Anti-proliferative activity of the quassinoid NBT-272 in childhood medulloblastoma cells
<p>Abstract</p> <p>Background</p> <p>With current treatment strategies, nearly half of all medulloblastoma (MB) patients die from progressive tumors. Accordingly, the identification of novel therapeutic strategies remains a major goal. Deregulation of c-MYC is evident i...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2007-01-01
|
| Series: | BMC Cancer |
| Online Access: | http://www.biomedcentral.com/1471-2407/7/19 |
| _version_ | 1811297521416273920 |
|---|---|
| author | Helson Lawrence Eberhart Charles G Stearns Duncan Rajtarova Julia Shalaby Tarek von Bueren André O Arcaro Alexandre Grotzer Michael A |
| author_facet | Helson Lawrence Eberhart Charles G Stearns Duncan Rajtarova Julia Shalaby Tarek von Bueren André O Arcaro Alexandre Grotzer Michael A |
| author_sort | Helson Lawrence |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>With current treatment strategies, nearly half of all medulloblastoma (MB) patients die from progressive tumors. Accordingly, the identification of novel therapeutic strategies remains a major goal. Deregulation of c-MYC is evident in numerous human cancers. In MB, over-expression of c-MYC has been shown to correlate with anaplasia and unfavorable prognosis. In neuroblastoma – an embryonal tumor with biological similarities to MB – the quassinoid NBT-272 has been demonstrated to inhibit cellular proliferation and to down-regulate c-MYC protein expression.</p> <p>Methods</p> <p>To study MB cell responses to NBT-272 and their dependence on the level of c-MYC expression, DAOY (wild-type, empty vector transfected or c-MYC transfected), D341 (c-MYC amplification) and D425 (c-MYC amplification) human MB cells were used. The cells were treated with different concentrations of NBT-272 and the impact on cell proliferation, apoptosis and c-MYC expression was analyzed.</p> <p>Results</p> <p>NBT-272 treatment resulted in a dose-dependent inhibition of cellular proliferation (IC50 in the range of 1.7 – 9.6 ng/ml) and in a dose-dependent increase in apoptotic cell death in all human MB cell lines tested. Treatment with NBT-272 resulted in up to 90% down-regulation of c-MYC protein, as demonstrated by Western blot analysis, and in a significant inhibition of c-MYC binding activity. Anti-proliferative effects were slightly more prominent in D341 and D425 human MB cells with c-MYC amplification and slightly more pronounced in c-MYC over-expressing DAOY cells compared to DAOY wild-type cells. Moreover, treatment of synchronized cells by NBT-272 induced a marked cell arrest at the G1/S boundary.</p> <p>Conclusion</p> <p>In human MB cells, NBT-272 treatment inhibits cellular proliferation at nanomolar concentrations, blocks cell cycle progression, induces apoptosis, and down-regulates the expression of the oncogene c-MYC. Thus, NBT-272 may represent a novel drug candidate to inhibit proliferation of human MB cells <it>in vivo</it>.</p> |
| first_indexed | 2024-04-13T06:06:34Z |
| format | Article |
| id | doaj.art-e86f90640fa34a18a3f809a51d1c131e |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-04-13T06:06:34Z |
