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Targeting ALDH1 to decrease tumorigenicity, growth and metastasis of human melanoma

Yue, Lilia,c; Huang, Zhi-Minga,c; Fong, Stephenc; Leong, Stanleyb; Jakowatz, James G.d; Charruyer-Reinwald, Alexa,c; Wei, Mariaa,c; Ghadially, Rubya,c

doi: 10.1097/CMR.0000000000000144
ORIGINAL ARTICLES: Translational research

Cells with aldehyde dehydrogenase activity (ALDH+) are the most tumorigenic cells in many cancers, including melanoma, making ALDH a candidate therapeutic target. We examined the effects of chemical inhibition of ALDH1 on the response of human melanoma xenografts to chemotherapy and the effects of ALDH1A1 RNA silencing on melanoma growth and metastasis. Addition of ALDH1 inhibitors (e.g. diethylaminobenzaldehyde) to dacarbazine chemotherapy, not only reduced tumor growth in vivo, but also resulted in a significant decrease in the number of residual cells capable of tumorigenesis. shRNA depletion of ALDH1A1 in melanoma cells resulted not only in a significant delay in appearance of xenograft melanomas and reduction in growth, but also significantly decreased the number of metastases and metastatic burden after lateral tail vein injections in mice. In summary, ALDH1 inhibition in combinatorial therapy with dacarbazine reduced the number of residual tumorigenic cells post-therapy and ALDH1A1 depletion had marked inhibitory effects on both melanoma growth and metastasis. These findings suggest that ALDH1 inhibition may not only be able to provide a therapeutic advantage in melanoma treatment, but may also prevent rapid relapse after therapy, as residual tumorigenic cells are fewer and metastatic ability is diminished.

Departments of aDermatology

bSurgery, University California at San Francisco

cDepartment of Dermatology, Veterans Affairs Medical Center, San Francisco

dDepartment of Surgery, University California at Irvine, Irvine, California, USA

Correspondence to Ruby Ghadially, MD, Department of Dermatology (190), 4150 Clement Street, San Francisco, CA 94121, USA Tel: +1 415 317 4668; fax: +1 415 575 0592; e-mail: ghadiallyr@derm.ucsf.edu

Received November 18, 2014

Accepted December 23, 2014

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