TY - JOUR
T1 - Targeting Retinaldehyde Dehydrogenases to Enhance Temozolomide Therapy in Glioblastoma
AU - Jiménez, Rafael
AU - Constantinescu, Andrada
AU - Yazir, Muhube
AU - Alfonso-Triguero, Paula
AU - Pequerul, Raquel
AU - Parés, Xavier
AU - Pérez-Alea, Mileidys
AU - Candiota, Ana Paula
AU - Farrés, Jaume
AU - Lorenzo, Julia
N1 - Publisher Copyright:
© 2024 by the authors.
PY - 2024/10/26
Y1 - 2024/10/26
N2 - Glioblastoma (GB) is an aggressive malignant central nervous system tumor that is currently incurable. One of the main pitfalls of GB treatment is resistance to the chemotherapeutic standard of care, temozolomide (TMZ). The role of aldehyde dehydrogenases (ALDHs) in the glioma stem cell (GSC) subpopulation has been related to chemoresistance. ALDHs take part in processes such as cell proliferation, differentiation, invasiveness or metastasis and have been studied as pharmacological targets in cancer treatment. In the present work, three novel α,β-acetylenic amino thiolester compounds, with demonstrated efficacy as ALDH inhibitors, were tested in vitro on a panel of six human GB cell lines and one murine GB cell line. Firstly, the expression of the ALDH1A isoforms was assessed, and then inhibitors were tested for their cytotoxicity and their ability to inhibit cellular ALDH activity. Drug combination assays with TMZ were performed, as well as an assessment of the cell death mechanism and generation of ROS. A knockout of several ALDH genes was carried out in one of the human GB cell lines, allowing us to discuss their role in cell proliferation, migration capacity and resistance to treatment. Our results strongly suggest that ALDH inhibitors could be an interesting approach in the treatment of GB, with EC50 values in the order of micromolar, decreasing ALDH activity in GB cell lines to 40–50%.
AB - Glioblastoma (GB) is an aggressive malignant central nervous system tumor that is currently incurable. One of the main pitfalls of GB treatment is resistance to the chemotherapeutic standard of care, temozolomide (TMZ). The role of aldehyde dehydrogenases (ALDHs) in the glioma stem cell (GSC) subpopulation has been related to chemoresistance. ALDHs take part in processes such as cell proliferation, differentiation, invasiveness or metastasis and have been studied as pharmacological targets in cancer treatment. In the present work, three novel α,β-acetylenic amino thiolester compounds, with demonstrated efficacy as ALDH inhibitors, were tested in vitro on a panel of six human GB cell lines and one murine GB cell line. Firstly, the expression of the ALDH1A isoforms was assessed, and then inhibitors were tested for their cytotoxicity and their ability to inhibit cellular ALDH activity. Drug combination assays with TMZ were performed, as well as an assessment of the cell death mechanism and generation of ROS. A knockout of several ALDH genes was carried out in one of the human GB cell lines, allowing us to discuss their role in cell proliferation, migration capacity and resistance to treatment. Our results strongly suggest that ALDH inhibitors could be an interesting approach in the treatment of GB, with EC50 values in the order of micromolar, decreasing ALDH activity in GB cell lines to 40–50%.
KW - aldehyde dehydrogenase
KW - cancer
KW - enzyme inhibition
KW - glioblastoma
KW - retinoic acid
UR - http://www.scopus.com/inward/record.url?scp=85208555067&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/1c5a8a60-4890-33cf-abd7-408b47919220/
UR - https://portalrecerca.uab.cat/en/publications/23a6022d-f2d9-4364-aeb0-fa2bef6243de
U2 - 10.3390/ijms252111512
DO - 10.3390/ijms252111512
M3 - Article
C2 - 39519068
AN - SCOPUS:85208555067
SN - 1661-6596
VL - 25
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 21
M1 - 11512
ER -