Investigating the Molecular Mechanism of Novel Quinuclidinone Derivatives in Lung Cancer Cells with Different p53 Status
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Ohio University / OhioLINK
2010
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1277928440 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-ohiou12779284402021-08-03T05:46:45Z Investigating the Molecular Mechanism of Novel Quinuclidinone Derivatives in Lung Cancer Cells with Different p53 Status Soans, Eroica Biochemistry chemotherapeutics sphingomyelinase apoptosis p53 ceramide bax <p>Most chemotherapeutics affect normal cells as much as cancer cells leading to many undesirable side effects. One major goal is to develop cancer targeted chemotherapeutics that minimize side effects. Previously, novel quinuclidinone derivatives that cause cytotoxicity in human non-small lung carcinoma epithelial cells null for p53 (H1299) were reported. Here the mechanism involved in this cytotoxic effect was investigated. Quinuclidinone derivatives 8a and 8b induced cytotoxicity mainly through apoptosis of lung cancer cells independent of p53 status with induction of S-phase arrest. Importantly, they cause lower cytotoxicity and minimal apoptosis in normal lung epithelial cells (NL-20). This effect could be related to the elevated sphingomyelinase activity we detected in cancer cells compared to normal cells.</p><p>Furthermore, we observed that different sphingomyelinase isoforms are involved in 8a and 8b induced cytotoxicity of cancer cells. Sphingomyelinase initiated apoptosis through ceramide up-regulation with increased phosphorylation of JNK. The extrinsic and intrinsic apoptosis pathways are involved in 8a and 8b induced apoptosis as seen with the processing of procaspase 8, up-regulation of bax, cytosol cytochrome c and caspase 9, and down-regulation of bcl-2 proteins. Also, the derivatives induced p53 dependent apoptosis through the mitochondrial pathway. Gene array analysis implicated the involvement of the TNF receptor super family. Together these results show that the mechanism by which quinuclidinone derivatives provoke cytotoxicity in lung cancer cells is through sphingomyelinase dependent apoptosis involving both extrinsic and the intrinsic pathways.</p> 2010-09-22 English text Ohio University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1277928440 http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1277928440 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Biochemistry chemotherapeutics sphingomyelinase apoptosis p53 ceramide bax |
| spellingShingle |
Biochemistry chemotherapeutics sphingomyelinase apoptosis p53 ceramide bax Soans, Eroica Investigating the Molecular Mechanism of Novel Quinuclidinone Derivatives in Lung Cancer Cells with Different p53 Status |
| author |
Soans, Eroica |
| author_facet |
Soans, Eroica |
| author_sort |
Soans, Eroica |
| title |
Investigating the Molecular Mechanism of Novel Quinuclidinone Derivatives in Lung Cancer Cells with Different p53 Status |
| title_short |
Investigating the Molecular Mechanism of Novel Quinuclidinone Derivatives in Lung Cancer Cells with Different p53 Status |
| title_full |
Investigating the Molecular Mechanism of Novel Quinuclidinone Derivatives in Lung Cancer Cells with Different p53 Status |
| title_fullStr |
Investigating the Molecular Mechanism of Novel Quinuclidinone Derivatives in Lung Cancer Cells with Different p53 Status |
| title_full_unstemmed |
Investigating the Molecular Mechanism of Novel Quinuclidinone Derivatives in Lung Cancer Cells with Different p53 Status |
| title_sort |
investigating the molecular mechanism of novel quinuclidinone derivatives in lung cancer cells with different p53 status |
| publisher |
Ohio University / OhioLINK |
| publishDate |
2010 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1277928440 |
| work_keys_str_mv |
AT soanseroica investigatingthemolecularmechanismofnovelquinuclidinonederivativesinlungcancercellswithdifferentp53status |
| _version_ |
1719425119257886720 |