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Article: Vincristine could partly suppress stromal support to T-ALL blasts during pegylated arginase I treatment

TitleVincristine could partly suppress stromal support to T-ALL blasts during pegylated arginase I treatment
Authors
KeywordsArginase
Bone marrow
Lymphoid leukemic cells
Mesenchymal stromal cell
Ornithine transcarbamylase
Stromal suppression
Issue Date2013
PublisherBioMed Central Ltd.
Citation
Experimental Hematology & Oncology, 2013, v. 2 n. 1, p. 11:1-9 How to Cite?
AbstractBACKGROUND: 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 Identifierhttp://hdl.handle.net/10722/195921
ISSN
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorFung, KLen_US
dc.contributor.authorChan, GCFen_US
dc.date.accessioned2014-03-21T02:21:03Z-
dc.date.available2014-03-21T02:21:03Z-
dc.date.issued2013en_US
dc.identifier.citationExperimental Hematology & Oncology, 2013, v. 2 n. 1, p. 11:1-9en_US
dc.identifier.issn2162-3619-
dc.identifier.urihttp://hdl.handle.net/10722/195921-
dc.description.abstractBACKGROUND: 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.languageengen_US
dc.publisherBioMed Central Ltd.-
dc.relation.ispartofExperimental Hematology & Oncologyen_US
dc.rightsExperimental Hematology & Oncology. Copyright © BioMed Central Ltd.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subjectArginase-
dc.subjectBone marrow-
dc.subjectLymphoid leukemic cells-
dc.subjectMesenchymal stromal cell-
dc.subjectOrnithine transcarbamylase-
dc.subjectStromal suppression-
dc.titleVincristine could partly suppress stromal support to T-ALL blasts during pegylated arginase I treatmenten_US
dc.typeArticleen_US
dc.identifier.emailChan, GCF: gcfchan@hku.hken_US
dc.identifier.authorityChan, GCF=rp00431en_US
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1186/2162-3619-2-11-
dc.identifier.pmid23574711-
dc.identifier.pmcidPMC3655039-
dc.identifier.hkuros228306en_US
dc.identifier.hkuros228246-
dc.identifier.hkuros268048-
dc.identifier.volume2en_US
dc.identifier.issue1-
dc.identifier.spage11:1en_US
dc.identifier.epage9en_US
dc.publisher.placeUK-

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