AUM302, a novel triple kinase PIM/PI3K/ mTOR inhibitor, is a potent in vitro pancreatic cancer growth inhibitor
Public Deposited- Creator
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Ingle K.
- Other Affiliation: Renaissance School of Medicine at Stony Brook University
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LaComb J.F.
- Other Affiliation: Renaissance School of Medicine at Stony Brook University
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Graves L.M.
- Affiliation: School of Medicine, Department of Pharmacology
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Baines A.T.
- Affiliation: School of Medicine, Department of Pharmacology
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Bialkowska A.B.
- Other Affiliation: Renaissance School of Medicine at Stony Brook University
- Abstract
- Pancreatic cancer is one of the leading causes of cancer deaths, with pancreatic ductal adenocarcinoma (PDAC) being the most common subtype. Advanced stage diagnosis of PDAC is common, causing limited treatment opportunities. Gemcitabine is a frequently used chemotherapeutic agent which can be used as a monotherapy or in combination. However, tumors often develop resistance to gemcitabine. Previous studies show that the proto-oncogene PIM kinases (PIM1 and PIM3) are upregulated in PDAC compared to matched normal tissue and are related to chemoresistance and PDAC cell growth. The PIM kinases are also involved in the PI3K/AKT/mTOR pathway to promote cell survival. In this study, we evaluate the effect of the novel multikinase PIM/PI3K/mTOR inhibitor, AUM302, and commercially available PIM inhibitor, TP-3654. Using five human PDAC cell lines, we found AUM302 to be a potent inhibitor of cell proliferation, cell viability, cell cycle progression, and phosphoprotein expression, while TP-3654 was less effective. Significantly, AUM302 had a strong impact on the viability of gemcitabine-resistant PDAC cells. Taken together, these results demonstrate that AUM302 exhibits antitumor activity in human PDAC cells and thus has the potential to be an effective drug for PDAC therapy.
- Date of publication
- 2023
- Keyword
- pancreatic ductal carcinoma
- cell cycle progression
- TOR Serine-Threonine Kinases
- pancreas carcinoma
- PANC-1 cell line
- upregulation
- MIA PaCa-2 cell line
- human cell
- cell viability
- apoptosis
- down regulation
- Antineoplastic Agents
- Cell Proliferation
- Protein Kinase Inhibitors
- Akt signaling
- target of rapamycin kinase
- protein phosphorylation
- Western blotting
- Growth Inhibitors
- BxPC-3 cell line
- Phosphoinositide-3 Kinase Inhibitors
- Capan-2 cell line
- pathology
- phosphatidylinositol 3 kinase inhibitor
- growth inhibitor
- Cell Line, Tumor
- protein kinase inhibitor
- antineoplastic agent
- Pancreatic Carcinoma
- cell cycle G1 phase
- metabolism
- tumor cell line
- IC50
- protein p21
- Carcinoma, Pancreatic Ductal
- cancer growth
- pancreas tumor
- protein expression
- Phosphatidylinositol 3-Kinases
- cancer mortality
- phosphatidylinositol 3 kinase
- antineoplastic activity
- Pancreatic Neoplasms
- Humans
- cell survival
- cell proliferation
- Hs 766T cell line
- Gemcitabine
- pancreas cancer
- mammalian target of rapamycin inhibitor
- Article
- cell cycle G0 phase
- protein kinase Pim 1
- human
- gemcitabine
- cell growth
- Myc protein
- DOI
- Identifier
- Resource type
- Article
- License
- Attribution 4.0 International
- Journal title
- PLoS ONE
- Journal volume
- 18
- Journal issue
- 11-Nov
- Language
- English
- Version
- Publisher
- ISSN
- 1932-6203
- Publisher
- Public Library of Science
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