AI Article Synopsis
- The combination of pemetrexed, sorafenib, and sildenafil shows increased effectiveness in killing various cancer cells, particularly in lung cancer.
- Sildenafil enhances the lethality of the two drugs by altering key signaling pathways related to cell survival and death.
- In animal studies, sildenafil also boosted the anti-tumor effects of the combination, suggesting that further clinical research is needed for this combination treatment.
Article 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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355112 | PMC |
| http://dx.doi.org/10.18632/oncotarget.14562 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Autophagy as a therapeutic mechanism to kill drug-resistant cancer cells.
Anticancer Drugs
February 2024
Department of Biochemistry and Molecular Biology.
Herein we discuss multiple pre-clinical projects developed by our group that have been translated into patients at Massey Cancer Center. Our work has used multi-kinase inhibitors, for example, sorafenib, regorafenib and neratinib, and combined with additional agents, for example, histone deacetylase inhibitors, the thymidylate synthase inhibitor pemetrexed, and PDE5 inhibitors. In broad-brush terms, our experience has been that these drug combinations enhance signaling by ATM-AMPK-ULK-1 and decrease signaling from growth factor receptors and RAS proteins, thereby lowering the activities of the intracellular signaling kinase ERK1/2, AKT, mTOR and p70 S6K .
View Article and Find Full Text PDFThe budget impact of adding pralsetinib to a US health plan formulary for treatment of non-small cell lung cancer and thyroid cancer with alterations.
J Manag Care Spec Pharm
February 2022
Blueprint Medicines Corporation, Cambridge, MA.
Lung cancer is the leading cause of cancer death in the United States. Non-small cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancers. Thyroid cancer, while generally not as lethal as lung cancer, has a large prevalent population and a rapidly increasing incidence in the United States.
View Article and Find Full Text PDFNovel Multitarget Therapies for Lung Cancer and Respiratory Disease.
Molecules
September 2020
Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
In recent years, multitarget drugs for neurological diseases such as Alzheimer's disease have been developed and well researched. Many studies have revealed that multitarget drugs are also useful for lung cancer and respiratory diseases. Pemetrexed is a multitargeted antifolate with strong antitumor activity against mesothelioma and lung adenocarcinoma.
View Article and Find Full Text PDFTRAIL in oncology: From recombinant TRAIL to nano- and self-targeted TRAIL-based therapies.
Pharmacol Res
May 2020
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address:
TNF-related apoptosis-inducing ligand (TRAIL) selectively induces the apoptosis pathway in tumor cells leading to tumor cell death. Because TRAIL induction can kill tumor cells, cancer researchers have developed many agents to target TRAIL and some of these agents have entered clinical trials in oncology. Unfortunately, these trials have failed for many reasons, including drug resistance, off-target toxicities, short half-life, and specifically in gene therapy due to the limited uptake of TRAIL genes by cancer cells.
View Article and Find Full Text PDFNot the comfy chair! Cancer drugs that act against multiple active sites.
Expert Opin Ther Targets
November 2019
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA.
: Discoveries of novel signal transduction pathways in the 1990s stimulated drug companies to develop small molecule tyrosine kinase and serine / threonine kinase inhibitors which were based on catalytic site inhibition. All kinases bind ATP and catalyze phosphate transfer and, therefore, inhibitors that block ATP binding and its metabolism would be predicted to have a known on-target specificity but were also likely to have many unknown or unrecognized targets due to similarities in all ATP binding pockets. This on-target off-target biology of kinase inhibitors, which exhibit a "signal" in the clinic, means that therapeutically valuable agents are acting through unknown biological processes to mediate their anti-tumor effects.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!