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Article: Vincristine could partly suppress stromal support to T-ALL blasts during pegylated arginase I treatment
Title | Vincristine could partly suppress stromal support to T-ALL blasts during pegylated arginase I treatment |
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Authors | |
Keywords | Arginase Bone marrow Lymphoid leukemic cells Mesenchymal stromal cell Ornithine transcarbamylase Stromal suppression |
Issue Date | 2013 |
Publisher | BioMed Central Ltd. |
Citation | Experimental Hematology & Oncology, 2013, v. 2 n. 1, p. 11:1-9 How to Cite? |
Abstract | BACKGROUND: Relapsed T-lineage acute lymphoblastic leukemia (T-ALL) has been an incurable disease. Recent reports showed that an L-arginine depleting enzyme, pegylated arginase (BCT-100) may be effective against T-ALL cells. On the other hand, studies including ours had shown the symbiosis of ALL blasts and human mesenchymal stromal cells (hMSCs) in bone marrow microenvironment during L-asparaginase treatment. As L-asparaginase and BCT-100 both act by depleting lymphoid cells of specific amino acid, we hypothesized that hMSCs may also protect T-ALL blasts from BCT-100 treatment in co-culture and such protection may be abrogated by pre-treating hMSCs with vincristine (VCR). METHODS: XTT assay was used to test sensitivities of T-ALL cell lines and hMSCs to BCT-100. Apoptosis of T-ALL cell lines with or without BCT-100 treatment were tested by annexin V / propidium iodide (AV/PI) assay using flow cytometer. Western blotting was performed to analyze the expression of ornithine transcarbamylase (OTC), an enzyme involved in L-arginine metabolism which may account for BCT-100 resistance. RESULTS: hMSCs were resistant to BCT-100 while CCRF-CEM, Jurkat and MOLT-4 were very sensitive to it. hMSCs could protect all the three cell lines from BCT-100 treatment in transwell co-culture. All the 3 T-ALL cell lines were also found to be rescued by an L-arginine precursor citrulline, while the breakdown product of BCT-100, ornithine only had limited salvaging effect on CCRF-CEM but not Jurkat and MOLT-4. Both hMSCs and 3 T-ALL cell lines express citrulline synthesis enzyme, ornithine transcarbamylase (OTC) at basal level while only hMSCs could express OTC at relatively higher level under BCT-100 treatment. Treating hMSCs with vincristine before co-culturing with T-ALL could resume the cytotoxicity of BCT-100 to CCRF-CEM and MOLT-4 cells. CONCLUSIONS: Our results suggest a possible strategy to overcome resistance to BCT-100 from cancer microenvironments by suppressing hMSCs either in marrow or in the perivascular niche using vincristine. |
Persistent Identifier | http://hdl.handle.net/10722/195921 |
ISSN | 2023 Impact Factor: 9.4 2023 SCImago Journal Rankings: 2.384 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Fung, KL | en_US |
dc.contributor.author | Chan, GCF | en_US |
dc.date.accessioned | 2014-03-21T02:21:03Z | - |
dc.date.available | 2014-03-21T02:21:03Z | - |
dc.date.issued | 2013 | en_US |
dc.identifier.citation | Experimental Hematology & Oncology, 2013, v. 2 n. 1, p. 11:1-9 | en_US |
dc.identifier.issn | 2162-3619 | - |
dc.identifier.uri | http://hdl.handle.net/10722/195921 | - |
dc.description.abstract | BACKGROUND: Relapsed T-lineage acute lymphoblastic leukemia (T-ALL) has been an incurable disease. Recent reports showed that an L-arginine depleting enzyme, pegylated arginase (BCT-100) may be effective against T-ALL cells. On the other hand, studies including ours had shown the symbiosis of ALL blasts and human mesenchymal stromal cells (hMSCs) in bone marrow microenvironment during L-asparaginase treatment. As L-asparaginase and BCT-100 both act by depleting lymphoid cells of specific amino acid, we hypothesized that hMSCs may also protect T-ALL blasts from BCT-100 treatment in co-culture and such protection may be abrogated by pre-treating hMSCs with vincristine (VCR). METHODS: XTT assay was used to test sensitivities of T-ALL cell lines and hMSCs to BCT-100. Apoptosis of T-ALL cell lines with or without BCT-100 treatment were tested by annexin V / propidium iodide (AV/PI) assay using flow cytometer. Western blotting was performed to analyze the expression of ornithine transcarbamylase (OTC), an enzyme involved in L-arginine metabolism which may account for BCT-100 resistance. RESULTS: hMSCs were resistant to BCT-100 while CCRF-CEM, Jurkat and MOLT-4 were very sensitive to it. hMSCs could protect all the three cell lines from BCT-100 treatment in transwell co-culture. All the 3 T-ALL cell lines were also found to be rescued by an L-arginine precursor citrulline, while the breakdown product of BCT-100, ornithine only had limited salvaging effect on CCRF-CEM but not Jurkat and MOLT-4. Both hMSCs and 3 T-ALL cell lines express citrulline synthesis enzyme, ornithine transcarbamylase (OTC) at basal level while only hMSCs could express OTC at relatively higher level under BCT-100 treatment. Treating hMSCs with vincristine before co-culturing with T-ALL could resume the cytotoxicity of BCT-100 to CCRF-CEM and MOLT-4 cells. CONCLUSIONS: Our results suggest a possible strategy to overcome resistance to BCT-100 from cancer microenvironments by suppressing hMSCs either in marrow or in the perivascular niche using vincristine. | - |
dc.language | eng | en_US |
dc.publisher | BioMed Central Ltd. | - |
dc.relation.ispartof | Experimental Hematology & Oncology | en_US |
dc.rights | Experimental Hematology & Oncology. Copyright © BioMed Central Ltd. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject | Arginase | - |
dc.subject | Bone marrow | - |
dc.subject | Lymphoid leukemic cells | - |
dc.subject | Mesenchymal stromal cell | - |
dc.subject | Ornithine transcarbamylase | - |
dc.subject | Stromal suppression | - |
dc.title | Vincristine could partly suppress stromal support to T-ALL blasts during pegylated arginase I treatment | en_US |
dc.type | Article | en_US |
dc.identifier.email | Chan, GCF: gcfchan@hku.hk | en_US |
dc.identifier.authority | Chan, GCF=rp00431 | en_US |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.1186/2162-3619-2-11 | - |
dc.identifier.pmid | 23574711 | - |
dc.identifier.pmcid | PMC3655039 | - |
dc.identifier.hkuros | 228306 | en_US |
dc.identifier.hkuros | 228246 | - |
dc.identifier.hkuros | 268048 | - |
dc.identifier.volume | 2 | en_US |
dc.identifier.issue | 1 | - |
dc.identifier.spage | 11:1 | en_US |
dc.identifier.epage | 9 | en_US |
dc.identifier.isi | WOS:000215298400011 | - |
dc.publisher.place | UK | - |
dc.identifier.issnl | 2162-3619 | - |