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Comparative study of doxycycline, sancycline, and 4-dedimethylamino sancycline (CMT-3) on epidermal melanogenesis

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Abstract

Melanogenesis is regulated by melanocytes, which synthesize the pigment melanin inside melanosomes; these melanosomes are exported through dendritic extensions to adjacent keratinocytes and result in skin coloration. Chemically modified tetracyclines (CMTs) are nonantimicrobial tetracyclines that retain the capacity to inhibit matrix metalloproteinases (MMPs) and have shown several biological benefits; in particular, CMT-3 [(4-dedimethylamino sancycline (SAN)] has emerged as a candidate for therapeutic benefits in our previous studies. However, to date, studies of the effects of CMT-3 or SAN on melanogenesis are lacking. We have previously reported the anti-melanogenic activity of CMT-308 (the 9-amino derivative of CMT-3). Herein, we have compared the three tetracycline analogs, doxycycline (DOX), SAN, and CMT-3, for their effects on melanogenesis using B16F10 mouse melanoma cells and have validated results in primary human melanocytes (HEMn-DP). DOX did not show any significant effects on intracellular melanin or melanosome export in DP cells while SAN was cytotoxic at high doses but without effects on melanogenesis at lower doses. However, CMT-3 showed a robust suppression of dendricity parameters (dendrite number, dendrite length, and proportion of dendritic cells) in DP cells which was associated, at least in part, with a significant reduction of intracellular tyrosinase activity. In spite of its inhibition of tyrosinase activity, CMT-3 had no significant effects on intracellular melanin levels, suggesting that it selectively targets melanosome export. Our results demonstrate a unique structure–activity relationship (SAR) for the effects of these compounds on melanogenesis and support the conclusion that removal of the 4-dimethylamino moiety confers the selective capacity to suppress melanosome export. Collectively, these results indicate that CMT-3 might be a candidate for diminishing hyperpigmentation skin disorders.

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Abbreviations

CMT:

Chemically modified tetracycline

SAN:

Sancycline

DOX:

Doxycycline

SAR:

Structure–activity relationship

KA:

Kojic acid

UV:

Ultraviolet

α-MSH:

Alpha-melanocyte stimulating hormone

L-DOPA:

3,4-Dihydroxy-L-phenylalanine

DMEM:

Dulbecco’s Modified Eagle’s Medium

HI-FBS:

Heat-inactivated fetal bovine serum

HMGS:

Human Melanocyte Growth Supplement

HEMn-DP:

Human epidermal melanocytes—darkly pigmented

BCA:

Bicinchoninic acid

NaOH:

Sodium hydroxide

TYR:

Tyrosinase

MITF:

Microphthalmia transcription factor

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Acknowledgements

This study did not receive any funding in the public, commercial, or not-for-profit sectors. We would like to acknowledge Dr. Lorne Golub (Stony Brook University) for contributions to the development of CMTs.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, 11794-5281, USA

    Shilpi Goenka & Sanford R. Simon

  2. Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, USA

    Sanford R. Simon

  3. Department of Pathology, Stony Brook University, Stony Brook, NY, USA

    Sanford R. Simon

Authors
  1. Shilpi Goenka
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SG conceptualized the research idea, designed, and conducted all experiments, wrote and critically revised the manuscript; SRS provided financial support. Both authors approved the final draft of the manuscript.

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Correspondence to Shilpi Goenka.

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Goenka, S., Simon, S.R. Comparative study of doxycycline, sancycline, and 4-dedimethylamino sancycline (CMT-3) on epidermal melanogenesis. Arch Dermatol Res 315, 249–257 (2023). https://doi.org/10.1007/s00403-021-02297-w

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