Research Papers:

Targeting aldehyde dehydrogenase activity in head and neck squamous cell carcinoma with a novel small molecule inhibitor

Jeewon Kim, June Ho Shin, Che-Hong Chen, Leslie Cruz, Lovisa Farnebo, Jieying Yang, Paula Borges, Gugene Kang, Daria Mochly-Rosen and John B. Sunwoo _

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Oncotarget. 2017; 8:52345-52356. https://doi.org/10.18632/oncotarget.17017

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Jeewon Kim1, June Ho Shin1,2, Che-Hong Chen3, Leslie Cruz3, Lovisa Farnebo2,4, Jieying Yang1, Paula Borges2, Gugene Kang5, Daria Mochly-Rosen3 and John B. Sunwoo1,2

1Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, CA, 94305, USA

2Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University, Stanford, CA, 94305, USA

3Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA, 94305, USA

4Division of Otorhinolaryngology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-58185, Linköping, Sweden

5Department of Developmental Biology, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA

Correspondence to:

John B. Sunwoo, email: sunwoo@stanford.edu

Keywords: aldehyde dehydrogenase, chemoresistance, head and neck squamous cell carcinoma, small molecule inhibitors

Received: September 28, 2015     Accepted: March 30, 2017     Published: April 10, 2017


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.

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