equally to this workCorrespondence: Rang-Woon ParkDepartment of Biochemistry and Cell Biology, School of Medicine, and Cell & Matrix Research Institute, Kyungpook National University, Daegu, 41944, Republic of KoreaTel +82 53 420 4822Fax +82 53 422 1466Email nwpark@knu.ac.krThoudam Debraj SinghDepartment of Medical Oncology Laboratory, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, IndiaEmail debraj.thoudam@gmail.comBackground: Thermal-responsive self-assembled elastin-like polypeptide (ELP)-based nanoparticles are an emerging platform for controlled delivery of therapeutic peptides, proteins and small molecular drugs. The antitumor effect of bioengineered chimeric polypeptide AP1-ELP-KLAK containing an interleukin-4 receptor (IL-4R) targeting peptide and pro-apoptotic peptide (KLAKLAK) was evaluated in glioblastoma (GBM) in vitro and in vivo.Methods and Results: Herein, the therapeutic effect of AP1-ELP-KLAK was tested in advanced, and less curable glioblastoma cells with higher expression of IL-4R. Glioblastoma cell lines stably expressing different reporter systems i.e., caspase-3 sensor (surrogate marker for cellular apoptosis) or effluc/enhanced firefly luciferase (cellular viability) were established to measure cell death non-invasively. Bioluminescence imaging (BLI) of D54/effluc and U97MG/effluc treated with AP1-ELP-KLAK exhibited higher cell death up to 2∼ 3-fold than the control. Treatment with AP1-ELP-KLAK resulted in time-dependent increase of caspase-3 sensor BLI activity in D54/C cells and D54/C tumor-bearing mice. Intravenous injection of AP1-ELP-KLAK dramatically reduced tumor growth by inducing cellular apoptosis in D54/effluc tumor-bearing mice. Further, the immuno-histological examination of the excised tumor tissue confirmed the presence of apoptotic cells as well as caspase-3 activation.Conclusion: Collectively, AP1-ELP-KLAK effectively induced cellular apoptosis of glioblastoma cells and non-invasive imaging provides a window for real-time monitoring of anti-tumor effect with the provision of improving therapeutic efficacy in a glioblastoma mice model.Keywords: tumor targeting, ELP, caspase-sensor, apoptosis, IL-4 receptor, glioblastoma |
| format |
article |
| author |
Sarangthem V Yi A Kim Y Rehemtulla A Lee BH Jeon YH Singh TD Park RW |
| author_facet |
Sarangthem V Yi A Kim Y Rehemtulla A Lee BH Jeon YH Singh TD Park RW |
| author_sort |
Sarangthem V |
| title |
Therapeutic Effect of IL-4 Receptor-Targeting Pro-Apoptotic Peptide (AP1-ELP-KLAK) in Glioblastoma Tumor Model |
| title_short |
Therapeutic Effect of IL-4 Receptor-Targeting Pro-Apoptotic Peptide (AP1-ELP-KLAK) in Glioblastoma Tumor Model |
| title_full |
Therapeutic Effect of IL-4 Receptor-Targeting Pro-Apoptotic Peptide (AP1-ELP-KLAK) in Glioblastoma Tumor Model |
| title_fullStr |
Therapeutic Effect of IL-4 Receptor-Targeting Pro-Apoptotic Peptide (AP1-ELP-KLAK) in Glioblastoma Tumor Model |
| title_full_unstemmed |
Therapeutic Effect of IL-4 Receptor-Targeting Pro-Apoptotic Peptide (AP1-ELP-KLAK) in Glioblastoma Tumor Model |
| title_sort |
therapeutic effect of il-4 receptor-targeting pro-apoptotic peptide (ap1-elp-klak) in glioblastoma tumor model |
| publisher |
Dove Medical Press |
| publishDate |
2021 |
| url |
https://doaj.org/article/9d4825e0b44742ec9bf20b6a4ff60770 |
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