Combination of mTOR Inhibitors Augments Potency while Activating PI3K Signaling in Pituitary Tumors.

Abstract

BACKGROUND:

Despite the success in treating some cancers, the efficacy of the mTOR inhibitors rapalogs as anti-cancer therapeutics has been limited.

AIMS:

We undertook to examine the effects of Torin1, a second-generation selective ATP-competitive mTOR inhibitor, in non-functioning pituitary tumor cells. During characterization of the molecular mechanisms that mediate Torin1 actions, there seemed to be a rationale for combining it with rapalogs.

METHODS:

Proliferation assays, flow cytometry and Western blotting were applied to assess the effects of Torin1, RAD001 and their combination on an MtT/E pituitary cell line and human-derived non-functioning pituitary tumor cells.

RESULTS:

Combined long treatments of Torin1 and RAD001 induced a pronounced reduction in cell growth and viability of both MtT/E pituitary cells and human-derived non-functioning pituitary tumor cells, superior to each drug alone. This was remarkable in the 10 nM combination and was reflected in a triggered decrease of cyclin D3 and p21/CIP expression. Interestingly, Akt-Thr308 and SIN1-Thr86 phosphorylations were robustly elevated in the combined treatment, accompanied by a reduction in PTEN expression. Phosphorylation of p70S6K was abolished in all individual and combined treatments. Akt-Ser473 phosphorylation, induced by RAD001, was reduced by the combined treatment to the same extent as when treated by Torin1 alone.

CONCLUSIONS:

Our results suggest that the differential signaling mechanisms induced by these compounds eventually converge to lead to an efficient blockade of the PI3K/Akt/mTOR pathway in pituitary tumor cells and may facilitate a reduction in treatment dosage.

• Authors: Hadara Rubinfeld, Ortal Cohen, Adi Kammer, Guang Yang, Zvi R Cohen, Moshe Hadani, Ilan Shimon
• Journal: Neuroendocrinology (Neuroendocrinology) Vol. 103 Issue 5 Pg. 592-604 ( 2016) ISSN: 1423-0194 [Electronic] Switzerland
• PMID: 26562326 (Publication Type: Journal Article)
• Copyright: © 2015 S. Karger AG, Basel.

Chemical References

• 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one
• Antineoplastic Agents
• Naphthyridines
• RNA, Messenger
• Phosphatidylinositol 3-Kinases
• PTEN Phosphohydrolase

Topics

• Adolescent
• Adult
• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols
• Cell Cycle (drug effects)
• Cell Line, Tumor (drug effects)
• Cell Survival (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Naphthyridines (pharmacology)
• PTEN Phosphohydrolase (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphorylation (drug effects)
• Pituitary Neoplasms (pathology)
• RNA, Messenger (metabolism)
• Signal Transduction (drug effects)
• Young Adult