Host-defense peptide mimicry for novel antitumor agents.
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 alpha(12)-3beta(12), 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 alpha(12)-3beta(12) to tumor-bearing mice significantly inhibited tumor progression and were associated with an improved toxicity profile when compared to doxorubicin. Moreover, a combination of alpha(12)-3beta(12) 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
Viktoria
V
Department of Biotechnology and Food Engineering, Technion, Haifa 32000, Israel.
Rotem
Shahar
S
Assaraf
Yehuda G
YG
Mor
Amram
A
D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D006224:Cricetinae; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000188:drug therapy; D051381:Rats
D000970:Antineoplastic Agents; D004317:Doxorubicin