Introduction of WT-TP53 into pancreatic cancer cells alters sensitivity to chemotherapeutic drugs, targeted therapeutics and nutraceuticals
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly metastatic malignancy and accounts for 85% of pancreatic cancers. PDAC patients have poor prognosis with a five-year survival of only 5–10%. Mutations at the TP53 gene are readily detected in pancreatic tumors isolated from PDAC patien...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal Article |
| Published: |
Pergamon
2018
|
| Online Access: | http://hdl.handle.net/20.500.11937/69662 |
| _version_ | 1848762100393967616 |
|---|---|
| author | Abrams, S. Lertpiriyapong, K. Yang, L. Martelli, A. Cocco, L. Ratti, S. Falasca, Marco Murata, R. Rosalen, P. Lombardi, P. Libra, M. Candido, S. Montalto, G. Cervello, M. Steelman, L. McCubrey, J. |
| author_facet | Abrams, S. Lertpiriyapong, K. Yang, L. Martelli, A. Cocco, L. Ratti, S. Falasca, Marco Murata, R. Rosalen, P. Lombardi, P. Libra, M. Candido, S. Montalto, G. Cervello, M. Steelman, L. McCubrey, J. |
| author_sort | Abrams, S. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly metastatic malignancy and accounts for 85% of pancreatic cancers. PDAC patients have poor prognosis with a five-year survival of only 5–10%. Mutations at the TP53 gene are readily detected in pancreatic tumors isolated from PDAC patients. We have investigated the effects of restoration of wild-type (WT) TP53 activity on the sensitivity of pancreatic cancer cells to: chemotherapy, targeted therapy, as well as, nutraceuticals. Upon introduction of the WT-TP53 gene into the MIA-PaCa-2 pancreatic cancer cell line, the sensitivity to drugs used to treat pancreatic cancer cells such as: gemcitabine, fluorouracil (5FU), cisplatin, irinotecan, oxaliplatin, and paclitaxel increased significantly. Likewise, the sensitivity to drugs used to treat other cancers such as: doxorubicin, mitoxantrone, and 4 hydroxy tamoxifen (4HT) also increased upon introduction of WT-TP53 into MIA-PaCa-2 cells. Furthermore, the sensitivity to certain inhibitors which target: PI3K/mTORC1, PDK1, SRC, GSK-3, and biochemical processes such as proteasomal degradation and the nutraceutical berberine as increased upon introduction of WT-TP53. Furthermore, in some cases, cells with WT-TP53 were more sensitive to the combination of drugs and suboptimal doses of the MDM2 inhibitor nutlin-3a. However, TP53-independent effects of nutlin-3a were observed upon treatment with either a proteasomal or a PI3K/mTOR inhibitor. These studies indicate the sensitizing effects that WT-TP53 can have in PDAC cells which normally lack WT-TP53 to various therapeutic agents and suggest approaches to improve PDAC therapy. |
| first_indexed | 2025-11-14T10:42:12Z |
| format | Journal Article |
| id | curtin-20.500.11937-69662 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T10:42:12Z |
| publishDate | 2018 |
| publisher | Pergamon |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-696622018-11-19T05:12:00Z Introduction of WT-TP53 into pancreatic cancer cells alters sensitivity to chemotherapeutic drugs, targeted therapeutics and nutraceuticals Abrams, S. Lertpiriyapong, K. Yang, L. Martelli, A. Cocco, L. Ratti, S. Falasca, Marco Murata, R. Rosalen, P. Lombardi, P. Libra, M. Candido, S. Montalto, G. Cervello, M. Steelman, L. McCubrey, J. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly metastatic malignancy and accounts for 85% of pancreatic cancers. PDAC patients have poor prognosis with a five-year survival of only 5–10%. Mutations at the TP53 gene are readily detected in pancreatic tumors isolated from PDAC patients. We have investigated the effects of restoration of wild-type (WT) TP53 activity on the sensitivity of pancreatic cancer cells to: chemotherapy, targeted therapy, as well as, nutraceuticals. Upon introduction of the WT-TP53 gene into the MIA-PaCa-2 pancreatic cancer cell line, the sensitivity to drugs used to treat pancreatic cancer cells such as: gemcitabine, fluorouracil (5FU), cisplatin, irinotecan, oxaliplatin, and paclitaxel increased significantly. Likewise, the sensitivity to drugs used to treat other cancers such as: doxorubicin, mitoxantrone, and 4 hydroxy tamoxifen (4HT) also increased upon introduction of WT-TP53 into MIA-PaCa-2 cells. Furthermore, the sensitivity to certain inhibitors which target: PI3K/mTORC1, PDK1, SRC, GSK-3, and biochemical processes such as proteasomal degradation and the nutraceutical berberine as increased upon introduction of WT-TP53. Furthermore, in some cases, cells with WT-TP53 were more sensitive to the combination of drugs and suboptimal doses of the MDM2 inhibitor nutlin-3a. However, TP53-independent effects of nutlin-3a were observed upon treatment with either a proteasomal or a PI3K/mTOR inhibitor. These studies indicate the sensitizing effects that WT-TP53 can have in PDAC cells which normally lack WT-TP53 to various therapeutic agents and suggest approaches to improve PDAC therapy. 2018 Journal Article http://hdl.handle.net/20.500.11937/69662 10.1016/j.jbior.2018.06.002 Pergamon restricted |
| spellingShingle | Abrams, S. Lertpiriyapong, K. Yang, L. Martelli, A. Cocco, L. Ratti, S. Falasca, Marco Murata, R. Rosalen, P. Lombardi, P. Libra, M. Candido, S. Montalto, G. Cervello, M. Steelman, L. McCubrey, J. Introduction of WT-TP53 into pancreatic cancer cells alters sensitivity to chemotherapeutic drugs, targeted therapeutics and nutraceuticals |
| title | Introduction of WT-TP53 into pancreatic cancer cells alters sensitivity to chemotherapeutic drugs, targeted therapeutics and nutraceuticals |
| title_full | Introduction of WT-TP53 into pancreatic cancer cells alters sensitivity to chemotherapeutic drugs, targeted therapeutics and nutraceuticals |
| title_fullStr | Introduction of WT-TP53 into pancreatic cancer cells alters sensitivity to chemotherapeutic drugs, targeted therapeutics and nutraceuticals |
| title_full_unstemmed | Introduction of WT-TP53 into pancreatic cancer cells alters sensitivity to chemotherapeutic drugs, targeted therapeutics and nutraceuticals |
| title_short | Introduction of WT-TP53 into pancreatic cancer cells alters sensitivity to chemotherapeutic drugs, targeted therapeutics and nutraceuticals |
| title_sort | introduction of wt-tp53 into pancreatic cancer cells alters sensitivity to chemotherapeutic drugs, targeted therapeutics and nutraceuticals |
| url | http://hdl.handle.net/20.500.11937/69662 |