EM011 activates a survivin-dependent apoptotic program in human non-small cell lung cancer cells
<p>Abstract</p> <p>Background</p> <p>Lung cancer remains a leading cause of cancer death among both men and women in the United States. Treatment modalities available for this malignancy are inadequate and thus new drugs with improved pharmacological profiles and superi...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2009-10-01
|
| Series: | Molecular Cancer |
| Online Access: | http://www.molecular-cancer.com/content/8/1/93 |
| _version_ | 1818790400620494848 |
|---|---|
| author | Yates Clayton Sharp Starlette M Karna Prasanthi Prakash Satya Aneja Ritu |
| author_facet | Yates Clayton Sharp Starlette M Karna Prasanthi Prakash Satya Aneja Ritu |
| author_sort | Yates Clayton |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Lung cancer remains a leading cause of cancer death among both men and women in the United States. Treatment modalities available for this malignancy are inadequate and thus new drugs with improved pharmacological profiles and superior therapeutic indices are being continually explored. Noscapinoids constitute an emerging class of anticancer agents that bind tubulin but do not significantly alter the monomer/polymer ratio of tubulin. EM011, a rationally-designed member of this class of non-toxic agents, is more potent than the lead molecule, noscapine.</p> <p>Results</p> <p>Here we report that EM011 inhibited proliferation of a comprehensive panel of lung cancer cells with IC<sub>50</sub>'s ranging from 4-50 μM. In A549 human non-small cell lung cancer cells, the antiproliferative activity was mediated through blockage of cell-cycle progression by induction of a transient but robust mitotic arrest accompanied by activation of the spindle assembly checkpoint. The mitotically-arrested A549 cells then override the activated mitotic checkpoint and aberrantly exit mitosis without cytokinesis resulting in pseudo G1-like multinucleated cells that either succumb directly to apoptosis or continue another round of the cell-cycle. The accumulated enormous DNA perhaps acts as genotoxic stress to trigger cell death. EM011-induced apoptotic cell death in A549 cells was associated with a decrease of the Bcl2/BAX ratio, activation of caspase-3 and cleavage of PARP. Furthermore, EM011 induced downregulation of survivin expression over time of treatment. Abrogation of survivin led to an increase of cell death whereas, overexpression caused decreased apoptosis.</p> <p>Conclusion</p> <p>These <it>in vitro </it>data suggest that EM011 mediates antiproliferative and proapoptotic activity in non-small cell A549 lung cancer cells by impeding cell-cycle progression and attenuating antiapoptotic signaling circuitries (viz. Bcl2, survivin). The study provides evidence for the potential usefulness of EM011 in chemotherapy of lung cancer.</p> |
| first_indexed | 2024-12-18T14:54:51Z |
| format | Article |
| id | doaj.art-9709375e2d2e45fc954d19315e192c99 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-18T14:54:51Z |
| publishDate | 2009-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-9709375e2d2e45fc954d19315e192c992022-12-21T21:04:04ZengBMCMolecular Cancer1476-45982009-10-01819310.1186/1476-4598-8-93EM011 activates a survivin-dependent apoptotic program in human non-small cell lung cancer cellsYates ClaytonSharp Starlette MKarna PrasanthiPrakash SatyaAneja Ritu<p>Abstract</p> <p>Background</p> <p>Lung cancer remains a leading cause of cancer death among both men and women in the United States. Treatment modalities available for this malignancy are inadequate and thus new drugs with improved pharmacological profiles and superior therapeutic indices are being continually explored. Noscapinoids constitute an emerging class of anticancer agents that bind tubulin but do not significantly alter the monomer/polymer ratio of tubulin. EM011, a rationally-designed member of this class of non-toxic agents, is more potent than the lead molecule, noscapine.</p> <p>Results</p> <p>Here we report that EM011 inhibited proliferation of a comprehensive panel of lung cancer cells with IC<sub>50</sub>'s ranging from 4-50 μM. In A549 human non-small cell lung cancer cells, the antiproliferative activity was mediated through blockage of cell-cycle progression by induction of a transient but robust mitotic arrest accompanied by activation of the spindle assembly checkpoint. The mitotically-arrested A549 cells then override the activated mitotic checkpoint and aberrantly exit mitosis without cytokinesis resulting in pseudo G1-like multinucleated cells that either succumb directly to apoptosis or continue another round of the cell-cycle. The accumulated enormous DNA perhaps acts as genotoxic stress to trigger cell death. EM011-induced apoptotic cell death in A549 cells was associated with a decrease of the Bcl2/BAX ratio, activation of caspase-3 and cleavage of PARP. Furthermore, EM011 induced downregulation of survivin expression over time of treatment. Abrogation of survivin led to an increase of cell death whereas, overexpression caused decreased apoptosis.</p> <p>Conclusion</p> <p>These <it>in vitro </it>data suggest that EM011 mediates antiproliferative and proapoptotic activity in non-small cell A549 lung cancer cells by impeding cell-cycle progression and attenuating antiapoptotic signaling circuitries (viz. Bcl2, survivin). The study provides evidence for the potential usefulness of EM011 in chemotherapy of lung cancer.</p>http://www.molecular-cancer.com/content/8/1/93 |
| spellingShingle | Yates Clayton Sharp Starlette M Karna Prasanthi Prakash Satya Aneja Ritu EM011 activates a survivin-dependent apoptotic program in human non-small cell lung cancer cells Molecular Cancer |
| title | EM011 activates a survivin-dependent apoptotic program in human non-small cell lung cancer cells |
| title_full | EM011 activates a survivin-dependent apoptotic program in human non-small cell lung cancer cells |
| title_fullStr | EM011 activates a survivin-dependent apoptotic program in human non-small cell lung cancer cells |
| title_full_unstemmed | EM011 activates a survivin-dependent apoptotic program in human non-small cell lung cancer cells |
| title_short | EM011 activates a survivin-dependent apoptotic program in human non-small cell lung cancer cells |
| title_sort | em011 activates a survivin dependent apoptotic program in human non small cell lung cancer cells |
| url | http://www.molecular-cancer.com/content/8/1/93 |
| work_keys_str_mv | AT yatesclayton em011activatesasurvivindependentapoptoticprograminhumannonsmallcelllungcancercells AT sharpstarlettem em011activatesasurvivindependentapoptoticprograminhumannonsmallcelllungcancercells AT karnaprasanthi em011activatesasurvivindependentapoptoticprograminhumannonsmallcelllungcancercells AT prakashsatya em011activatesasurvivindependentapoptoticprograminhumannonsmallcelllungcancercells AT anejaritu em011activatesasurvivindependentapoptoticprograminhumannonsmallcelllungcancercells |