title: Targeting melanocyte and melanoma stem cells by 8-hydroxy-2-dipropylaminotetralin.
abstract: Monobenzyl ether of hydroquinone (MBEH) is cytotoxic towards melanocytes. Its treatment efficacy is limited by an inability to eradicate stem cells. By contrast, 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-DPAT) affects melanocyte stem cell survival. MBEH and 8-DPAT were added to melanocytes and melanoma cells to compare cytotoxicity. Stem cell content among viable cells was determined by fluorocytometry using markers CD34, Pax3, and CD271. Immunostaining was used to identify stem cells in skin explants treated with MBEH or 8-DPAT ex vivo. Mice were exposed to MBEH or 8-DPAT and scanned for depigmentation before harvesting skin. MBEH exposure prompted a relative increase in stem cells among cultured melanocytes and melanoma cells, as treatment preferentially eliminated differentiated cells and spared the stem cells. Viability of this remaining, enriched stem cell population was however rapidly reduced by exposure to 8-DPAT within melanocyte and melanoma cell cultures. In human skin explants, the abundance of melanocyte stem cells was also visibly reduced after 8-DPAT treatment, in contrast to tissue exposed to MBEH. Meanwhile, significant depigmentation of the mouse pelage and loss of differentiated melanocytes was observed in vivo in response to topical application of MBEH, but not 8-DPAT. Prolonged application of the latter agent instead appeared to effectively reduce the abundance of melanocyte stem cells in the dermis. This furthers the idea that MBEH and 8-DPAT target complementary cell populations. Results indicate that combination treatment may demonstrate superior therapeutic activity by eliminating both differentiated and tumor initiating populations.
authors.affiliation: Departments of Medicine and Radiology, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Bonchak
authors.affiliation: Oncology Research Institute, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Eby
authors.affiliation: Oncology Research Institute, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Willenborg
authors.affiliation: Oncology Research Institute, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: David
authors.initials: D
authors.lastname: Chrobak
authors.affiliation: Oncology Research Institute, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Henning
authors.affiliation: Illinois Mathematics and Science Academy, Aurora, IL, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Krzywiec
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, MA, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Johnson
authors.affiliation: Oncology Research Institute, Loyola University Medical Center, Maywood, IL, USA; Departments of Pathology, Microbiology and Immunology, Loyola University Medical Center, Maywood, IL, USA. Electronic address: ilepool@luc.edu.
authors.forename: I Caroline
authors.initials: IC
authors.lastname: Le Poole
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000494:pharmacology*; D000287:Administration, Topical; D000818:Animals; D002454:Cell Differentiation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D006801:Humans; D006873:Hydroquinones / Q000008:administration & dosage / Q000494:pharmacology*; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects*; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D062327:Skin Lightening Preparations / Q000008:administration & dosage / Q000494:pharmacology; D012880:Skin Pigmentation / Q000187:drug effects; D046509:Tissue Culture Techniques; D014407:Tumor Cells, Cultured
chemical_list: D006873:Hydroquinones; D062327:Skin Lightening Preparations; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C006429:monobenzone
keywords: 8-DPAT; MBEH; Melanocyte; Melanoma; Pigmentation; Stem cells; Viability