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Targeting aldehyde dehydrogenase activity in head and neck squamous cell carcinoma with a novel small molecule inhibitor
Stanford University, CA 94305 USA.
Stanford University, CA 94305 USA.
Stanford University, CA 94305 USA.
Stanford University, CA 94305 USA.
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 32, p. 52345-52356Article in journal (Refereed) Published
Abstract [en]

Chemoresistant cancer cells express high levels of aldehyde dehydrogenases (ALDHs), particularly in head and neck squamous cell carcinoma (HNSCC). The ALDH family of enzymes detoxify both exogenous and endogenous aldehydes. Since many chemotherapeutic agents, such as cisplatin, result in the generation of cytotoxic aldehydes and oxidative stress, we hypothesized that cells expressing high levels of ALDH may be more chemoresistant due to their increased detoxifying capacity and that inhibitors of ALDHs may sensitize them to these drugs. Here, we show that overall ALDH activity is increased with cisplatin treatment of HNSCC and that ALDH3A1 protein expression is particularly enriched in cells treated with cisplatin. Activation of ALDH3A1 by a small molecule activator (Alda-89) increased survival of HNSCC cells treated with cisplatin. Conversely, treatment with a novel small molecule ALDH inhibitor (Aldi-6) resulted in a marked decrease in cell viability, and the combination of Aldi-6 and cisplatin resulted in a more pronounced reduction of cell viability and a greater reduction in tumor burden in vivo than what was observed with cisplatin alone. These data indicate that ALDH3A1 contributes to cisplatin resistance in HNSCC and that the targeting of ALDH, specifically, ALDH3A1, appears to be a promising strategy in this disease.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC , 2017. Vol. 8, no 32, p. 52345-52356
Keywords [en]
aldehyde dehydrogenase; chemoresistance; head and neck squamous cell carcinoma; small molecule inhibitors
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-140048DOI: 10.18632/oncotarget.17017ISI: 000407124100027OAI: oai:DiVA.org:liu-140048DiVA, id: diva2:1136612
Note

Funding Agencies|NIH [DE024402, NIAAA11147, T32 CA09151]; Developmental Cancer Research Grant for Translational Medicine from the Stanford Cancer Institute

Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2018-01-13

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Farnebo, Lovisa
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Division of Speech language pathology, Audiology and OtorhinolaryngologyFaculty of Medicine and Health SciencesDepartment of Otorhinolaryngology in Linköping
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