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dc.contributor.authorAbrams, S.
dc.contributor.authorLertpiriyapong, K.
dc.contributor.authorYang, L.
dc.contributor.authorMartelli, A.
dc.contributor.authorCocco, L.
dc.contributor.authorRatti, S.
dc.contributor.authorFalasca, Marco
dc.contributor.authorMurata, R.
dc.contributor.authorRosalen, P.
dc.contributor.authorLombardi, P.
dc.contributor.authorLibra, M.
dc.contributor.authorCandido, S.
dc.contributor.authorMontalto, G.
dc.contributor.authorCervello, M.
dc.contributor.authorSteelman, L.
dc.contributor.authorMcCubrey, J.
dc.date.accessioned2018-08-08T04:41:52Z
dc.date.available2018-08-08T04:41:52Z
dc.date.created2018-08-08T03:50:52Z
dc.date.issued2018
dc.identifier.citationAbrams, S. and Lertpiriyapong, K. and Yang, L. and Martelli, A. and Cocco, L. and Ratti, S. and Falasca, M. et al. 2018. Introduction of WT-TP53 into pancreatic cancer cells alters sensitivity to chemotherapeutic drugs, targeted therapeutics and nutraceuticals. Advances in Biological Regulation. 69: pp. 16-34.
dc.identifier.urihttp://hdl.handle.net/20.500.11937/69662
dc.identifier.doi10.1016/j.jbior.2018.06.002
dc.description.abstract

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.

dc.publisherPergamon
dc.titleIntroduction of WT-TP53 into pancreatic cancer cells alters sensitivity to chemotherapeutic drugs, targeted therapeutics and nutraceuticals
dc.typeJournal Article
dcterms.source.issn2212-4926
dcterms.source.titleAdvances in Biological Regulation
curtin.departmentSchool of Pharmacy and Biomedical Sciences
curtin.accessStatusFulltext not available


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