co-treatment of naringenin and ketoprofen-rgd suppresses cell proliferation via calmodulin/pde/camp/pka axis pathway in leukemia and ovarian cancer cells

Background: naringenin (nar) has anti-inflammatory and anticarcinogenic properties. arginine-glycine- aspartate (rgd) is a tripeptidic sequence used as an integrin ligand and targeting system for delivering chemotherapeutic agents to cancer cells. objectives: in this study, the inhibitory effects of nar and ketoprofen-rgd on leukemia and ovarian cancer cells (k562 and skov3) were explored for the first time, focusing on their proliferation activity and their anti-inflammatory capacity. methods: analyses were conducted on the calmodulin (cam)-dependent phosphodiesterase 1 (pde1) activation by ketoprofen-rgd, nar, and their combination. these drugs’ effects on protein kinase a (pka) activation, intracellular cyclic adenosine monophosphate (camp) level, and pde1 inhibition were identified. later, it was also evaluated if ketoprofen-rgd alone or in combination with nar had anti-inflammatory effects. results: nar improved the antagonizing consequences of ketoprofen-rgd on the cam protein, which hinders pde1, improving pka activity and camp levels. a mixture of ketoprofen-rgd and nar and ketoprofen-rgd alone diminished k562 and skov3 cell viability through the camp/pka pathway by inhibiting pde1 and cam. these two compounds showed anti-inflammatory effects on both cell lines. conclusions: this study indicated for the first time that combining ketoprofen-rgd and nar can be a promising anti-inflammatory therapeutic regimen for treating leukemia and ovarian cancer.