Retinoic Acid, Accutane, vitamin A, and cancer

Retinoic Acid, Accutane, vitamin A, and cancer

Vitamin A can control cell growth and cancer cell death; a concentrated form, Isotretinoin, 13-cis-retinoic acid, or Accutane originally developed to treat acne, has sometimes been used to treat cancer and is now finding a role to restrict the regrowth of cancer stem cells in brain cancer.

Retinoic Acid and Retinol

Vitamin A is Retinol.

Retinoic Acid is a metabolite of vitamin A. Both forms are Retinoids. All-trans-retinoic acid is required for health in all chordate animals - from fish to humans. While too much vitamin A is known to cause toxicity in the body, you can concentrate retinoic acid to effect the job required. 

An antioxidant, retinoic acid has effects in cell growth and differentiation, and high doses are  known to play a role in p27 regulation, apoptosis and cell cycle arrest in cancer. A variety of cancers have been shown to be suppressed by retinoic acid including brain, lung,melanoma, prostate, breast, ovarian, bladder, oral, and skin cancers (1).

And all-trans retinoic acid provides a great number of signaling metabolites, In a normal heathy individual some of these cause the differentiation of 'blank' repair stem cells into normal body cells. This led to the theory that retinoids could equally cause cancer stem cells (the cells at the heart of all cancers; the cells no orthodox cancer drugs are capable of killing) to be reversed into 'normal' cancer cells that drugs can kill, or even all the way back into normal healthy cells! One 2015 study showed that, indeed, vitamin A could reverse cancer stem cells in Pancreatic cancer, known to have high levels of cancer stem cells (2). The researchers showed that it could regulate self-renewal and suggested it could be very useful alongside chemotherapy treatments.

Go to: Vitamin A and cancer

Sources of vitamin A: Retinoic acid can cause toxicity in cells and so small doses of supplements are generally advised. Vitamin A, can be found in cod liver oil, beef liver, carrots, sweet potato, red pepper, black eyed peas, watermelon, dried apricots, mango and tomato juice. It can be made safely in the body from beta-carotene.

Dr Young S. Kim, head of cancer and nutrition at the NCI has vitamin A in her list of nine compounds that can slow down cancer and prevent recurrence. Activation of the RA signaling pathway seems to both prevent and potentially correct cancer, for example, reversing pre-malignant epithelial lesions. Disruption of the pathway is linked to blood and lymph cancers and even brain and medullablastoma (3).

Research on bone marrow involvement in blood and lymph cancers has shown that cancer stem cell strength is achieved by blocking retinoid signaling action, and this also promotes drug resistance (4).

Accutane - an off-label drug for cancer?

Accutane is an acne drug for cystic acne, approved for more than 25 years, and is 13-cis-retinoic acid. As a drug, 13-cis-retinoic is also called Isotretinoin. It is an isomer of all-trans-retinoic acid and not present at the same levels as all-trans in the human body. Often, acne treatments are presented as 'related to natural vitamin A' or 'a form of vitamin A'.. As an acne medication it aims to reduce the amount of oil produced by your oil glands in the skin and bring about skin renewal.

Such retinoic acids can be 100 times more concentrated than vitamin A. Accutane has been used as a chemotherapy. From the Website 'Chemocare' we see that 'retinoids control normal cell growth, cell differentiation (the normal process of making cells different from each other), and cell death during embryonic development and in certain tissues later in life.  Retinoids effects on the cells are controlled by two major classes of retinoid receptors on the nucleus:  retinoic acid receptors (RAR) and retinoid-X-receptors (RXR). And Accutane works by binding to these receptors and blocking cell growth.

Accutane was used by Professor Ben Williams as part of a package of 'repurposed' or 'off-label' drugs he used to beat his Glioblastoma brain cancer in 1998. (See here). Not just to block cancer cell growth, not to block recurrence. Accutane can be used along with resveratrol to turn cancer stem cells into normal cancer cells. This concentrated form of vitamin A metabolites can block cancer stem cells regrowing.

It's worth saying that Accutane appears to have rather a lot of side-effects - see here. It has been withdrawn from wide circulation by the manufacturer (Roche) because of these and that it seemed to cause IBS. 

Vitamin A, Accutane, cancer treatment overall

Certainly retinoids do react with cancer-forming pathways, such as oestrogen signaling in breast cancer and it is known that vitamin A has anti-cancer effects. However cells metabolise retinoids rapidly and epigenetic changes help tumours become retinoid resistant.

As a result, using retinoids as an anti-cancer cancer treatment requires other drugs and natural compounds in a total combination that can also block methylation and histone increases.

Retinoic acid and Neuroblastoma

Children with high risk neuroblastoma, have been treated with 13 cis-retinoic acid or isotretinoin for 6 months after being treated with chemotherapy and a stem-cell transplant. It is known to reduce the risk of recurrence. The drug is pulsed, two weeks on, two weeks off. Scientists are currently trying to develop new drugs from retinoids with less side effects.

Accutane may cause cancer

This drug must not be used in the long term. There are also reports that after several years of use it can even cause cancer - colorectal and some types of leukemia.

Go to: Repurposed off-label drugs for cancer

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References

1. Retinoic acid and cancer treatment; Mei-Chih Chen et al; Biomedicine (Taipei);  2014;4(4):22; 

2. Retinoic Acid Reduces Stem Cell-Like Features in Pancreatic Cancer Cells; Marta Herreros-Villanueva, Tze-Kiong Er, Luis Bujanda; Pancreas, 2015 Aug;44(6):918-24.

3. Retinoic acid receptors: from molecular mechanisms to cancer therapy; Alessandra Di Masi et al; Mol Aspects Med 2015 Feb;41:1-115.

4. Retinoic acid, CYP26, and drug resistance in the stem cell niche; Salvador Alonso, Richard J Jones, Gabriel Ghiaur;  Exp Hematol; 2017 Oct;54:17-25.

Annual Review of Pathology 2011: https://www.ncbi.nlm.nih.gov/m/pubmed/21073338/

2022 Research
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