1,1-Bis(3'-indolyl)-1-(<it>p</it>-substituted phenyl)methanes induce autophagic cell death in estrogen receptor negative breast cancer
<p>Abstract</p> <p>Background</p> <p>A novel series of methylene-substituted DIMs (C-DIMs), namely 1,1-bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing t-butyl (DIM-C-pPhtBu) and phenyl (DIM-C-pPhC6H5) groups inhibit proliferation of invasive estrogen re...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2010-12-01
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| Series: | BMC Cancer |
| Online Access: | http://www.biomedcentral.com/1471-2407/10/669 |
| _version_ | 1818359260789080064 |
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| author | Chadalapaka Gayathri Barhoumi Rola Burghardt Robert C Frankel Arthur E Su Yunpeng Vanderlaag Kathy Jutooru Indira Safe Stephen |
| author_facet | Chadalapaka Gayathri Barhoumi Rola Burghardt Robert C Frankel Arthur E Su Yunpeng Vanderlaag Kathy Jutooru Indira Safe Stephen |
| author_sort | Chadalapaka Gayathri |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>A novel series of methylene-substituted DIMs (C-DIMs), namely 1,1-bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing t-butyl (DIM-C-pPhtBu) and phenyl (DIM-C-pPhC6H5) groups inhibit proliferation of invasive estrogen receptor-negative MDA-MB-231 and MDA-MB-453 human breast cancer cell lines with IC50 values between 1-5 uM. The main purpose of this study was to investigate the pathways of C-DIM-induced cell death.</p> <p>Methods</p> <p>The effects of the C-DIMs on apoptotic, necrotic and autophagic cell death were determined using caspase inhibitors, measurement of lactate dehydrogenase release, and several markers of autophagy including Beclin and light chain associated protein 3 expression (LC3).</p> <p>Results</p> <p>The C-DIM compounds did not induce apoptosis and only DIM-C-pPhCF<sub>3 </sub>exhibited necrotic effects. However, treatment of MDA-MB-231 and MDA-MB-453 cells with C-DIMs resulted in accumulation of LC3-II compared to LC3-I protein, a characteristic marker of autophagy, and transient transfection of green fluorescent protein-LC3 also revealed that treatment with C-DIMs induced a redistribution of LC3 to autophagosomes after C-DIM treatment. In addition, the autofluorescent drug monodansylcadaverine (MDC), a specific autophagolysosome marker, accumulated in vacuoles after C-DIM treatment, and western blot analysis of lysates from cells treated with C-DIMs showed that the Beclin 1/Bcl-2 protein ratio increased.</p> <p>Conclusion</p> <p>The results suggest that C-DIM compounds may represent a new mechanism-based agent for treating drug-resistant ER-negative breast tumors through induction of autophagy.</p> |
| first_indexed | 2024-12-13T20:42:04Z |
| format | Article |
| id | doaj.art-21ebe214f6f94c8f837e8ea35f13db72 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-13T20:42:04Z |
| publishDate | 2010-12-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-21ebe214f6f94c8f837e8ea35f13db722022-12-21T23:32:06ZengBMCBMC Cancer1471-24072010-12-0110166910.1186/1471-2407-10-6691,1-Bis(3'-indolyl)-1-(<it>p</it>-substituted phenyl)methanes induce autophagic cell death in estrogen receptor negative breast cancerChadalapaka GayathriBarhoumi RolaBurghardt Robert CFrankel Arthur ESu YunpengVanderlaag KathyJutooru IndiraSafe Stephen<p>Abstract</p> <p>Background</p> <p>A novel series of methylene-substituted DIMs (C-DIMs), namely 1,1-bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing t-butyl (DIM-C-pPhtBu) and phenyl (DIM-C-pPhC6H5) groups inhibit proliferation of invasive estrogen receptor-negative MDA-MB-231 and MDA-MB-453 human breast cancer cell lines with IC50 values between 1-5 uM. The main purpose of this study was to investigate the pathways of C-DIM-induced cell death.</p> <p>Methods</p> <p>The effects of the C-DIMs on apoptotic, necrotic and autophagic cell death were determined using caspase inhibitors, measurement of lactate dehydrogenase release, and several markers of autophagy including Beclin and light chain associated protein 3 expression (LC3).</p> <p>Results</p> <p>The C-DIM compounds did not induce apoptosis and only DIM-C-pPhCF<sub>3 </sub>exhibited necrotic effects. However, treatment of MDA-MB-231 and MDA-MB-453 cells with C-DIMs resulted in accumulation of LC3-II compared to LC3-I protein, a characteristic marker of autophagy, and transient transfection of green fluorescent protein-LC3 also revealed that treatment with C-DIMs induced a redistribution of LC3 to autophagosomes after C-DIM treatment. In addition, the autofluorescent drug monodansylcadaverine (MDC), a specific autophagolysosome marker, accumulated in vacuoles after C-DIM treatment, and western blot analysis of lysates from cells treated with C-DIMs showed that the Beclin 1/Bcl-2 protein ratio increased.</p> <p>Conclusion</p> <p>The results suggest that C-DIM compounds may represent a new mechanism-based agent for treating drug-resistant ER-negative breast tumors through induction of autophagy.</p>http://www.biomedcentral.com/1471-2407/10/669 |
| spellingShingle | Chadalapaka Gayathri Barhoumi Rola Burghardt Robert C Frankel Arthur E Su Yunpeng Vanderlaag Kathy Jutooru Indira Safe Stephen 1,1-Bis(3'-indolyl)-1-(<it>p</it>-substituted phenyl)methanes induce autophagic cell death in estrogen receptor negative breast cancer BMC Cancer |
| title | 1,1-Bis(3'-indolyl)-1-(<it>p</it>-substituted phenyl)methanes induce autophagic cell death in estrogen receptor negative breast cancer |
| title_full | 1,1-Bis(3'-indolyl)-1-(<it>p</it>-substituted phenyl)methanes induce autophagic cell death in estrogen receptor negative breast cancer |
| title_fullStr | 1,1-Bis(3'-indolyl)-1-(<it>p</it>-substituted phenyl)methanes induce autophagic cell death in estrogen receptor negative breast cancer |
| title_full_unstemmed | 1,1-Bis(3'-indolyl)-1-(<it>p</it>-substituted phenyl)methanes induce autophagic cell death in estrogen receptor negative breast cancer |
| title_short | 1,1-Bis(3'-indolyl)-1-(<it>p</it>-substituted phenyl)methanes induce autophagic cell death in estrogen receptor negative breast cancer |
| title_sort | 1 1 bis 3 indolyl 1 it p it substituted phenyl methanes induce autophagic cell death in estrogen receptor negative breast cancer |
| url | http://www.biomedcentral.com/1471-2407/10/669 |
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