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Cited by 160Retinoids in leukemia and cellular processesAcute Myeloid Leukemia ResearchEpigenetics and DNA Methylation

Unlocking the potential of retinoic acid in anticancer therapy

Open access
Schenk, T, Stengel, S, Zelent, A·2014·British Journal of Cancer
DOI 10.1038/bjc.2014.412PMC PMC4260020
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Abstract

All-trans-retinoic acid (ATRA) is a physiologically active metabolite of vitamin A. Its antitumour activities have been extensively studied in a variety of model systems and clinical trials; however, to date the only malignancy responsive to ATRA treatment is acute promyelocytic leukaemia (APL) where it induces complete remission in the majority of cases when administered in combination with light chemotherapy and/or arsenic trioxide. After decades of studies, the efficacy of ATRA to treat other acute myeloid leukaemia (AML) subtypes and solid tumours remains poor. Recent studies directed to improve ATRA responsiveness in non-APL AML seem to indicate that the lack of effective ATRA response in these tumours may be primarily due to aberrant epigenetics, which negatively affect ATRA-regulated gene expression and its antileukaemic activity. Epigenetic reprogramming could potentially restore therapeutic effects of ATRA in all AML subtypes. This review discusses the current progresses in the understanding how ATRA can be utilised in the therapy of non-APL AML and other cancers.

AI snapshot

Written from the paper’s full text.

TL;DR

All-trans-retinoic acid (ATRA) is highly effective in acute promyelocytic leukaemia (APL) but has limited efficacy in non-APL AML and most solid tumours. This review argues that aberrant epigenetics repress ATRA-regulated gene expression and that combining ATRA with epigenetic drugs, especially LSD1 inhibitors, may restore differentiation therapy responses.

Key findings

  • In APL, ATRA plus chemotherapy and/or arsenic trioxide (ATO) produces complete remission rates in excess of 93% and 5-year overall survival approaching 100%; a phase 3 trial in low-risk APL found ATRA plus ATO without chemotherapy improved complete remission and extended overall survival versus standard ATRA plus chemotherapy (P=0.02).
  • In non-APL AML, results are limited and mixed: low-dose cytosine arabinoside (LDAC) plus ATRA improved time to treatment failure and survival in patients older than 60 years versus LDAC alone; mutant NPM1 without FLT3-ITD predicted response to ATRA added to intensive chemotherapy; ATRA plus LDAC induced complete remission in “poor prognosis” AML, especially with <50% bone marrow infiltration; however, other phase 2 studies showed no or non-significant effects.
  • Epigenetic repression of RARA is implicated: RARA2 promoter is hypermethylated in AML cell lines; primary AML samples show reduced RARα1 and RARα2 expression, with RARA2 promoter histones having decreased H3 acetylation and decreased H3K4 di-methylation despite unmethylated promoters.
  • LSD1 inhibition plus ATRA enhanced differentiation: ATRA plus tranylcypromine increased CD11b+ cells by 21-fold in HL-60 and 16-fold in TEX cells, and up to 11-fold in primary AML patient samples; it also reduced clonogenic capacity in vitro and engraftment of primary AML cells in NOD.SCID gamma mice.

Methods

  • Narrative review of ATRA biology, retinoic acid receptor signalling, non-genomic effects, and preclinical/clinical studies in APL, non-APL AML, and other malignancies.
  • Discusses combination strategies including ATRA with chemotherapy, arsenic trioxide, growth factors, signal transduction inhibitors, telomerase inhibitors, interferons, and epigenetic drugs such as DNA methyltransferase inhibitors, histone deacetylase inhibitors, and LSD1 inhibitors.
  • No systematic search strategy, data extraction, or meta-analysis is described.

