Hydroxychloroquine modulates metabolic activity and proliferation and induces autophagic cell death of human dermal fibroblasts.
Hydroxychloroquine (HCQ) is a commonly used therapeutic agent in skin disorders. Some reports also suggest that HCQ can be useful in fibroblastic diseases of the skin. Here, we investigated the effects of HCQ in human dermal fibroblasts (HDFs). HCQ significantly reduced the metabolic activity and suppressed cell proliferation (IC(50) = approximately 30 microM) of HDFs. The antiproliferative effect of HCQ was associated with decreased activation of the extracellular signal-regulated kinases 1/2 but not with inhibition of the mammalian target of the rapamycin pathway or with dephosphorylation of Akt. HCQ induced a distinct type of cell death in HDFs, characterized by surface exposure of phosphatidylserine but a lack of morphological signs of apoptosis and absence of DNA fragmentation. The HCQ-treated HDFs instead showed autophagic vacuoles with double membranes and digested organelle content. These vacuoles showed light-chain 3 immunostaining, in accordance with increased protein amounts of this autophagy marker. Induction of autophagic cell death by HCQ was also paralleled by increased expression of Beclin-1, a key regulator of autophagy. Our findings indicate that HDFs are target cells of HCQ and form a rationale on the basis of which the in vivo effects of antimalarials can be studied in patients with aberrant fibroblast function.
Ramser
Bettina
B
Department of Dermatology, University of Münster, Münster, Germany.
Kokot
Agatha
A
Metze
Dieter
D
Weiss
Nina
N
Luger
Thomas A
TA
Böhm
Markus
M
D000962:Antimalarials / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects
D000962:Antimalarials; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D015415:Biomarkers; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D006886:Hydroxychloroquine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3