calpain-inhibitor-iii and Colorectal-Neoplasms

Several studies have reported that plant-derived natural products have cancer chemopreventive and chemotherapeutic properties. The aim of the present study was to determine the antiproliferative and pro-apoptotic potential of Limoniastrum guyonianum aqueous gall extract (G extract) on human colorectal cancer BE cell line and, if so, to characterize the mechanism involved. The G extract-induced growth inhibitory effect was associated with an arrest of cell cycle progression in G2/M phase as shown by the cell phase distribution. In addition, G extract promoted in a concentration-dependent manner these cells towards apoptosis as indicated by the presence of cleaved poly(ADP-ribose) polymerase (PARP). In order to characterize the mechanism involved in the antiproliferative and pro-apoptotic signaling pathway activated by G extract, calpain activity and the expression of the cell cycle inhibitor p16(INK4A) were determined. The present findings indicated that G extract exhibited significant inhibitory activity against calpain and caused a marked and concentration-dependent upregulation of p16(INK4A). These effects could be ascribed to the presence of condensed tannins and polyphenols such as epicatechin and epigallocatechin gallate in G extract.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Calpain; Cell Cycle; Cell Proliferation; Colorectal Neoplasms; Cyclin-Dependent Kinase Inhibitor p16; Dipeptides; Humans; Plant Extracts; Plumbaginaceae; Poly(ADP-ribose) Polymerases

In this study, we have investigated the effects of luteolin on colorectal cancer cells. Our results demonstrate that luteolin is able to induce cytotoxicity and cell cycle perturbation in a dose-dependent manner. By triggering poly(ADP-ribose) polymerase (PARP) cleavage, this molecule is able to induce the apoptosis of BE colorectal cancer cells. We have also studied the potential involvement of calpains in the proapoptotic effects of luteolin. Our data show that luteolin exhibits moderate inhibitory activity against calpain. Thus, treatment of these cells with both luteolin and the calpain inhibitor MDL 28170 causes an increase in the luteolin-induced apoptosis as proved by the enhancement of 89- and 26-kDa PARP fragments. This effect is concomitant with the downregulation of the DNA methyltransferase 1 (DNMT1) expression and the epigenetic integrator ubiquitin-like containing PHD Finger 1 (UHRF1). As a result, luteolin induces an upregulation of a tumor suppressor gene: p16(INK4A). This study further proposes that calpain might be involved in the epigenetic code inheritance by regulating the epigenetic integrator UHRF1. We conclude from these results that targeting calpain, UHRF1, and DNMT1 using luteolin could be an interesting way to prevent and/or treat colorectal cancers.

Topics: Apoptosis; Calpain; CCAAT-Enhancer-Binding Proteins; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Cyclin-Dependent Kinase Inhibitor p16; Dipeptides; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; Down-Regulation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Luteolin; Poly(ADP-ribose) Polymerases; Ubiquitin-Protein Ligases; Up-Regulation