Abstract
Current chemotherapy regimens often include non-specific cytostatic/cytotoxic drugs, which do not distinguish between normal and tumor cells, therefore causing considerable systemic toxicity. We previously reported the synthesis and anti-proliferative activity of a novel synthetic 2-aminothiophene-3-carboxylic acid ester derivative TJ191 that selectively targets certain cancer cells without affecting the proliferation of other cancer cells or normal fibroblasts or immune cells (over 600-fold selectivity). In a panel of ten human T-cell leukemia/lymphoma cell lines and peripheral blood mononuclear cells (PBMCs), we now found that transforming growth factor β type III receptor (TβRIII) expression correlates inversely with TJ191 sensitivity, but not with sensitivity against classical chemotherapeutic drugs, thus serving as a predictive marker for TJ191 sensitivity. Accordingly, CRISPR/Cas9-mediated knock-out of TβRIII partially restored the susceptibility of TJ191-resistant cells to this novel compound. Our findings highlight TJ191 as a potent and selective anti-cancer molecule with pronounced activity against human malignant T-cells expressing low levels of TβRIII.
References
Nov 15, 1991·Cell·X F WangR A Weinberg
Feb 7, 2002·The Journal of Surgical Research·Hisashi ShinoharaNobuhiko Tanigawa
Oct 19, 2002·Oncogene·Xiufen LeiLuZhe Sun
Jun 18, 2003·Cell·Yigong Shi, Joan Massagué
Mar 19, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Rebecca L Elliott, Gerard C Blobe
Jun 24, 2006·Nature Reviews. Cancer·Brian Bierie, Harold L Moses
Aug 18, 2006·Journal of Medicinal Chemistry·Carlos García-AparicioSonsoles Velazquez
Sep 23, 2006·Nature Reviews. Cancer·Robert H Shoemaker
Dec 13, 2006·The Journal of Clinical Investigation·Mei DongGerard C Blobe
Feb 7, 2007·Cancer Research·Ryan S TurleyGerard C Blobe
Jan 5, 2008·Carcinogenesis·Elizabeth C FingerGerard C Blobe
Nov 1, 2008·Cancer Research·Vincent T DeVita, Edward Chu
Feb 22, 2011·Journal of Medicinal Chemistry·Alberto Diez-TorrubiaSonsoles Velázquez
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
Sep 25, 2012·Nature Reviews. Drug Discovery·Rosemary J Akhurst, Akiko Hata
Jun 5, 2013·Investigational New Drugs·J BalzariniR Romagnoli
Sep 26, 2013·Nature Reviews. Cancer·Caitriona HolohanPatrick G Johnston
Sep 23, 2014·ChemMedChem·Joice ThomasWim Dehaen
Oct 8, 2014·Nature Reviews. Clinical Oncology·James H Doroshow, Shivaani Kummar
Feb 28, 2015·Cell·Naoki OshimoriElaine Fuchs
May 26, 2016·Oncotarget·María-Dolores CanelaSandra Liekens
Apr 4, 2017·European Journal of Medicinal Chemistry·Joice ThomasJan Balzarini