Anti-Breast Cancer Activities of Ketoprofen-RGD Conjugate by Targeting Breast Cancer Stem-Like Cells and Parental Cells

Abstract

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.

Co-treatment of Naringenin and Ketoprofen-RGD Suppresses Cell Proliferation via Calmodulin/PDE/cAMP/PKA Axis Pathway in Leukemia and Ovarian Cancer Cells

“…PDE1 inhibitors have been unraveled as targeted anticancer agents that can suppress the growth of cancer cells with no harmful effect on normal cells ( 26 ). Our previous investigation showed that ketoprofen-RGD could be considered a promising anticancer agent with pro-apoptotic properties against breast cancer cells ( 18 ).…”

“…Then, the cells were treated with ketoprofen-RGD (3 μM) alone and in combination with Nar (50 μM). The cells were exposed to forskolin (FSK, 0.5 μM) as a standard anti-inflammatory agent ( 18 ). Subsequently, the ELISA method was used to measure the levels of some pro-inflammatory cytokines.…”

“…However, there is limited information on its effectiveness in treating other types of cancer or its potential as a cancer treatment. Ketoprofen-RGD has shown promising anticancer properties, particularly in breast cancer stem-like cells (BCSCs) and their parental cells ( 18 ).…”

Naringenin Enhances Anti-Proliferation Effect of FMSP On K562 Human Chronic Myelogenous Leukemia Cells Via Targeting Calmodulin Signaling Pathway

“…Previous studies have indicated that plant-derived phytochemicals have signi cant ant-cancer activities both alone or in combination with synthetic compounds [13,14]. Results of our previous investigation showed that 1-ferrocenyl-3-(4-methylsulfonylphenyl)propen-1-one (FMSP, Fig.…”

Single-Cell Proteomic Profiling Identifies Nanoparticle Enhanced Therapy for Triple Negative Breast Cancer Stem Cells

“…Integrin αvβ3 strongly binds to the arginine-glycine-aspartic acid (RGD) tripeptide sequence; therefore, RGD peptides can be used as drug or drug delivery tools in treating integrin αvβ3 expressing tumors and tumor vasculature cells [ 15 , 16 ]. Combining RGD peptides with nanotechnology could preferentially inhibit tumor tissues in a targeted manner without affecting normal tissues.…”