Although new chemotherapeutic agents are improving the survival rate of cancer patients, all of them have serious toxic side effects. Thus, it is still necessary to search for new agents with minimal side effects or to enhance the effectiveness of known cytotoxic agents at a reduced dose. The modification of peptides by adding myristol group is commonly used to facilitate intracellular delivery. It has been shown recently that the combination of myristoylation and the cationic charge of peptide confer new biological activity to the peptide. We examined the possibility of using such peptides for the treatment of cancer. In present studies, we evaluated the effect of two N-myristoylated cationic peptides (myrCP) on several human cancer cell lines: H1299 (lung), MCF7 (breast), and PC3 (prostate). The first peptide mimics the endogenous Protein kinase C (PKC) pseudosubstrate region and it is considered as a selective inhibitor of PKC (myr-SIYRRGARRWRKL-OH). This peptide has a dual effect on cancer cells as it prevents proliferation by inhibiting PKC and also serves as a cytotoxic agent. The second peptide that is a scrambled version of the first peptide (myr-RLYRKRIWRSAGR-OH) was used as a control to ensure that cytotoxic effect is not only dependent on PKC inhibition. We found that both myrCP had superior cytotoxic effect on cancer cells. Moreover, they dramatically enhanced the activity of commonly used chemotherapeutic agents such as mitoxantrone and cisplatin which were active in combination with peptides at significantly lower concentration. Since the lipophilic nature of myristoylation facilitates penetration of these peptides across cell membranes, we analyzed what lipids can be involved in such interaction. Membrane lipid arrays showed that myrCP preferably binds to PtdIns (3, 4, 5) P3, phosphatidic acid and at less extent to PI (4, 5) P2. Our results suggested that lipid membrane composition of cells could play an essential role in efficacy of myrCP. In summary, the potential outcome of the current studies will be the development of a useful therapeutic tool for efficient killing of tumor cells. Considering that cytotoxic effects of myrCP are non-specific to the type of cancer, a similar strategy can be applied for many different malignancies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B248.
Citation Format: Karina Krotova, George Aslanidi. Antitumor activity mediated by N-myristoylated cationic peptides (myrCP). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B248.