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.

Autologously transplanted dermis‐derived cells alleviated monobenzone‐induced vitiligo in mouse

“…Monobenzone or monobenzyl ether hydroquinone (MBEH) is a topical agent approved by the US Food and Drug Administration (FDA), which is used to even the skin tone providing pigment loss by damaging the melanocytes in unaffected areas of vitiligo patients who have widespread (over more than 50% of their skin) depigmentation problem. [18][19][20] Pigment loss due to contact with MBEH is clinically and histologically similar to vitiligo. It has been observed that healthy people who topically apply MBEH to lighten their skin tone develop the disease.…”

Discovery of new depigmenting compounds and their efficacy to treat hyperpigmentation: Evidence from in vitro study

“…27,35,37,38 On the other hand, hydroquinone (C 6 H 6 O 2 ) possesses intracellular cytotoxic effect that reduces pigmentation level by nonselectively destroying the epidermal melanocytes and keratinocytes. [39][40][41] Due to aggressive mode of action of hydroquinone in reducing level of pigmentation, it is associated with skin cancer. 40,41 In recent years, cosmetic products containing hydroquinone have been banned in most countries, but its usage for medical purpose can be compromised under strict regulation.…”

“…Previously known depigmenting compounds such as azelaic acid (C 9 H 16 O 4 ) selectively reduce hyperpigmentation in abnormal melanocytes, and it has minimum effect to normal melanocytes . On the other hand, hydroquinone (C 6 H 6 O 2 ) possesses intracellular cytotoxic effect that reduces pigmentation level by nonselectively destroying the epidermal melanocytes and keratinocytes . Due to aggressive mode of action of hydroquinone in reducing level of pigmentation, it is associated with skin cancer .…”

A Zebrafish Embryo as an Animal Model for the Treatment of Hyperpigmentation in Cosmetic Dermatology Medicine

“…Replacing the mammalian model with the zebrafish embryo model for evaluation of efficacy and safety of depigmenting compounds is an interesting topic of discussion in the skin-care industry [ 73 , 74 , 75 , 92 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 ]. However, in the cosmetic or even dermatological industry, these compounds are formulated in combination of a carrier or vehicle to facilitate its effect on human skin [ 73 , 74 , 79 , 86 , 115 ].…”

“…Regardless of its applications and benefits, skin depigmentation may also give adverse effect especially over long period of time. Melanin is a photoprotective component, and plays a physiological role as a UV absorbent, which is known to protect skin from harmful and excessive UV radiation intensity, DNA damage as well as development of cancer cells [ 1 , 16 , 114 , 116 ]. Melanin during melanogenesis, enzymes such as catalase, glutathione peroxidase and superoxide dismutase are synthesized and dedicated to removing radicals [i.e., reactive oxygen radical (ROS), superoxide anion (O 2 •- ), hydrogen peroxide (H 2 O 2 ), and singlet oxygen ( 1 O 2 )] [ 1 , 16 ].…”