| Autor: |
S. L. Abrams, K. Lertpiriyapong, L. V. Yang, A. M. Martelli, L. Cocco, S. Ratti, M. Falasca, R. M. Murata, P. L. Rosalen, P. Lombardi, M. Libra, G. Montalto, M. Cervello, L. S. Steelman, J. A. McCubrey. |
| Přispěvatelé: |
S.L. Abrams, K. Lertpiriyapong, L.V. Yang, A.M. Martelli, L. Cocco, S. Ratti, M. Falasca, R.M. Murata, P.L. Rosalen, P. Lombardi, M. Libra, G. Montalto, M. Cervello, L.S. Steelman, J.A. McCubrey. |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| Předmět: |
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| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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