Retinoids for Cancer Treatment

Retinoids currently play a limited role in cancer treatment and prevention despite potential in physiological pathways. Toxicity represents the main limitation to the prolonged use of retinoids.

Retinoids are natural and artificial compounds that are similar in structure or biological activity to retinol or vitamin A.  Retinoids are critical in vision, normal embryonic development, and in the control of cellular growth, differentiation, proliferation, and apoptosis.

Inside cells, retinoids bind to nuclear receptors that regulate concerted programs of gene expression.  Both retinoic acid receptor (RAR) and retinoid X receptor (RXR) are important in drug action.  These programs elicit physiologic changes inducing cell differentiation, anti-proliferation, pro-apoptotic, and anti-oxidant effects. Retinoids modulate the growth of both normal and malignant cells. They exert their effects through a variety of binding proteins including cellular retinol-binding protein (CRBP), retinol-binding proteins (RBP), cellular retinoic acid-binding protein (CRABP), and the RAR and RXR nuclear receptors.

Retinoids in cancer treatment

Scientists have investigated retinoids as potential chemotherapeutic or chemopreventive agents, and have found they promote differentiation and cancer cell death in a number of experimental systems (2, 3). Some of the most successful therapeutic uses of retinoids are due to their differentiation-inducing effects, i.e., they induce the maturation of cancer cells into normal cells.

In humans, retinoids have been shown to reverse premalignant human epithelial lesions, induce the differentiation of myeloid cells, and prevent lung, liver, and breast cancer (1). These applications include:

Acute promyelocytic leukemia

Retinoid can effectively treat a rare leukemia, acute promyelocytic leukemia (APL). APL is characterized by selective expansion of immature myeloid precursors or malignant myeloid cells. In 1995, the FDA approved all-trans retinoic acid (tretinoin) for treating APL. Marketed under the trade name of Vesanoid®, it is administered orally. In vitro tests show that tretinoin forces APL cells to differentiate and stops them from proliferating.

Kaposi’s sarcoma

Alitretinoin (9-cis RA) is FDA-approved for the topical treatment of cutaneous lesions of Kaposi’s sarcoma (4). Alitretinoin regulates nuclear genes and mitochondrial gene transcription (5). Marketed under the brand name of Panretin®, it is applied topically on the skin.

Cutaneous T-cell lymphoma.

Bexarotene (brand name: Targretin) is a synthetic retinoid approved by the FDA to treat skin problems caused by cutaneous T-cell lymphoma that are unresponsive to other treatments (6). Bexarotene is administered either orally or as a topical gel. It selectively binds and activates retinoid X receptor subtypes.

Breast cancer

Retinoids may be able to breast cancer (7) although they are not widely used for that purpose. Scientists have shown they can inhibit breast cancer cells at the early stages of tumor progression, but their effectiveness diminishes as the tumors become more aggressive.

The precise mechanism by which natural and synthetic retinoids inhibit the proliferation of breast cancer cells has not been elucidated. Retinoids are currently in clinical trials as a single drug or in combination with interferons and estrogen antagonists to treat or prevent the progression of breast cancer

Retinoic Acid in cancer prevention

In children with high-risk neuroblastoma, treatment with Isoretinoid (13-cis-retinoic acid) reduces the risk of the cancer coming back after high-dose chemotherapy and stem cell transplant. The drug is marketed under different brand names (e.g. Accutane®), and is administered orally.

Isotretinoin is also effective in preventing head, neck and thyroid cancer. It exhibits immuno-modulatory and anti-inflammatory responses. Its exact mechanism of action is unknown.

Precancerous lesions such as leukoplakia, actinic keratosis, and cervical dysplasia can be effectively treated by the classical retinoids.  Natural and synthetic retinoids are currently in clinical trials for the treatment of many cancers forms, including lymphoma, leukemia, melanoma, lung cancer, liver cancer, cervical cancer, kidney cancer, neuroblastoma, and glioblastoma.

References

    1. Bushue N, Wan YJY. Retinoid pathway and cancer therapeutics. Advanced Drug Delivery Reviews. 2010;62(13):1285-1298.Baumann L, Vujevich J, Halem M, et al. Open-label pilot study of alitretinoin gel 0.1% in the treatment of photoaging. Cutis. 2005;76(1):69-73.
    2. Idres N, Benoit G, Flexor MA, Lanotte M, Chabot GG. Granulocytic differentiation of human NB4 promyelocytic leukemia cells induced by all-trans retinoic acid metabolites. Cancer Research. 2001;61(2):700-705.
    3. Nagy L, Thomazy VA, Shipley GL, et al. ACTIVATION OF RETINOID-X RECEPTORS INDUCES APOPTOSIS IN HL-60 CELL-LINES. Molecular and Cellular Biology. 1995;15(7):3540-355
    4. Baumann L, Vujevich J, Halem M, et al. Open-label pilot study of alitretinoin gel 0.1% in the treatment of photoaging. Cutis. 2005;76(1):69-73.
    5. Lin Y-W, Lien L-M, Yeh T-S, Wu H-M, Liu Y-L, Hsieh R-H. 9-cis retinoic acid induces retinoid X receptor localized to the mitochondria for mediation of mitochondrial transcription. Biochemical and Biophysical Research Communications. 2008;377(2):351-354.
    6. Qu L, Tang X. Bexarotene: a promising anticancer agent. Cancer Chemotherapy and Pharmacology. 2010;65(2):201-205.
    7. Zanardi S, Serrano D, Argusti A, Barile M, Puntoni M, Decensi A. Clinical trials with retinoids for breast cancer chemoprevention. Endocrine-Related Cancer. 2006;13(1):51-68.

Specific Retinoid Cancer Drugs

Alitretinoin

Brand/Trade Names: Panretin, 9-cis-retinoic acid

Formula: C20H28O2

Mechanism:

Class: Retinoid

Administration: topical (gel)

Notes: A form of Vitamin A

Bexarotene

Brand/Trade Names: Targretin

Formula: ‎C24H28O2

Mechanism:

Class: Retinoid

Administration: topical and oral

Notes: Considered a third-generation retinoid

Isotretinoin

Brand/Trade Names: Acutane

Formula: C20H28O2

Mechanism:

Class: Retinoid

Administration: Oral

Notes:

Tretinoin

Brand/Trade Names: Vesanoid

Formula: ‎C20H28O2

Mechanism:

Class: Retinoid

Administration: topical

Notes: