|Ph.D Student||Held-Kuznetsov Viktoria|
|Subject||Antitumoral Properties of Peptido-Mimetic Library:|
Functional and Mechanistic Characterization
|Department||Department of Biotechnology and Food Engineering||Supervisor||Professor Amram Mor|
|Full Thesis text|
cancer continues to pose major obstacles stressing the need for novel antitumor
agents that can evade mechanisms of multidrug resistance (MDR).
While evidence is accumulating for the anticancer properties of host defense peptides (HDPs) their systemic use is presently prohibited due to various limitations inherent to peptide-pharmaceuticals.
This study aims to test the hypothesis that HDP-mimics, oligomers of acyl-lysyl (OAKs), previously reported to generate improved antimicrobials, might generate novel anticancer derivatives.
For this purpose, various members of the OAK library were screened against cancer and normal cells. Analysis of the structure activity relationships revealed important trends for selective anticancer activity of OAKs. Then, a promising representative designated α12-3b12 was selected for further characterization. Focusing on the murine prostate adenocarcinoma cell line, TRAMP-C2, activity of the OAK was explored in terms of in-vitro characteristics including selectivity, the mode of action and its relation to MDR. Afterwards, its in vivo properties were investigated in terms of toxicity, pharmacokinetics and antitumor efficacy in order to assess its potential local and systemic use as a single agent or in combination with doxorubicin.
The in-vitro data provided evidence for the OAKs ability to generate novel compounds that exert selective cytotoxicity against malignant cells, apparently by an intracellular multi-target mode of action that overcame major modalities of chemoresistance. In addition, both systemic and local administrations of α12-3β12 significantly inhibited tumor progression in mice and were associated with an improved toxicity profile when compared to doxorubicin. Moreover, a combination of α12-3β12 with doxorubicin demonstrated a potential for 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.