Limitations

  • The paper states no explicit limitations.
  • As a narrative review, it lacks described systematic search/selection criteria and formal risk-of-bias assessment (evident from the text).
  • The text notes that much remains to be understood about non-genomic ATRA effects, that ATRA efficacy in non-APL AML is limited with mixed trial results, and that clinical experience combining ATRA with signal transduction inhibitors is sparse—only midostaurin- and cladribine-based induction chemotherapy have been studied in a clinical trial with ATRA in relapsed or refractory AML.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/bjc.2014.412

Cites

36 of 36 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 32 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    Epigenetic reprogramming could potentially restore therapeutic effects of ATRA in all AML subtypes.

    “Epigenetic reprogramming could potentially restore therapeutic effects of ATRA in all AML subtypes.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    The ability of PML/RARα to block differentiation of transfected myeloid cells depends on an intact N-CoR-binding region in the RAR moiety of the fusion protein.

    “ability of PML/RARα to block differentiation of transfected myeloid cells depends on an intact N-CoR-binding region in the RAR moiety of the fusion protein (Racanicchi et al, 2005).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Racanicchi et al, 2005 source

      Not checked in the free run.

    • Rests on an assumption: The most common RARA translocation partner is the PML gene.
    • Rests on an assumption: Fusion of PML sequences to the B-F regions of RARA increases the affinity of the fusion receptor for co-repressors so that higher (pharmacological) levels of ATRA are required to induce its dissociation.
  • Premisecitation

    Breitman et al (1980) showed that the HL-60 cell line could be induced to undergo granulocytic differentiation by micromolar concentrations of ATRA.

    “Breitman et al (1980) showed that the HL-60 cell line, which was allegedly derived from a patient with APL, could be induced to undergo granulocytic differentiation by micromolar concentrations of ATRA.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Breitman et al, 1980 source

      Not checked in the free run.

  • Premisecitation

    The t(15;17) translocation, the cytogenetic marker for APL, involves the RARA gene on chromosome 17q21.

    “the t(15;17) translocation, the cytogenetic marker for APL involves the RARA gene on chromosome 17q21”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sirulnik et al, 2003 source

      Not checked in the free run.

  • Interpretationreasoning

    The activity of ATRA in leukaemia cells is dependent on complex interactions between genomic and non-genomic pathways.

    “The activity of ATRA in leukaemia cells is dependent on complex interactions between genomic and non-genomic pathways.”
    Quote in the paperSubstantial claim
  • May combine two claims. 17

  • May combine two claims.

    Premisecitation

    A recent phase 3 trial showed that combination treatment of ATRA and ATO without chemotherapy leads to CR and an extended overall survival compared with the standard ATRA and chemotherapy treatment (P=0.02) in patients with low-risk APL.

    “A recent phase 3 trial showed that combination treatment of ATRA and ATO without chemotherapy leads to CR and an extended overall survival compared with the standard ATRA and chemotherapy treatment (P=0.02) in patients with low-risk APL (Lo-Coco et al, 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lo-Coco et al, 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ATRA effectiveness in AML has been observed in cells that lack PML/RARα, as HL-60 cells can be induced to differentiate into mature granulocytes.

    “One argument against such a view is that ATRA effectiveness in AML has been observed in cells that lack PML/RARα, as HL-60 cells, that can be induced to differentiate into mature granulocytes (Breitman et al, 1980).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Breitman et al, 1980 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The success of ATRA in APL shows that the concept of differentiation therapy can be an effective strategy in leukaemia and provided a rationale for its use in the treatment of other cancers.

    “This success of ATRA in APL shows that the concept of differentiation therapy can be an effective strategy in leukaemia and provided a rationale for its use in the treatment of other cancers.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    To date, the only malignancy responsive to ATRA treatment is acute promyelocytic leukaemia (APL), where ATRA induces complete remission in the majority of cases when combined with light chemotherapy and/or arsenic trioxide.

    “to date the only malignancy responsive to ATRA treatment is acute promyelocytic leukaemia (APL) where it induces complete remission in the majority of cases when administered in combination with light chemotherapy and/or arsenic trioxide.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lo-Coco et al, 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Huang et al (1987) reported successful use of ATRA to induce complete remission in patients with APL, without an apparent increase in the severity of the haemorrhagic diathesis observed at presentation.

