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Host‐defense peptide mimicry for novel antitumor agents
Author(s) -
Held-Kuznetsov Viktoria,
Rotem Shahar,
Assaraf Yehuda G.,
Mor Amram
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-136358
Subject(s) - peptide , doxorubicin , molecular mimicry , multiple drug resistance , efflux , cancer research , mechanism of action , pharmacology , toxicity , druggability , chemistry , biology , medicine , biochemistry , immunology , chemotherapy , in vitro , antibody , gene , antibiotics , organic chemistry
ABSTRACT 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 α 12 ‐3 β 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 cytotox‐icity against malignant cells, apparently via an intracel‐lular multitarget mode of action, thereby overcoming major modalities of chemoresistance. Both systemic and local administrations of α 12 ‐3 β 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 α 12 ‐3 β 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, V., Rotem, S., Assaraf, Y. G., Mor, A. Host‐defense peptide mimicry for novel antitumor agents. FASEBJ. 23, 4299‐4307 (2009). www.fasebj.org