Oncotarget

Research Papers:

Galeterone and its analogs inhibit Mnk-eIF4E axis, synergize with gemcitabine, impede pancreatic cancer cell migration, invasion and proliferation and inhibit tumor growth in mice

Andrew K. Kwegyir-Afful, Francis N. Murigi, Puranik Purushottamachar, Vidya P. Ramamurthy, Marlena S. Martin and Vincent C.O. Njar _

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Oncotarget. 2017; 8:52381-52402. https://doi.org/10.18632/oncotarget.14154

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Abstract

Andrew K. Kwegyir-Afful1,2, Francis N. Murigi1,2, Puranik Purushottamachar1,2, Vidya P. Ramamurthy1,2, Marlena S. Martin1,2,4 and Vincent C.O. Njar1,2,3

1Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA

2Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA

3Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA

4Current Address: Bernard J. Dunn School of Pharmacy, Shenandoah University, Ashburn, VA 20147, USA

Correspondence to:

Vincent C.O. Njar, email: vnjar@som.umaryland.edu

Keywords: pancreatic cancer resistance, galeterone (gal) and its analogs

Received: June 30, 2016    Accepted: November 19, 2016    Published: December 24, 2016

ABSTRACT

Survival rate for pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is poor, with about 80% of patients presenting with the metastatic disease. Gemcitabine, the standard chemotherapeutic agent for locally advanced and metastatic PDAC has limited efficacy, attributed to innate/acquired resistance and activation of pro-survival pathways. The Mnk1/2-eIF4E and NF-κB signaling pathways are implicated in PDAC disease progression/metastasis and also associated with gemcitabine-induced resistance in PDAC. Galeterone (gal), a multi-target, agent in phase III clinical development for prostate cancer has also shown effects on the aforementioned pathways. We show for the first time, that gal/analogs (VNPT55, VNPP414 and VNPP433-3β) profoundly inhibited cell viability of gemcitabine-naive/resistance PDAC cell lines and strongly synergized with gemcitabine in gemcitabine-resistant PDAC cells. In addition, to inducing G1 cell cycle arrest, gal/analogs induced caspase 3-mediated cell-death of PDAC cells. Gal/analogs caused profound downregulation of Mnk1/2, peIF4E and NF-κB (p-p65), metastatic inducing factors (N-cadherin, MMP-1/-2/-9, Slug, Snail and CXCR4) and putative stem cell factors, (β-Catenin, Nanog, BMI-1 and Oct-4). Gal/analog also depleted EZH2 and upregulated E-Cadherin. These effects resulted in significant inhibition of PDAC cell migration, invasion and proliferation. Importantly, we also observed strong MiaPaca-2 tumor xenograft growth inhibition (61% to 92%). Collectively, these promising findings strongly support further development of gal/analogs as novel therapeutics for PDAC.


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