PDE5 inhibitors enhance the lethality of [pemetrexed + sorafenib]
Laurence Booth1, Jane L Roberts1, Andrew Poklepovic2
1Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298-0035, USA.
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.
Insights
Sildenafil enhances the cancer-killing effects of pemetrexed and sorafenib in lung cancer models. This three-drug combination shows promise for future clinical studies in cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Pemetrexed and sorafenib demonstrate clinical activity in various cancers.
- The potential of sildenafil to augment this combination therapy requires investigation.
Purpose of the Study:
- To determine if sildenafil enhances the cytotoxic effects of pemetrexed and sorafenib.
- To elucidate the molecular mechanisms underlying the enhanced cell killing.
Main Methods:
- In vitro studies using diverse lung cancer cell lines.
- In vivo xenograft models.
- Analysis of key signaling pathways (AKT, mTOR, STAT, JNK) and protein expression (MCL-1, BCL-XL, Beclin1).
Main Results:
- Sildenafil significantly enhanced the lethality of pemetrexed + sorafenib in vitro and anti-tumor activity in vivo.
- The combination modulated signaling pathways and protein expression, including increased autophagy markers.
- Enhanced cell killing was dependent on death receptor signaling, autophagosome formation, and PKG signaling.
Conclusions:
- Sildenafil potentiates the anti-cancer effects of pemetrexed and sorafenib through complex molecular mechanisms.
- The combination therapy warrants further clinical investigation for cancer treatment.
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