Apoptosis May Explain the Pharmacological Mode of Action and Adverse Effects of Isotretinoin, Including Teratogenicity

Melnik, Bodo C.

doi:10.2340/00015555-2535

Cited by 91 publications

(100 citation statements)

References 123 publications

(148 reference statements)

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“…Isotretinoin treatment changed the ratio of the differentiating pool of sebocytes vs the undifferentiating cell pool from 2:1 to 1:7 . Translational evidence suggests that isotretinoin's desired anti‐acne effect and its adverse effects including teratogenicity are based on isotretinoin‐mediated apoptosis . According to a scientific hypothesis, isotretinoin‐mediated apoptosis may result from increased nuclear activity of FoxO1 and other FoxO transcription factors.…”

Section: Introductionmentioning

confidence: 99%

Effect of oral isotretinoin on the nucleo‐cytoplasmic distribution of FoxO1 and FoxO3 proteins in sebaceous glands of patients with acne vulgaris

Agamia

Roshdy

Abdelmaksoud

et al. 2018

Experimental Dermatology

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Oral isotretinoin is the most effective anti‐acne drug with the strongest sebum‐suppressive effect caused by sebocyte apoptosis. It has been hypothesized that upregulation of nuclear FoxO transcription factors and p53 mediate isotretinoin‐induced sebocyte apoptosis in vivo. It is the aim of our study to analyse the distribution of the pro‐apoptotic transcription factors FoxO1 and FoxO3 in the nuclear and cytoplasmic compartments of human sebocytes in vivo before and during isotretinoin treatment of acne patients. Immunohistochemical analysis of skin biopsies with antibodies distinguishing phosphorylated and non‐phosphorylated human FoxO1 and FoxO3 proteins was performed before isotretinoin treatment, six weeks after initiation of isotretinoin therapy, and in acne‐free control patients not treated with isotretinoin. Our in vivo study demonstrates a significant increase in the nucleo‐cytoplasmic ratio of non‐phosphorylated FoxO1 and FoxO3 during isotretinoin treatment of acne patients. Translational and presented experimental evidence indicates that upregulation of nuclear FoxO1 and FoxO3 proteins is involved in isotretinoin‐induced pro‐apoptotic signalling in sebocytes confirming the scientific hypothesis of isotretinoin‐mediated upregulation of FoxO expression.

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Section: Introductionmentioning

confidence: 99%

Effect of oral isotretinoin on the nucleo‐cytoplasmic distribution of FoxO1 and FoxO3 proteins in sebaceous glands of patients with acne vulgaris

Agamia

Roshdy

Abdelmaksoud

et al. 2018

Experimental Dermatology

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“…Isotretinoin (13-cis-retinoic acid) is a retinol derivative used in the treatment of severe acne and some types of cancer [25,26]. The usage dose is 0.5–1 mg.kg -1 [27] and its most common side effects are skin xerosis, especially on exposed skin, cheilitis, telogen effluvium, inflammatory bowel disease and myalgia [28]. Despite its exact mechanism of action remains unknown, several studies have shown that this drug induces apoptosis in sebaceous gland cells.…”

Section: Introductionmentioning

confidence: 99%

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi

et al. 2017

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Polyamines are essential compounds to all living organisms and in the specific case of Trypanosoma cruzi, the causative agent of Chagas disease, they are exclusively obtained through transport processes since this parasite is auxotrophic for polyamines. Previous works reported that retinol acetate inhibits Leishmania growth and decreases its intracellular polyamine concentration. The present work describes a combined strategy of drug repositioning by virtual screening followed by in vitro assays to find drugs able to inhibit TcPAT12, the only polyamine transporter described in T. cruzi. After a screening of 3000 FDA-approved drugs, 7 retinoids with medical use were retrieved and used for molecular docking assays with TcPAT12. From the docked molecules, isotretinoin, a well-known drug used for acne treatment, showed the best interaction score with TcPAT12 and was selected for further in vitro studies. Isotretinoin inhibited the polyamine transport, as well as other amino acid transporters from the same protein family (TcAAAP), with calculated IC50 values in the range of 4.6–10.3 μM. It also showed a strong inhibition of trypomastigote burst from infected cells, with calculated IC50 of 130 nM (SI = 920) being significantly less effective on the epimastigote stage (IC50 = 30.6 μM). The effect of isotretinoin on the parasites plasma membrane permeability and on mammalian cell viability was tested, and no change was observed. Autophagosomes and apoptotic bodies were detected as part of the mechanisms of isotretinoin-induced death indicating that the inhibition of transporters by isotretinoin causes nutrient starvation that triggers autophagic and apoptotic processes. In conclusion, isotretinoin is a promising trypanocidal drug since it is a multi-target inhibitor of essential metabolites transporters, in addition to being an FDA-approved drug largely used in humans, which could reduce significantly the requirements for its possible application in the treatment of Chagas disease.

