Research Papers:
PDE5 inhibitors enhance the lethality of [pemetrexed + sorafenib]
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Abstract
Laurence Booth1, Jane L. Roberts1, Andrew Poklepovic2, Paul Dent1
1Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298-0035, USA
2Department of Biochemistry and Medicine, Virginia Commonwealth University, Richmond, VA 23298-0035, USA
Correspondence to:
Paul Dent, email: [email protected]
Keywords: sildenafil, autophagy, pemetrexed, chaperone, lung cancer
Received: November 16, 2016 Accepted: January 02, 2017 Published: January 09, 2017
ABSTRACT
The combination of pemetrexed and sorafenib has significant clinical activity against a wide variety of tumor types in patients and the present studies were performed to determine whether sildenafil enhances the killing potential of [pemetrexed + sorafenib]. In multiple genetically diverse lung cancer cell lines, sildenafil enhanced the lethality of [pemetrexed + sorafenib]. The three-drug combination reduced the activities of AKT, mTOR and STAT transcription factors; increased the activities of eIF2α and ULK-1; lowered the expression of MCL-1, BCL-XL, thioredoxin and SOD2; and increased the expression of Beclin1. Enhanced cell killing by sildenafil was blocked by inhibition of death receptor signaling and autophagosome formation. Enforced activation of STAT3 and AKT or inhibition of JNK significantly reduced cell killing. The enhanced cell killing caused by sildenafil was more reliant on increased PKG signaling than on the generation of nitric oxide. In vivo sildenafil enhanced the anti-tumor properties of [pemetrexed + sorafenib]. Based on our data we argue that additional clinical studies combining pemetrexed, sorafenib and sildenafil are warranted.
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PII: 14562