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  • Review Article
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The promise of retinoids to fight against cancer

Nature Reviews Cancer volume 1, pages 181–193 (2001)Cite this article

Key Points

  • Retinoids and rexinoids exert their action by signalling through nuclear receptor heterodimers that can activate or silence specific gene networks.

  • The most widely studied retinoid, all-trans retinoic acid (ATRA), causes differentiation of acute promyelocytic leukaemia (APL) cells through activation of the retinoid receptor RARα, but RARβ and rexinoid receptors (RXRs) might also be responsible for some of the antitumour activity of retinoids.

  • Crosstalk with other transcription factors, particularly AP1 (FOS–JUN), might account for some of the antitumour activity of retinoids.

  • In humans, pharmacological doses of ATRA cause differentiation of APL cells that contain the PML–RARα fusion protein, but clinical data indicate that retinoids might also be useful for the treatment of other human cancers.

  • As well as activating differentiation, retinoids can also activate tumour-specific death signalling pathways; these contribute to the efficacy of retinoid therapy.

  • Retinoids are cancer preventive and their use has been approved for the treatment of several precancerous conditions.

Abstract

Retinoids have a reputation for being both detrimental and beneficial: they are teratogens, but they also have tumour-suppressive capacity. Cell biology and genetics have significantly improved our understanding of the mechanisms that underlie the anti-proliferative action of retinoids. Recent elucidation of the pathways that are activated by retinoids will help us to exploit the beneficial aspects of this powerful class of compounds for cancer therapy and prevention.

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Figure 1: Mechanisms of transcriptional repression and activation by RAR–RXR heterodimers.
Figure 2: Retinoids and rexinoids can interfere with events leading to tumorigenesis at several levels.
Figure 3: Molecular basis of retinoid responsivity and non-responsivity in APL cells.
Figure 4: Retinoids affect TRAIL-mediated death signalling at several levels.

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Acknowledgements

Online Tables 1 and 2 are also available from the authors on request. We thank P. Germain for critically reading the manuscript and all our colleagues for discussion and communicating unpublished studies to us, in particular S. Minucci, P. G. Pelicci, A. Zelent, D. Grimwade, P. Chambon, M. Lanotte, C. Chomienne, Y. Shiratori and A. Fanjul. We apologize to all colleagues whose work could only be cited inadequately due to space limitation. L.A. is particularly grateful for support by the Institut National de la Santé et de la Recherche Médicale (INSERM). Our studies mentioned in the text have been supported by funds from the European Community, the AICR, INSERM, the Centre National de la Recherche Scientifique, the Hôpital Universitaire de Strasbourg and Bristol-Myers Squibb.

Author information

Authors and Affiliations

  1. Dipartimento di Patologia Generale e Oncologia, Seconda Università degli Studi di Napoli, via L. de Crecchio, 80138, Napoli, Italy

    Lucia Altucci

  2. Institut de Génétique et de Biologie Moléculaire et Cellulaire, (IGBMC)/CNRS/INSERM/ULP, BP 163, 67404 Illkirch Cedex, C. U. de Strasbourg, France

    Lucia Altucci & Hinrich Gronemeyer

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Supplementary information

Supplementary Table 1 Growth-inhibitory and apoptogenic effects of retinoids in preclinical studies.

Supplementary Table 2 Retinoid/rexinoid receptors retinoid/rexinoid responsivity and tumour progression. (PDF 89 kb)

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DATABASES

CancerNet:

acute myeloid leukaemia

breast cancer

prostate carcinoma

squamous-cell carcinomas

 LocusLink:

AIB1

AML1

caspase-8

CBP

c-FOS

c-JUN

cytochrome c

DR4

DR5

EGR1

ETO

FAS

FASL

Fos

GR

HDAC

Hras1

IFN-α

IFN-β

JNK

Kras2

NCoR

NPM

NUMA

p300

p38 mitogen-activated protein kinase

p53

PKA

PLZF

PML

PPARγ

protein kinase C

RARα

RARβ

RARγ

retinaldehyde dehydrogenase-2

RXRα

RXRβ

RXRγ

SMRT

STAT5B

TIF2

TR3/NGFIB/Nur77

TRAIL

TRAP

WAF1

 Medscape DrugInfo:

arsenic trioxide

sodium phenylbutyrate

tamoxifen

Glossary

AP1

A transcription factor that is composed of c-JUN, either as a homodimer or as a heterodimer with c-FOS. Both are 'immediate-early genes': expression of these genes is low or undetectable in quiescent cells, but is activated within minutes after extracellular stimulation, such as addition of a growth factor.

ACUTE PROMYELOCYTIC LEUKAEMIA

(APL). A subtype of acute myelocytic leukaemia (AML), also referred to as AML–M3 in the French–American–British (FAB) classification; it is caused by chromosomal translocations involving RARα; the most common translocation (t(15;17)) generates a PML–RARα fusion protein that causes a block in differentiation of promyelocytes.

TERATOGEN

An agent that is capable of causing malformations in embryos.

COREPRESSORS (CoRs)

Proteins that cooperate with nuclear hormone receptors to repress transcription. CoRs tether histone deacetylase (HDAC)-containing complexes to target gene promoters. The two main nuclear receptor corepressors are NCoR (nuclear receptor corepressor) and SMRT (silencing mediator for retinoid and thyroid hormone receptor).

CO-ACTIVATORS (CoAs)

Proteins that cooperate with nuclear hormone receptors to activate transcription. Two classes are known: the p160 family, which recruits histone acetyltransferases, and the TRAP/DRIP/SMCC complex, which is thought to interact with the basal transcription machinery.

MORPHOGEN

A diffusible substance that carries positional information in the embryo, thereby determining the differentiation pathway that cells detecting this information will undergo.

CRE–LOX

A technology that allows genes to be ablated in a tissue-selective and inducible manner.

PHORBOL ESTERS

Polycyclic esters that are isolated from croton oil. The most common is phorbol myristoyl acetate (PMA, also known as 12,13-tetradecanoyl phorbol acetate or TPA). They are potent co-carcinogens or tumour promoters because they mimic diacylglycerol, thereby irreversibly activating protein kinase C.

SQUAMOUS- AND SPINOUS-CELL CARCINOMAS

Carcinomas that develop from the squamous or spinous layers of the epithelium.

BASAL-CELL CARCINOMA

A common carcinoma that is derived from the basal cells of the epidermis; often a consequence of exposure to sunlight and much more common in those with fair skin; it rarely metastasizes.

LEIOMYOMA

A benign tumour of smooth muscle in which parallel arrays of smooth muscle cells form bundles that are arranged in a whorled pattern. Leiomyoma of the uterus (fibroid) is the most common form.

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Altucci, L., Gronemeyer, H. The promise of retinoids to fight against cancer. Nat Rev Cancer 1, 181–193 (2001). https://doi.org/10.1038/35106036

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