Anti-Cancer Potential of a new Derivative of Caffeic Acid Phenethyl Ester targeting the Centrosome
Catello Giordano,
Jonatan Kendler,
Maximilian Sexl,
Sebastian Kollman,
Maxim Varenicja,
Boglárka Szabó,
Gerald Timelthaler,
Dominik Kirchhofer,
Oldamur Hollóczki,
Suzanne D. Turner,
Richard Moriggl,
Lukas Kenner,
Mohamed Touaibia,
Olaf Merkel
Affiliations
Catello Giordano
Department of Pathology, Medical University of Vienna, Vienna, Austria
Jonatan Kendler
Department of Biological Sciences and Pathobiology, Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
Maximilian Sexl
Department of Biological Sciences and Pathobiology, Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
Sebastian Kollman
Department of Biological Sciences and Pathobiology, Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
Maxim Varenicja
Department of Physical Chemistry, University of Debrecen, Debrecen, Hungary
Boglárka Szabó
Department of Physical Chemistry, University of Debrecen, Debrecen, Hungary
Gerald Timelthaler
Center for Cancer Research, Medical University of Vienna, Vienna, Austria
Dominik Kirchhofer
Center for Cancer Research, Medical University of Vienna, Vienna, Austria
Oldamur Hollóczki
Department of Physical Chemistry, University of Debrecen, Debrecen, Hungary
Suzanne D. Turner
European Research Initiative on ALK-Related Malignancies (ERIA), Cambridge, UK; Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; Faculty of Medicine, Masaryk University, Brno, Czech Republic
Richard Moriggl
Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Salzburg, Austria
Lukas Kenner
Department of Pathology, Medical University of Vienna, Vienna, Austria; European Research Initiative on ALK-Related Malignancies (ERIA), Cambridge, UK; Christian Doppler Laboratory (CDL) for Applied Metabolomics, Medical University of Vienna, Vienna, Austria; Unit of Laboratory Animal Pathology, University of Veterinary Medicine, Vienna, Austria; Center for Biomarker Research in Medicine (CBMed) Core Lab 2, Medical University of Vienna, Vienna, Austria; Department of Molecular Biology, Umeå University, Umeå, Sweden
Mohamed Touaibia
Chemistry and Biochemistry Department, Université de Moncton, Moncton, New Brunswick, Canada; Corresponding author. Chemistry and Biochemistry Department, Université de Moncton, Moncton, New Brunswick, Canada.
Olaf Merkel
Department of Pathology, Medical University of Vienna, Vienna, Austria; European Research Initiative on ALK-Related Malignancies (ERIA), Cambridge, UK; Corresponding author. Department of Pathology, Medical University of Vienna, Vienna, Austria.
Anaplastic Large Cell Lymphoma (ALCL) is an aggressive T-cell lymphoma affecting children and young adults. About 30% of patients develop therapy resistance therefore new precision medicine drugs are highly warranted. Multiple rounds of structure-activity optimization of Caffeic Acid Phenethyl Ester have resulted in CM14. CM14 causes upregulation of genes involved in oxidative stress response and downregulation of DNA replication genes leading to G2/M arrest and subsequent apoptosis induction. In accordance with this, an unbiased proteomics approach, confocal microscopy and molecular modeling showed that TUBGCP2, member of the centrosomal γ-TuRC complex, is a direct interaction partner of CM14. CM14 overcomes ALK inhibitor resistance in ALCL and is also active in T-cell Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia. Interestingly, CM14 also induced cell death in docetaxel-resistant prostate cancer cells thus suggesting an unexpected role in solid cancers. Thus, we synthesized and thoroughly characterized a novel TUBGCP2 targeting drug that is active in ALCL but has also potential for other malignancies.
