Optimization Of The Anticancer Peptides And Study On Their Action Mechanisms

Nowadays, cancer remains to be a disease with high morbidity and mortality, which makes it number one threaten to human health. Modern cancer treatments usually utilize anticancer drugs of small molecules to kill cancer cells. However, it has many disadvantages such as harmful side effects, limited cell selectivity. Moreover, repeat usage of anticancer drugs often ends up with multi-drug resistance of the cancer cells. As a consequence, researchers are paying more attention to develop novel anticancer drugs for the treatment of cancer.Anticancer peptides are regarded as potential alternative agents for cancer treatment. They could interact with cancer cells through electrostatic attraction, and defy the malignant cells through apoptotic mechanism or cell lysis. Most anticancer peptides are isolated from biological sources, and the sequences can be changed to improve bioactivity. Besides, the designed peptides could be easily synthesized utilizing standard Fmoc solid-phase synthesis method. In this research, a novel anticancer peptide was derived from Mauriporin and named as ZXR-1 (FKIGGFIKKLWRSKLA). ZXR-1 could form well-defined a-helix conformation in hydrophobic environments, and MTT results showed this peptide had a concentration-dependent anticancer activity on Hela, SACC-83, HepG2, HuH-7 and PC-3 (IC50 27.9-141.7μM) cells. More investigation revealed that ZXR-1 could inhibit tumor cell proliferation through both apoptotic and necrotic mechanisms. After analyzing the helical wheel of ZXR-1, we replaced the polar residue lysine at the hydrophobic surface of the peptide with a nonpolar leucine and got peptide ZXR-2 (FKIGGFIKKLWRSLLA). It was found that this sequence mutation led to cytotoxic activity improvement (IC50 7.5-14.2μM). More importantly, the acion mechanism changed to cell lysis, meanwhile the apoptosis mechanism disappeared. Our results suggest that not only the efficiency of anticancer peptide can be improved, but also their acting mechanisms on cancer cells can be changed by simple sequence mutation.