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.