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Article: Growth suppressive effect of pegylated arginase in malignant pleural mesothelioma xenografts

TitleGrowth suppressive effect of pegylated arginase in malignant pleural mesothelioma xenografts
Authors
KeywordsApoptosis
BCT-100
Cell cycle arrest
Mesothelioma
Pegylated arginase
Xenografts
Issue Date2017
PublisherBioMed Central Ltd. The Journal's web site is located at http://respiratory-research.com/
Citation
Respiratory Research, 2017, v. 18, p. 80:1-11 How to Cite?
AbstractBACKGROUND: Malignant pleural mesothelioma (MPM) is a difficult-to-treat global disease. Pegylated arginase (BCT-100) has recently shown anti-tumor effects in hepatocellular carcinoma, acute myeloid leukemia and melanoma. This study aims to investigate the effects of PEG-BCT-100 in MPM. METHODS: A panel of 5 mesothelioma cell lines (H28, 211H, H226, H2052 and H2452) was used to study the in vitro effects of BCT-100 by crystal violet staining. The in vivo effects of BCT-100 were studied using 211H and H226 nude mice xenografts. Protein expression (argininosuccinate synthetase, ornithine transcarbamylase, cleaved PARP, cleaved caspase 3, cyclins (A2, D3, E1 and H), CDK4 and Ki67) and arginine concentration were evaluated by Western blot and ELISA respectively. Cellular localization of BCT-100 was detected by immunohistochemistry and immunoflorescence. TUNEL assay was used to identify cellular apoptotic events. RESULTS: Argininosuccinate synthetase was expressed in H28, H226, and H2452 cells as well as 211H and H266 xenografts. Ornithine transcarbamylase was undetectable in all cell lines and xenograft models. BCT-100 reduced in vitro cell viability (IC50 values at 13-24 mU/ml, 72 h) across different cell lines and suppressed tumor growth in both 211H and H226 xenograft models. BCT-100 (60 mg/kg) significantly suppressed tumor growth (p < 0.01) with prolonged median survival (p < 0.01) in both xenograft models. Combining BCT-100 with pemetrexed or cisplatin conferred no additional benefits over single agents. Serum and intratumoral arginine levels were effectively decreased by BCT-100, associated with cytosolic accumulation of BCT-100 within tumor cells. Apoptosis (PARP cleavage in 211H xenografts; Bcl-2 downregulation, and cleavage of PARP and caspase 3 in H226 xenografts; positive TUNEL staining in both) and G1 arrest (downregulation of cyclin A2, D3, E1 and CDK4 in 211H xenografts; suppression of cyclin A2, E1, H and CDK4 in H226 xenografts) were evident with BCT-100 treatment. Furthermore, proliferative factor Ki67 was downregulated in BCT-100 treatments arms. CONCLUSIONS: BCT-100 suppressed tumor growth with prolonged median survival partially mediated by intratumoral arginine depletion resulting in apoptosis and G1 arrest in mesothelioma xenograft models. The findings provide scientific evidence to support further clinical development of BCT-100 in treatment of MPM.
Persistent Identifierhttp://hdl.handle.net/10722/241775
ISSN
2010 Impact Factor: 2.859
2023 SCImago Journal Rankings: 1.498
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLam, SK-
dc.contributor.authorLi, YV-
dc.contributor.authorXU, S-
dc.contributor.authorLEUNG, LL-
dc.contributor.authorU, KP-
dc.contributor.authorZHENG, YF-
dc.contributor.authorCHENG, PN-
dc.contributor.authorHo, JCM-
dc.date.accessioned2017-06-20T01:48:24Z-
dc.date.available2017-06-20T01:48:24Z-
dc.date.issued2017-
dc.identifier.citationRespiratory Research, 2017, v. 18, p. 80:1-11-
dc.identifier.issn1465-9921-
dc.identifier.urihttp://hdl.handle.net/10722/241775-
dc.description.abstractBACKGROUND: Malignant pleural mesothelioma (MPM) is a difficult-to-treat global disease. Pegylated arginase (BCT-100) has recently shown anti-tumor effects in hepatocellular carcinoma, acute myeloid leukemia and melanoma. This study aims to investigate the effects of PEG-BCT-100 in MPM. METHODS: A panel of 5 mesothelioma cell lines (H28, 211H, H226, H2052 and H2452) was used to study the in vitro effects of BCT-100 by crystal violet staining. The in vivo effects of BCT-100 were studied using 211H and H226 nude mice xenografts. Protein expression (argininosuccinate synthetase, ornithine transcarbamylase, cleaved PARP, cleaved caspase 3, cyclins (A2, D3, E1 and H), CDK4 and Ki67) and arginine concentration were evaluated by Western blot and ELISA respectively. Cellular localization of BCT-100 was detected by immunohistochemistry and immunoflorescence. TUNEL assay was used to identify cellular apoptotic events. RESULTS: Argininosuccinate synthetase was expressed in H28, H226, and H2452 cells as well as 211H and H266 xenografts. Ornithine transcarbamylase was undetectable in all cell lines and xenograft models. BCT-100 reduced in vitro cell viability (IC50 values at 13-24 mU/ml, 72 h) across different cell lines and suppressed tumor growth in both 211H and H226 xenograft models. BCT-100 (60 mg/kg) significantly suppressed tumor growth (p < 0.01) with prolonged median survival (p < 0.01) in both xenograft models. Combining BCT-100 with pemetrexed or cisplatin conferred no additional benefits over single agents. Serum and intratumoral arginine levels were effectively decreased by BCT-100, associated with cytosolic accumulation of BCT-100 within tumor cells. Apoptosis (PARP cleavage in 211H xenografts; Bcl-2 downregulation, and cleavage of PARP and caspase 3 in H226 xenografts; positive TUNEL staining in both) and G1 arrest (downregulation of cyclin A2, D3, E1 and CDK4 in 211H xenografts; suppression of cyclin A2, E1, H and CDK4 in H226 xenografts) were evident with BCT-100 treatment. Furthermore, proliferative factor Ki67 was downregulated in BCT-100 treatments arms. CONCLUSIONS: BCT-100 suppressed tumor growth with prolonged median survival partially mediated by intratumoral arginine depletion resulting in apoptosis and G1 arrest in mesothelioma xenograft models. The findings provide scientific evidence to support further clinical development of BCT-100 in treatment of MPM.-
dc.languageeng-
dc.publisherBioMed Central Ltd. The Journal's web site is located at http://respiratory-research.com/-
dc.relation.ispartofRespiratory Research-
dc.rightsRespiratory Research. Copyright © BioMed Central Ltd.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectApoptosis-
dc.subjectBCT-100-
dc.subjectCell cycle arrest-
dc.subjectMesothelioma-
dc.subjectPegylated arginase-
dc.subjectXenografts-
dc.titleGrowth suppressive effect of pegylated arginase in malignant pleural mesothelioma xenografts-
dc.typeArticle-
dc.identifier.emailLam, SK: sklam77@hku.hk-
dc.identifier.emailLi, YV: avicky@hku.hk-
dc.identifier.emailHo, JCM: jhocm@hku.hk-
dc.identifier.authorityHo, JCM=rp00258-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1186/s12931-017-0564-3-
dc.identifier.scopuseid_2-s2.0-85018992572-
dc.identifier.hkuros272745-
dc.identifier.volume18-
dc.identifier.spage80:1-
dc.identifier.epage11-
dc.identifier.isiWOS:000400645100006-
dc.publisher.placeUnited Kingdom-
dc.identifier.issnl1465-9921-

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