    “Huang and colleagues reported the successful use of ATRA to induce complete remission (CR) in patients with APL, without an apparent increase in the severity of the haemorrhagic diathesis observed at presentation (Huang et al, 1987).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Huang et al, 1987

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both RARA1 and RARA2 promoters are unmethylated in AML patient samples, while histones associated with the RARA2 promoter have decreased levels of overall acetylation of histone H3 and decreased levels of di-methylation of histone H3 lysine 4.

    “Moreover, both RARA1 and RARA2 promoters (Glasow et al, 2008) are unmethylated in AML patient samples, while histones associated with the RARA2 promoter have decreased levels of overall acetylation of histone H3 and decreased levels of di-methylation of histone H3 lysine 4.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Glasow et al, 2008 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    It is evident that combinatorial therapies targeting multiple gene silencing mechanisms may be the most effective strategy in reactivating ATRA-sensitive gene expression and differentiation of AML cells, as well as mediating anticancer activities of ATRA in general.

    “It is evident that combinatorial therapies targeting multiple gene silencing mechanisms may be the most effective strategy in reactivating ATRA-sensitive gene expression and differentiation of AML cells, as well as mediating anticancer activities of ATRA in general.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: These epigenetic modifying drugs have been shown to be only partly effective against different cancers when used alone.

  • May combine two claims.

    Premisecitation

    The ATRA derivative 13-cis-retinoic acid (13-cis-RA) is successfully used in the treatment of children with high-risk neuroblastoma, reducing the risk of recurrence after high-dose chemotherapy and stem cell transplantation and increasing long-term survival.

    “For example, the ATRA derivative 13-cis-retinoic acid (13-cis-RA) is successfully used in the treatment of children with high-risk neuroblastoma, reducing the risk of recurrence after high-dose chemotherapy and stem cell transplantation and increasing long-term survival (Matthay et al, 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Matthay et al, 2009 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Overall, the efficacy achieved so far with ATRA in patients with non-APL AML is limited and there is much room for improvement.

    “Overall, these studies show that the efficacy achieved so far with ATRA in patients with non-APL AML is limited and there is much room for improvement.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premiseown data

    The treatment also lead to diminished clonogenic capacity of AML cells in vitro and engraftment of primary AML cells from patients in vivo in NOD.SCID gamma (NSG) mice, suggesting that LSD1i/ATRA combinations may also target LICs.

    “The treatment also lead to diminished clonogenic capacity of AML cells in vitro and engraftment of primary AML cells from patients in vivo in NOD.SCID gamma (NSG) mice, suggesting that LSD1i/ATRA combinations may also target LICs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Schenk et al, 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    Co-treatment with ATRA and TCP increased the fraction of CD11b+ cells in primary AML patient samples by a factor up to 11-fold and induced morphological changes consistent with differentiation of patient blasts into polymorphonuclear leukocytes.

    “Mirroring the results in cell lines, co-treatment with ATRA and TCP increased the fraction of CD11b+ cells in primary AML patient samples by a factor up to 11-fold and induced morphological changes, including formation of cytoplasmic neutrophil granules, consistent with differentiation of patient blasts into polymorphonuclear leukocytes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Schenk et al, 2012 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In the context of non-APL AML, epi-drugs such as LSD1 inhibitors are most effective when combined with ATRA and vice versa.

    “In the context of non-APL AML, epi-drugs such as LSD1 inhibitors are most effective when combined with ATRA and vice versa.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Treatment of AML with targeted therapies is particularly promising due to the fact that AMLs have far fewer mutations than most other adult cancers, with an average of only 13 mutations.

    “Treatment of AML with targeted therapies is particularly promising due to the fact that AMLs have far fewer mutations than most other adult cancers, with an average of only 13 mutations (Mardis et al, 2009; Cancer Genome Atlas Research Network, 2013).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Mardis et al, 2009 source

      Not checked in the free run.