| publishDate | 2007-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-e86f90640fa34a18a3f809a51d1c131e2022-12-22T02:59:15ZengBMCBMC Cancer1471-24072007-01-01711910.1186/1471-2407-7-19Anti-proliferative activity of the quassinoid NBT-272 in childhood medulloblastoma cellsHelson LawrenceEberhart Charles GStearns DuncanRajtarova JuliaShalaby Tarekvon Bueren André OArcaro AlexandreGrotzer Michael A<p>Abstract</p> <p>Background</p> <p>With current treatment strategies, nearly half of all medulloblastoma (MB) patients die from progressive tumors. Accordingly, the identification of novel therapeutic strategies remains a major goal. Deregulation of c-MYC is evident in numerous human cancers. In MB, over-expression of c-MYC has been shown to correlate with anaplasia and unfavorable prognosis. In neuroblastoma – an embryonal tumor with biological similarities to MB – the quassinoid NBT-272 has been demonstrated to inhibit cellular proliferation and to down-regulate c-MYC protein expression.</p> <p>Methods</p> <p>To study MB cell responses to NBT-272 and their dependence on the level of c-MYC expression, DAOY (wild-type, empty vector transfected or c-MYC transfected), D341 (c-MYC amplification) and D425 (c-MYC amplification) human MB cells were used. The cells were treated with different concentrations of NBT-272 and the impact on cell proliferation, apoptosis and c-MYC expression was analyzed.</p> <p>Results</p> <p>NBT-272 treatment resulted in a dose-dependent inhibition of cellular proliferation (IC50 in the range of 1.7 – 9.6 ng/ml) and in a dose-dependent increase in apoptotic cell death in all human MB cell lines tested. Treatment with NBT-272 resulted in up to 90% down-regulation of c-MYC protein, as demonstrated by Western blot analysis, and in a significant inhibition of c-MYC binding activity. Anti-proliferative effects were slightly more prominent in D341 and D425 human MB cells with c-MYC amplification and slightly more pronounced in c-MYC over-expressing DAOY cells compared to DAOY wild-type cells. Moreover, treatment of synchronized cells by NBT-272 induced a marked cell arrest at the G1/S boundary.</p> <p>Conclusion</p> <p>In human MB cells, NBT-272 treatment inhibits cellular proliferation at nanomolar concentrations, blocks cell cycle progression, induces apoptosis, and down-regulates the expression of the oncogene c-MYC. Thus, NBT-272 may represent a novel drug candidate to inhibit proliferation of human MB cells <it>in vivo</it>.</p>http://www.biomedcentral.com/1471-2407/7/19 |
| spellingShingle | Helson Lawrence Eberhart Charles G Stearns Duncan Rajtarova Julia Shalaby Tarek von Bueren André O Arcaro Alexandre Grotzer Michael A Anti-proliferative activity of the quassinoid NBT-272 in childhood medulloblastoma cells BMC Cancer |
| title | Anti-proliferative activity of the quassinoid NBT-272 in childhood medulloblastoma cells |
| title_full | Anti-proliferative activity of the quassinoid NBT-272 in childhood medulloblastoma cells |
| title_fullStr | Anti-proliferative activity of the quassinoid NBT-272 in childhood medulloblastoma cells |
| title_full_unstemmed | Anti-proliferative activity of the quassinoid NBT-272 in childhood medulloblastoma cells |
| title_short | Anti-proliferative activity of the quassinoid NBT-272 in childhood medulloblastoma cells |
| title_sort | anti proliferative activity of the quassinoid nbt 272 in childhood medulloblastoma cells |
| url | http://www.biomedcentral.com/1471-2407/7/19 |
| work_keys_str_mv | AT helsonlawrence antiproliferativeactivityofthequassinoidnbt272inchildhoodmedulloblastomacells AT eberhartcharlesg antiproliferativeactivityofthequassinoidnbt272inchildhoodmedulloblastomacells AT stearnsduncan antiproliferativeactivityofthequassinoidnbt272inchildhoodmedulloblastomacells AT rajtarovajulia antiproliferativeactivityofthequassinoidnbt272inchildhoodmedulloblastomacells AT shalabytarek antiproliferativeactivityofthequassinoidnbt272inchildhoodmedulloblastomacells AT vonbuerenandreo antiproliferativeactivityofthequassinoidnbt272inchildhoodmedulloblastomacells AT arcaroalexandre antiproliferativeactivityofthequassinoidnbt272inchildhoodmedulloblastomacells AT grotzermichaela antiproliferativeactivityofthequassinoidnbt272inchildhoodmedulloblastomacells |