kla-peptide and Prostatic-Neoplasms

Prostate cancer is the most common cancer in the Western world. A bi-functional peptide was combined with wingless-related integration site (WNT) inhibitors to determine if there is an additive therapeutic effect when they are used against prostate cancer, since their efficacy has already been proven when used alone.. A bi-functional peptide (TP-LYT) was designed with a target domain (LTVSPWY) and a lytic domain (KLAKLAK). A synergistic effect of peptides and WNT inhibitors was demonstrated, increasing the toxicity against cancer cells.. Our findings potentially allow safer treatment since lower concentrations of WNT inhibitors can be used in combination with this bi-functional peptide.

Topics: Antineoplastic Combined Chemotherapy Protocols; Ciclopirox; Drug Synergism; Ethacrynic Acid; Humans; Intercellular Signaling Peptides and Proteins; Male; Molecular Targeted Therapy; Oligopeptides; Peptides; Prostatic Neoplasms; Protein Domains; Pyridones; Wnt Proteins

Tumor Necrosis Factor-alpha Related Apoptosis Inducing Ligand (TRAIL) and agonistic antibodies to death receptors (DR) 4 and 5 have attracted significant attention in recent years due to their ability to selectively induce apoptosis in malignant cells while demonstrating little cytotoxicity in normal cells. Although these candidates are promising in cancer therapy, a number of tumor cells are resistant to TRAIL-mediated apoptosis. We describe the use of a cationic amphipathic lytic peptide, KLA (single letter sequence HHHHHKLAKLAKKLAKLAKC), for the chemosensitization of TRAIL-resistant LNCaP and PC3-PSMA human prostate cancer cells to DR agonistic antibodies. 'Single-agent' treatment with DR agonistic antibodies did not result in loss of viability of these cells confirming the resistance of these cells. However, the combination treatment of KLA followed by DR agonists resulted in greater cell death compared to the individual treatments acting alone, indicating synergistic action between the two components of the combination treatment. The combination of lytic peptide and DR agonists resulted in a significant increase in activated caspase-3 cleavage and cytochrome-C protein levels in cells, indicating a role for the caspase-mediated apoptotic pathway. In addition, KLA treatment also resulted in increased localization of DR5 and lipid rafts in LNCaP cells. Our results demonstrate, for the first time, that lytic peptides can be employed for sensitizing TRAIL-resistant prostate cancer cells to DR-mediated apoptosis resulting in novel combination treatments for the ablation of advanced cancer cells.

Topics: Antineoplastic Agents; Apoptosis; Caspase 3; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Intercellular Signaling Peptides and Proteins; Male; Peptides; Prostatic Neoplasms; Receptors, Death Domain; TNF-Related Apoptosis-Inducing Ligand