Introduction of WT-TP53 into pancreatic cancer cells alters sensitivity to chemotherapeutic drugs, targeted therapeutics and nutraceuticals. (August 2018)

• Record Type: Journal Article
• Authors: Abrams, Stephen L.; Lertpiriyapong, Kvin; Yang, Li V.; Martelli, Alberto M.; Cocco, Lucio; Ratti, Stefano; Falasca, Marco; Murata, Ramiro M.; Rosalen, Pedro L.; Lombardi, Paolo; Libra, Massimo; Candido, Saverio; Montalto, Giuseppe; Cervello, Melchiorre; Steelman, Linda S.; McCubrey, James A.
• Is Part Of: Advances in biological regulation. Volume 69(2018)
• Page Start: 16
• Page End: 34
• Publication Date: 2018-08
• Subjects: TP53 -- Drug sensitivity -- Targeted therapeutics -- Signal transduction inhibitors; Cellular control mechanisms -- Periodicals; Biological control systems -- Periodicals; Molecular biology -- Periodicals; Periodicals; 571.74
• DOI: 10.1016/j.jbior.2018.06.002
• Languages: English
• ISSNs: 2212-4926

Abstract

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.