Abstract
3164 Background: Components of the extracellular matrix (ECM), especially collagens, are involved in tumor cell development, proliferation and dissemination and therefore represent a potential target for tumor therapy. The ECM-associated proline-rich structures are susceptible to suitable toxic proline analogs, which disrupt protein assembly and functions. Methods: An extensive panel of proline analogs (lead compound: cis-4-hydroxy-L-proline; CHP) and the collagen inhibitor L-azetidine-2-carboxylic acid were tested for cytotoxicity against a large panel of cell lines. In addition to a tetrazolium-based assay (MTT), cell cycle analysis (propidium iodide) and apoptosis assays (annexin V) were performed. Amino acid uptake was studied using radioactive proline and differentiation was assessed by measuring induction of alkaline phosphatase (ALP). Results: Antiproliferative activity of CHP was found in cell lines derived from colon carcinomas, pancreatic, prostatic, and breast cancer as well as osteosarcoma and glioma (IC50: 35 - 175 μg/ml) and increased activity was detected under acidic extracellular conditions prevailing in solid tumors. Cell cycle arrest was found preferentially in G2M and apoptotic cells were detectable following prolonged exposure (7 - 10 days). CHP treatment of 2 colon carcinoma cell lines (HT29, CaCo-2) resulted in induction of the differentiation marker ALP. Proline competition tests indicated uptake of CHP via alpha-(methylamino)-isobutyric acid (MeAIB)-sensitive amino acid transport. Extensive testing of other cytotoxic proline-related compounds led to the characterization of N-methylated CHP derivatives, which show no interference with transport of proline, and proved to be capable of enhancing the CHP-induced toxicity by up to 30 %. Conclusions: Highly efficient proline analogs in combination exhibit considerable toxicity in vitro against diverse cell lines and should be studied in extended clinical CHP trials as agents modulating tumor cell growth by targeting ECM and/or critical proline residues of tumor-associated proteins. No significant financial relationships to disclose.
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