    • cites Cancer Genome Atlas Research Network, 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The ligand-dependent activities of endogenous and transiently expressed RARα isoforms are enhanced by G/GM-CSF and correlate with an increased expression of ATRA inducible genes as well as leukaemic cell differentiation.

    “The ligand-dependent activities of endogenous and transiently expressed RARα isoforms are enhanced by G/GM-CSF and correlate with an increased expression of ATRA inducible genes as well as leukaemic cell differentiation (Glasow et al, 2005).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Glasow et al, 2005 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    This work shows that LSD1 is an important therapeutic target and highlights the potential for drugs targeting aberrant epigenetics in combination with retinoids.

    “This work shows that LSD1 is an important therapeutic target and highlights the potential for drugs targeting aberrant epigenetics in combination with retinoids (Figure 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Both are heterochromatin markers associated with reduced gene expression indicating that epigenetically driven decrease in RARA expression may be a factor in the pathogenesis of AML and contribute to the differentiation blockade.

    “Both are heterochromatin markers associated with reduced gene expression indicating that epigenetically driven decrease in RARA expression may be a factor in the pathogenesis of AML and contribute to the differentiation blockade.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The promoter of the RARA isoform RARA2, but not RARA1, is hypermethylated in AML cell lines.
    • Rests on an assumption: Levels of RARα2 expression are markedly reduced in AML patient samples compared with normal myeloid cells expressing CD33 or CD34.
    • Rests on an assumption: Expression of the RARα1 isoform is also significantly reduced in primary AML cells.

  • May combine two claims.

    Premisecitation

    LSD1 is highly expressed in AML patients and its overexpression has been correlated with impaired survival in various other tumours.

    “LSD1 is highly expressed in AML patients (www.proteinatlas.org) and its overexpression has been correlated with impaired survival in various other tumours (Hayami et al, 2011).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hayami et al, 2011 source

      Not checked in the free run.

    • cites www.proteinatlas.org

      Not checked in the free run.

17 of 17

  • The paper relies on this without support.

    Retinoic acid receptors are not mutated in cancer cells.

    “Retinoic acid receptors are not mutated in cancer cells, so ATRA could potentially exert its anticancer effects in many malignancies.”

  • The paper relies on this without support.

    ATRA has low toxicity.

    “All-trans-retinoic acid is a promising compound for treatment of a variety of cancers because of its specific effects on cell proliferation, differentiation, and apoptosis, as well as its low toxicity.”

  • The paper relies on this without support.

    The promoter of the RARA isoform RARA2, but not RARA1, is hypermethylated in AML cell lines.

    “The promoter of the RARA isoform RARA2, but not RARA1, is hypermethylated in AML cell lines, and induction of differentiation and expression of RARA2 can be stimulated with DNA demethylating agents and ATRA treatment.”

  • The paper relies on this without support.

    Levels of RARα2 expression are markedly reduced in AML patient samples compared with normal myeloid cells expressing CD33 or CD34.

    “Consistent with what has been observed in cell lines, levels of RARα2 expression are also markedly reduced in AML patient samples compared with normal myeloid cells expressing CD33 or CD34.”

  • The paper relies on this without support.

    Expression of the RARα1 isoform is also significantly reduced in primary AML cells.

    “However, in contrast to AML cell lines and normal myeloid cells, expression of the RARα1 isoform is also significantly reduced in primary AML cells.”

  • The paper relies on this without support.

    So far ATRA is only routinely and effectively used to treat APL and precancerous lesions such as leukoplakia, actinic keratosis, and cervical dysplasia.

    “Nevertheless, so far ATRA is only routinely and effectively used to treat APL and precancerous lesions such as leukoplakia, actinic keratosis, and cervical dysplasia.”

  • The paper relies on this without support.

    Incorporation of chemotherapy and up-front use of ATRA in combination with arsenic trioxide (ATO) leads to CR rates in excess of 93% with patients achieving 5-year overall survival rates approaching 100%.

