No abstract

Linear arginine‐glycine‐aspartic acid (RGD) and asparagine‐glycine‐arginine (NGR) peptide‐nonsteroidal anti‐inflammatory drug conjugates were synthesized to evaluate their anticancer effect. Two well‐known targeting peptide sequences, RGD and NGR, were conjugated with naproxen and ibuprofen. It is expected that the RGD peptide selectively binds to αv‐integrin receptors, which are highly expressed in cancer cells, and that the NGR peptide selectively targets aminopeptidase N (APN/CD13, EC 3.4.11.2), which is overexpressed in blood vessels of tumors. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six‐carbon linker (hexanoic acid) was also used as a spacer. Cytotoxic effects of the synthesized compounds were evaluated against several cancer cell lines, including MCF‐7, A2780 (αvβ3 positive), OVCAR3 (high αvβ3), HT‐1‐80, and SKOV‐3 cells (CD13 positive). The NGR conjugate forms of both ibuprofen and naproxen showed better activity against the SKOV‐3 tumor cell line. The improved binding of these conjugates to their receptors was confirmed by docking studies.

A simple catalyst-free, and highly regioselective approach to 2-hydroxyalkyl dithiocarbamates is described which involves a one-pot reaction of various amines and carbon disulfide,CS 2 , with epoxides in ethanol at room temperature.

Background: Cancer stem cells (CSCs) play an important role in various stages of cancer development, advancement, and therapy resistance. Ketoprofen-RGD has been revealed to act as an anti-cancer agent against some tumors. Objective: We aimed to explore the effects of a novel Ketoprofen-RGD compound on the suppression of breast cancer stem-like cells (BCSCs) and their parental cells. Methods: Mammospheres were developed from MCF-7 cells and assessed by CSC surface markers through flowcytometry. The antiproliferative and pro-apoptotic activities of Ketoprofen-RGD were measured by MTS assay and flowcytometry. The expression levels of stemness markers and JAK2/STAT proteins were measured by quantitative real time-PCR (qRT-PCR) and western blotting, respectively. Intracellular reactive oxygen species (ROS) was measured using a cell permeable, oxidant-sensitive fluorescence probe (carboxyH2DCFDA). Results: Ketoprofen-RGD significantly reduced the mammosphere formation rate and the expression of three out of six stemness markers and remarkably decreased viability and induced apoptosis of spheroidal and parental cells compared to controls. Further experiments using CD95L, as a death ligand, and ZB4 antibody, as an extrinsic apoptotic pathway blocker, showed that Ketoprofen-RGD induced intrinsic pathway, suggesting a mechanism by which Ketoprofen-RGD triggers apoptosis. ROS production was also another way to induce apoptosis. Results of western blot analysis also revealed a marked diminish in the phosphorylation of JAK2 and STAT proteins. Conclusion: Our study, for the first time, elucidated an anti-BCSC activity for Ketoprofen-RGD via declining stemness markers, inducing toxicity, and apoptosis in these cells and parental cells. These findings may suggest this compound as a promising anti-breast cancer.

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.