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Host-defense peptide mimicry for novel antitumor agents

Viktoria Held-Kuznetsov^*, Shahar Rotem^*, Yehuda G. Assaraf and Amram Mor^*,1

^* Department of Biotechnology and Food Engineering and

The Fred Wyszkowski Cancer Research Laboratory, Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel

¹ Correspondence: Department of Biotechnology and Food Engineering, Technion, Haifa 32000, Israel. E-mail: amor{at}tx.technion.ac.il

Although evidence is accumulating for promising anticancer properties of host-defense peptides (HDPs), their potential therapeutic use suffers from limitations inherent to peptide pharmaceuticals, including poor bioavailability and potential toxicity. Therefore, we tested the hypothesis that HDP mimics might generate improved anticancer derivatives. Oligomers of acyl-lysyl (OAKs) varying with respect to charge, hydrophobicity, and backbone length were screened against prostate adenocarcinoma cell line TRAMP-C2 using the XTT assay. A promising 11-mer sequence, designated ₁₂-3β₁₂, was further characterized in terms of selectivity (using human primary fibroblasts and malignant cells), mechanism of action and its relation to multidrug resistance (using 7 ABC multidrug efflux transporters), and antitumor efficacy (as assessed in C57BL/6J mice bearing TRAMP-C2 tumors). The OAK exerted rapid and selective cytotoxicity against malignant cells, apparently via an intracellular multitarget mode of action, thereby overcoming major modalities of chemoresistance. Both systemic and local administrations of ₁₂-3β₁₂ to tumor-bearing mice significantly inhibited tumor progression and were associated with an improved toxicity profile when compared to doxorubicin. Moreover, a combination of ₁₂-3β₁₂ with doxorubicin can lead to tumor eradication. Collectively, the current findings establish the potential of an HDP-mimetic approach for developing simplified yet robust antitumor agents that bear a key advantage of overcoming MDR phenomena. Held-Kuznetsov, V., Rotem, S., Assaraf, Y. G., Mor, A. Host-defense peptide mimicry for novel antitumor agents.

Key Words: antimicrobial peptide • peptide-mimetic • drug design • monotherapy • combination therapy • multidrug resistance