Abstract
The present studies focused on the ability of the phosphodiesterase 5 (PDE5) inhibitor sildenafil to enhance the anti-cancer properties of clinically relevant concentrations of the dietary diarylheptanoid curcumin. In gastrointestinal tumor cells, sildenafil and curcumin interacted in a greater than additive fashion to kill. Inhibition of the extrinsic apoptotic pathway suppressed killing by ∼50%, as did blockade of the intrinsic apoptotic pathway. Sildenafil and curcumin reduced mTORC1 and mTORC2 activity and increased Beclin1 levels and the numbers of autophagosomes and autolysosomes in cells in a PERK-eIF2α-dependent fashion. Knock down of Beclin1 or ATG5 partially suppressed killing. In contrast, stable knock out of ATG16-L1 unexpectedly enhanced killing, an effect not altered by Beclin1/ATG5 knock down. Curcumin and sildenafil exposure reduced the expression of MCL-1, BCL-XL, thioredoxin and superoxide dismutase 2 (SOD2) in an eIF2α-dependent fashion. Curcumin and sildenafil interacted in a greater than additive fashion to increase the levels of reactive oxygen species; knock down of thioredoxin or SOD2 enhanced killing and over-expression of thioredoxin or SOD2 suppressed killing. In vivo, curcumin and sildenafil interacted to suppress the growth of colon cancer tumors. Multiplex analyses of plasma taken after drug exposure at animal nadir indicated that the levels of M-CSF, CXCL-9, PDGF and G-CSF were significantly increased by [curcumin + sildenafil] and that expression of CXCL1 and CCL5 were significantly reduced. Cells isolated from in vivo treated [curcumin + sildenafil] tumors were resistant to in vitro [curcumin + sildenafil] exposure, a phenotype that was blocked by the colon cancer therapeutic regorafenib.
Highlights
Prior studies have demonstrated that phosphodiesterase 5 (PDE5) inhibitors such as sildenafil enhance the anti-cancer properties of the NSAID celecoxib [1]
Curcumin interacted with the PDE5 inhibitor sildenafil or with the NSAID celecoxib to kill multiple GI tumor cell lines within 24h (Figures 1A-1B and Supplementary Figure 1)
In colony formation assays, a 24h exposure to curcumin significantly reduced the clonogenicity of liver and colon cancer cells that was itself significantly enhanced by combined exposure with sildenafil (Figure 1D)
Summary
Prior studies have demonstrated that phosphodiesterase 5 (PDE5) inhibitors such as sildenafil enhance the anti-cancer properties of the NSAID celecoxib [1]. PDE5 inhibitors enhance killing by a derivative of celecoxib which does not inhibit COX2, OSU-03012 [2, 3]. Ourselves and others have shown that PDE5 inhibitors have anti-cancer properties in combination with multi-kinase inhibitors and can enhance the lethality of standard of care chemotherapeutic agents such as doxorubicin or cisplatin; two clinical trials using sildenafil in combination with other drugs are presently open at VCU Massey Cancer Center (NCT02466802; NCT01817751) [4,5,6,7,8]. PDE5 catalyzes the degradation of cyclic GMP (cGMP); cGMP acts to cause activation of protein kinase G (PKG). PKG signaling in a cell-type dependent fashion, via activation of the ERK1/2, p38 MAPK, JNK1/2 and NFκB pathways, enhances inducible nitric oxide synthase (iNOS)
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