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2 results on '"Karnthaler-Benbakka C"'

1. Targeting a Targeted Drug: An Approach Toward Hypoxia-Activatable Tyrosine Kinase Inhibitor Prodrugs

Author

Melanie Haider, Claudia Karnthaler-Benbakka, Dina Baier, Diana Groza, Bettina Koblmüller, Walter Berger, Katharina Holste, Bernhard K. Keppler, Christian R. Kowol, Petra Heffeter, Alessio Terenzi, Karnthaler-Benbakka C., Groza D., Koblmuller B., Terenzi A., Holste K., Haider M., Baier D., Berger W., Heffeter P., Kowol C.R., and Keppler B.K.

Subjects
medicine.drug_class, Pharmacology, 010402 general chemistry, 01 natural sciences, Biochemistry, Article, Tyrosine-kinase inhibitor, 03 medical and health sciences, Nitroreductase, 0302 clinical medicine, tyrosine kinase inhibitors, Drug Discovery, medicine, cancer, Epidermal growth factor receptor, General Pharmacology, Toxicology and Pharmaceutics, biology, hypoxia, Sunitinib, Chemistry, Organic Chemistry, Prodrug, targeted therapeutic, 0104 chemical sciences, Settore CHIM/03 - Chimica Generale E Inorganica, Cell culture, 030220 oncology & carcinogenesis, biology.protein, Molecular Medicine, Erlotinib, prodrug, Tyrosine kinase, medicine.drug
Abstract

Tyrosine kinase inhibitors (TKIs), which have revolutionized cancer therapy over the past 15 years, are limited in their clinical application due to serious side effects. Therefore, we converted two approved TKIs (sunitinib and erlotinib) into 2-nitroimidazole-based hypoxia-activatable prodrugs. Kinetics studies showed very different stabilities over 24 h; however, fast reductive activation via E. coli nitroreductase could be confirmed for both panels. The anticancer activity and signaling inhibition of the compounds against various human cancer cell lines were evaluated in cell culture. These data, together with molecular docking simulations, revealed distinct differences in the impact of structural modifications on drug binding to the enzymes: whereas the catalytic pocket of the epidermal growth factor receptor (EGFR) accepted all new erlotinib derivatives, the vascular endothelial growth factor receptor (VEGFR)-inhibitory potential in the case of the sunitinib prodrugs was dramatically diminished by derivatization. In line, hypoxia dependency of ERK signaling inhibition was observed with the sunitinib prodrugs, while oxygen levels had no impact on the activity of the erlotinib derivatives. Overall, proof of principle could be shown for this concept, and the results obtained are an important basis for the future development of tyrosine kinase inhibitor prodrugs.

Published
2016
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2. Synergistic anticancer activity of arsenic trioxide with erlotinib is based on inhibition of EGFR-mediated DNA double-strand break repair.

Author

Kryeziu K, Jungwirth U, Hoda MA, Ferk F, Knasmüller S, Karnthaler-Benbakka C, Kowol CR, Berger W, and Heffeter P

Subjects
Acid Anhydride Hydrolases, Animals, Arsenic Trioxide, BRCA1 Protein biosynthesis, DNA Breaks, Double-Stranded drug effects, DNA Repair drug effects, DNA Repair genetics, DNA Repair Enzymes biosynthesis, DNA-Binding Proteins biosynthesis, Drug Synergism, ErbB Receptors antagonists & inhibitors, ErbB Receptors metabolism, Erlotinib Hydrochloride, Gene Expression Regulation, Neoplastic drug effects, Humans, Mice, Neoplasms drug therapy, Neoplasms pathology, Phosphorylation drug effects, Rad51 Recombinase biosynthesis, Signal Transduction drug effects, Signal Transduction genetics, Xenograft Model Antitumor Assays, Arsenicals pharmacology, ErbB Receptors genetics, Neoplasms genetics, Oxides pharmacology, Quinazolines pharmacology
Abstract

Arsenic trioxide (ATO), one of the oldest remedies used in traditional medicine, was recently rediscovered as an anticancer drug and approved for treatment of relapsed acute promyelocytic leukemia. However, its activity against nonhematologic cancers is rather limited so far. Here, we show that inhibition of ATO-mediated EGF receptor (EGFR) activation can be used to potently sensitize diverse solid cancer types against ATO. Thus, combination of ATO and the EGFR inhibitor erlotinib exerted synergistic activity against multiple cancer cell lines. Subsequent analyses revealed that this effect was based on the blockade of ATO-induced EGFR phosphorylation leading to more pronounced G2-M arrest as well as enhanced and more rapid induction of apoptosis. Comparable ATO-sensitizing effects were also found with PI3K/AKT and mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitors, suggesting an essential role of the EGFR-mediated downstream signaling pathway in cancer cell protection against ATO. H2AX staining and comet assay revealed that erlotinib significantly increases ATO-induced DNA double-strand breaks (DSB) well in accordance with a role of the EGFR signaling axis in DNA damage repair. Indeed, EGFR inhibition led to downregulation of several DNA DSB repair proteins such as Rad51 and Rad50 as well as reduced phosphorylation of BRCA1. Finally, the combination treatment of ATO and erlotinib was also distinctly superior to both monotreatments against the notoriously therapy-resistant human A549 lung cancer and the orthotopic p31 mesothelioma xenograft model in vivo. In conclusion, this study suggests that combination of ATO and EGFR inhibitors is a promising therapeutic strategy against various solid tumors harboring wild-type EGFR., (©2013 AACR)

Published
2013
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