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“…Thus, isotretinoin-induced p53-mediated apoptosis not only explains its desired sebum-suppressive effect via induction of sebocyte apoptosis [2,10] but may also explain its harmful teratogenicity induced by exaggerated NCC apoptosis during embryogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…It has recently been suggested that isotretinoin′s major desired and adverse drug effects including teratogenicity are related to apoptosis such as sebocyte and NCC apoptosis, respectively. [1,2] The prodrug isotretinoin is intracellularly isomerized to ATRA (s16). …”

mentioning

confidence: 99%

Overexpression of p53 explains isotretinoin's teratogenicity

Melnik

2017

Experimental Dermatology

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The precise molecular basis of retinoid embryopathy is yet unknown.This hypothesis predicts that isotretinoin (13-cis retinoic acid), the prodrug of all-trans retinoic acid (ATRA), exaggerates neural crest cell (NCC) apoptosis via upregulation of the pro-apoptotic transcription factor p53, the guardian of the genome. Increased p53 signalling is associated with Treacher Collins-, CHARGE-and fetal alcohol syndrome, which exhibit dysmorphic craniofacial features resembling retinoid embryopathy. In addition, developmental studies of NCC homeostasis in the zebrafish support the pivotal role of p53. Translational evidence implies that isotretinoin-stimulated overactivation of p53 during embryogenesis represents the molecular basis of isotretinoin′s teratogenicity. | INTRODUCTIONIsotretinoin, the most effective drug for the treatment of severe acne, is teratogenic. The majority of malformations induced by isotretinoin treatment during pregnancy primarily affect neural crest cells (NCCs) leading to craniofacial dysmorphic features involving cardiac, thymic and central nervous system structures (s1-s6), which have also been observed in pigtail monkeys exposed to ATRA during gestation (s7,s8). During craniofacial development, massive cell death occurs in vertebrates (s9). In the developing nervous system a well-regulated balance of apoptotic signalling ensures appropriate cell differentiation and maturation (s10,s11). Isotretinoin-treated NCCs often became rounded or spindle-shaped, separated from their neighbours, and frequently detached from the substrate or clumped together (s12).Animal studies confirmed that administration of isotretinoin increases apoptosis of NCCs (s13-s15). It has recently been suggested that isotretinoin′s major desired and adverse drug effects including teratogenicity are related to apoptosis such as sebocyte and NCC apoptosis, respectively. [1,2] The prodrug isotretinoin is intracellularly isomerized to ATRA (s16). | ISOTRETINOIN AND P53-INDUCED APOPTOSISIn sebocytes, increased expression of the pro-apoptotic proteins tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), TRAIL-receptor 1 (DR4) and insulin-like growth factor-binding pro- has been identified as a target gene of p53 (s28). Thus, isotretinoinmediated upregulation of p53 and PAX-2 may explain the NCC abnormalities reported in isotretinoin exposed macaque embryos. HOX transcription factors, which are also induced by ATRA (s29-s31), play a crucial role in NCC-dependent branchial arch pattering (s32-s35). Intriguingly, HOX binding sites have been identified on the TP53promoter and compromised HOXA5 function limited p53 expression (s36). Thus, ATRA-induced HOX gene expression may further enhance p53 expression explaining the interplay between ATRA, HOX and p53 in retinoid teratogenicity (Figure 1). NCCs and sebocytes may be especially susceptible to isotretinoin either due to their increased capacity for isomerization to ATRA (s16) or higher ATRA gradients due to decreased CYP26-mediated degradation of ATRA (s37). |...

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Apoptosis May Explain the Pharmacological Mode of Action and Adverse Effects of Isotretinoin, Including Teratogenicity

Cited by 91 publications

References 123 publications

Effect of oral isotretinoin on the nucleo‐cytoplasmic distribution of FoxO1 and FoxO3 proteins in sebaceous glands of patients with acne vulgaris

Effect of oral isotretinoin on the nucleo‐cytoplasmic distribution of FoxO1 and FoxO3 proteins in sebaceous glands of patients with acne vulgaris

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi

Overexpression of p53 explains isotretinoin's teratogenicity

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