    “Incorporation of chemotherapy and up-front use of ATRA in combination with arsenic trioxide (ATO) lead to CR rates in excess of 93% with patients achieving 5-year overall survival rates approaching 100%.”

  • The paper relies on this without support.

    The most common RARA translocation partner is the PML gene.

    “The most common RARA translocation partner is the PML gene.”

  • The paper relies on this without support.

    Fusion of PML sequences to the B-F regions of RARA increases the affinity of the fusion receptor for co-repressors so that higher (pharmacological) levels of ATRA are required to induce its dissociation.

    “Fusion of PML sequences to the B-F regions of RARA increases the affinity of the fusion receptor for co-repressors so that higher (pharmacological) levels of ATRA are required to induce its dissociation.”

  • The paper relies on this without support.

    Although HDACi have been used both alone and in combination with ATRA in patients with AML (including APL) the results were of limited value.

    “Although HDACi have been used both alone and in combination with ATRA in patients with AML (including APL) the results were of limited value.”

  • The paper relies on this without support.

    These epigenetic modifying drugs have been shown to be only partly effective against different cancers when used alone.

    “These epigenetic modifying drugs have been shown to be only partly effective against different cancers when used alone.”
11 of 11

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • RAR-RXR heterodimers interact with a DNA sequence known as the retinoic acid-response element, which facilitates binding of co-activators to histone acetylase, leading to transcription of target genes.

    “RAR–RXR heterodimers interact with a deoxyribonucleic acid sequence known as the retinoic acid-response element35, which facilitates the binding of co-activators to histone acetylase, ultimately leading to the transcription of target genes (Fig. 2).”

    From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [35]

  • In the nucleus, RA triggers gene transcription by binding to heterodimers formed by RA receptors (RARα, RARβ, RARγ) and retinoid X receptors (RXRα, RXRβ, RXRγ).

    “In the nucleus, RA triggers gene transcription by binding to heterodimers formed by RA receptors (RARα, RARβ, and RARγ) and retinoid X receptors (RXRα, RXRβ, and RXRγ).”

    From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [35]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Abstract says only APL responds to ATRA, but later reports effectiveness in non-APL AML

    Minor

    The abstract says APL is the only malignancy responsive to ATRA treatment, whereas the non-APL AML section says clinical trials have shown ATRA to be effective in that disease when combined with other agents.

1 of 1

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Authors
Schenk, T., Stengel, S., & Zelent, A.
Affiliations
  • Institute of Cancer Research (GB)
  • Sylvester Comprehensive Cancer Center (US)
Corresponding author
Zelent, A
ORCID
Venue
British Journal of Cancer
Publisher
Springer Science and Business Media LLC
Published
2014-11
Volume
111
Issue
11
Pages
2039-2045
ISSN
  • 0007-0920 (ISSN-L)
  • 1532-1827
DOI
10.1038/bjc.2014.412
PMC
PMC4260020
OpenAlex
W1977587477
Semantic Scholar
896b5cdf515b1113f073a9f2e78c2b316a418cf3
Cited by
160
References
36
Citations by year
2026: 6 · 2025: 8 · 2024: 8 · 2023: 12 · 2022: 14 · 2021: 16 · 2020: 13 · 2019: 18 · 2018: 16 · 2017: 16 · 2016: 17 · 2015: 14 · 2014: 1 · 2012: 1
FWCI
1.51
Type
journal article
Language
en
Open access
Licence
Locations
  • British Journal of Cancer (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
all-trans retinoic acid, vitamin A metabolites, acute promyelocytic leukemia, acute myeloid leukemia, epigenetic reprogramming, ATRA resistance, arsenic trioxide, solid tumors, antitumour activity, gene expression regulation
MeSH terms
Animals, Antineoplastic Agents, Humans, Tretinoin, Leukemia, Myeloid, Acute, Leukemia, Promyelocytic, Acute, Receptors, Retinoic Acid

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