[pemetrexed + sildenafil], via autophagy-dependent HDAC downregulation, enhances the immunotherapy response of NSCLC cells.

Article Details

Citation

Booth L, Roberts JL, Poklepovic A, Dent P

[pemetrexed + sildenafil], via autophagy-dependent HDAC downregulation, enhances the immunotherapy response of NSCLC cells.

Cancer Biol Ther. 2017 Sep 2;18(9):705-714. doi: 10.1080/15384047.2017.1362511.

PubMed ID
28812434 [ View in PubMed
]
Abstract

Pemetrexed is an approved therapeutic in NSCLC and ovarian cancer. Our studies focused on the ability of [pemetrexed + sildenafil] exposure to alter the immunogenicity of lung and ovarian cancer cells. Treatment of lung and ovarian cancer cells with [pemetrexed + sildenafil] in vitro rapidly reduced the expression of PD-L1, PD-L2 and ornithine decarboxylase (ODC), and increased the expression of class I MHCA. In a cell-specific fashion, some cells also released the immunogenic nuclear protein HMGB1 into the extracellular environment. [Pemetrexed + sildenafil] reduced the expression of multiple histone deacetylases that was blocked by knock down of autophagy regulatory proteins. [Pemetrexed + sildenafil] lethality was enhanced by the histone deacetylase inhibitors AR42 and sodium valproate; AR42 and valproate as single agents also rapidly reduced the expression of PD-L1, PD-L2 and ODC, and increased expression of MHCA and CerS6. Nitric oxide and CerS6 signaling was required for drug-induced death receptor activation and tumor cell killing. In vivo, [pemetrexed + sildenafil] lethality against lung cancer cells was enhanced by sodium valproate. Using syngeneic mouse lung cancer cells [pemetrexed + sildenafil] enhanced the anti-tumor effects of antibodies directed to inhibit PD-1 or CTLA4. [Pemetrexed + sildenafil] interacted with the anti-PD-1 antibody to strongly enhance tumor infiltration by M1 macrophages; activated NK cells and activated T cells. Our data demonstrate that treatment of tumor cells with [pemetrexed + sildenafil] results in tumor cell killing and via autophagy-dependent downregulation of HDACs, it opsonizes the remaining tumor cells to anti-tumor immunotherapy antibodies.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
SildenafilOrnithine decarboxylaseProteinHumans
Unknown
Downregulator
Details
SildenafilProgrammed cell death 1 ligand 1ProteinHumans
Unknown
Downregulator
Details
Valproic acidHistone deacetylase (Protein Group)Protein groupHumans
Unknown
Inhibitor
Details
Valproic acidOrnithine decarboxylaseProteinHumans
Unknown
Downregulator
Details
Valproic acidProgrammed cell death 1 ligand 1ProteinHumans
Unknown
Downregulator
Details