MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer
<p>Abstract</p> <p>Background</p> <p>Prostate cancer is a common disease in men and at present there is no effective therapy available due to its recurrence despite androgen deprivation therapy. The epidermal growth factor receptor family (EGFR/HER1, HER2/neu and HER3)/...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2009-05-01
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| Series: | BMC Cancer |
| Online Access: | http://www.biomedcentral.com/1471-2407/9/142 |
| _version_ | 1818326023874281472 |
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| author | Croce Kimiko Riley Christopher Stejskal Amy Cooke Larry S Qi Wenqing Saldanha Jose W Bearss David Mahadevan Daruka |
| author_facet | Croce Kimiko Riley Christopher Stejskal Amy Cooke Larry S Qi Wenqing Saldanha Jose W Bearss David Mahadevan Daruka |
| author_sort | Croce Kimiko |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Prostate cancer is a common disease in men and at present there is no effective therapy available due to its recurrence despite androgen deprivation therapy. The epidermal growth factor receptor family (EGFR/HER1, HER2/neu and HER3)/PI3K/Akt signaling axis has been implicated in prostate cancer development and progression. However, Erlotinib, an EGFR tyrosine kinase inhibitor, has less effect on proliferation and apoptosis in prostate cancer cell lines. In this study, we evaluate whether MP470, a novel receptor tyrosine kinase inhibitor alone or in combination with Erlotinib has inhibitory effect on prostate cancer <it>in vitro </it>and <it>in vivo</it>.</p> <p>Methods</p> <p>The efficacy of MP470 or MP470 plus Erlotinib was evaluated <it>in vitro </it>using three prostate cancer cell lines by MTS and apoptosis assays. The molecular mechanism study was carried out by phosphorylation antibody array, immunoblotting and immunohistochemistry. A LNCaP mouse xenograft model was also used to determine the tumor growth inhibition by MP470, Erlotinib or the combination treatments.</p> <p>Results</p> <p>MP470 exhibits low μM IC<sub>50 </sub>in prostate cancer cell lines. Additive effects on both cytotoxicity and induction of apoptosis were observed when LNCaP were treated with MP470 in combination with Erlotinib. This combination treatment completely inhibited phosphorylation of the HER family members (HER1, 2, 3), binding of PI3K regulatory unit p85 to HER3 and downstream Akt activity even after androgen depletion. Furthermore, in a LNCaP mouse xenograft model, the MP470-Erlotinib combination produced 30–65% dose-dependent tumor growth inhibition (TGI).</p> <p>Conclusion</p> <p>We propose that MP470-Erlotinib targets the HER family/PI3K/Akt pathway and may represent a novel therapeutic strategy for prostate cancer.</p> |
| first_indexed | 2024-12-13T11:53:47Z |
| format | Article |
| id | doaj.art-559aec17a2ba47a2ac50607f370c3472 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-13T11:53:47Z |
| publishDate | 2009-05-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-559aec17a2ba47a2ac50607f370c34722022-12-21T23:47:16ZengBMCBMC Cancer1471-24072009-05-019114210.1186/1471-2407-9-142MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancerCroce KimikoRiley ChristopherStejskal AmyCooke Larry SQi WenqingSaldanha Jose WBearss DavidMahadevan Daruka<p>Abstract</p> <p>Background</p> <p>Prostate cancer is a common disease in men and at present there is no effective therapy available due to its recurrence despite androgen deprivation therapy. The epidermal growth factor receptor family (EGFR/HER1, HER2/neu and HER3)/PI3K/Akt signaling axis has been implicated in prostate cancer development and progression. However, Erlotinib, an EGFR tyrosine kinase inhibitor, has less effect on proliferation and apoptosis in prostate cancer cell lines. In this study, we evaluate whether MP470, a novel receptor tyrosine kinase inhibitor alone or in combination with Erlotinib has inhibitory effect on prostate cancer <it>in vitro </it>and <it>in vivo</it>.</p> <p>Methods</p> <p>The efficacy of MP470 or MP470 plus Erlotinib was evaluated <it>in vitro </it>using three prostate cancer cell lines by MTS and apoptosis assays. The molecular mechanism study was carried out by phosphorylation antibody array, immunoblotting and immunohistochemistry. A LNCaP mouse xenograft model was also used to determine the tumor growth inhibition by MP470, Erlotinib or the combination treatments.</p> <p>Results</p> <p>MP470 exhibits low μM IC<sub>50 </sub>in prostate cancer cell lines. Additive effects on both cytotoxicity and induction of apoptosis were observed when LNCaP were treated with MP470 in combination with Erlotinib. This combination treatment completely inhibited phosphorylation of the HER family members (HER1, 2, 3), binding of PI3K regulatory unit p85 to HER3 and downstream Akt activity even after androgen depletion. Furthermore, in a LNCaP mouse xenograft model, the MP470-Erlotinib combination produced 30–65% dose-dependent tumor growth inhibition (TGI).</p> <p>Conclusion</p> <p>We propose that MP470-Erlotinib targets the HER family/PI3K/Akt pathway and may represent a novel therapeutic strategy for prostate cancer.</p>http://www.biomedcentral.com/1471-2407/9/142 |
| spellingShingle | Croce Kimiko Riley Christopher Stejskal Amy Cooke Larry S Qi Wenqing Saldanha Jose W Bearss David Mahadevan Daruka MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer BMC Cancer |
| title | MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer |
| title_full | MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer |
| title_fullStr | MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer |
| title_full_unstemmed | MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer |
| title_short | MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer |
| title_sort | mp470 a novel receptor tyrosine kinase inhibitor in combination with erlotinib inhibits the her family pi3k akt pathway and tumor growth in prostate cancer |
| url | http://www.biomedcentral.com/1471-2407/9/142 |
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