Retinol for combating leukemia cells

Vitamin A, also known as retinol, is present in milk, liver, egg yolk, butter and other foodstuffs and as carotene in vegetables that have a yellow-orange colour, such as carrots and pumpkins.

This vitamin is accumulated in the liver where it is transformed into retinoid. Given that vitamin A, as such, has no effect on our organism, it is the retinoids that are responsible for the physiological activity of the vitamin.

Retinoids take part in three processes: in cell death, in cell differentiation and in cell proliferation.

Some ten years ago the Department of Cell Biology and Histology at the University of the Basque Country initiated research into how cell death was boosted by means of retinoids. It was thought that this potential could be used in the fight against cancer cells.

Clean and programmed death

Two types of death occur in cells: necrosis and apoptosis. Necrosis defines a pathological death, i.e. a death caused by a lack or deficit within the cell such as lack of oxygen or food.

On the other hand, apoptosis is the pre-programmed death of a cell. A number of cells have to die in order that our organism function correctly: for example, when the feet of a foetus are developed in the womb of a mother, at first the fingers are united by a membrane. This membrane has to disappear and, so, the cells thereof have to die off so that the hands may develop correctly. This cellular death is programmed in the embryo genes and has a concrete function. This is apoptosis.

All cells, in fact, have the necessary information to be able to undergo apoptosis but, of course, not all cells have to die. Both internal and external stimuli are what initiate this mechanism in those cases where it is necessary. Various modulating substances are involved amongst which are the retinoids.

Boosting apoptosis

Amongst these retinoids, researchers from the University of the Basque Country chose retinamide for their investigations. Retinamide is a synthetic retinoid, i.e. our body does not produce this substance naturally.

Natural retinoids are used to treat various diseases (e.g. those of the skin) but they turn out to be quite poisonous in the doses required – they are not well tolerated. This is why synthetic retinoids are created.

Specifically, the University research team analysed the effect of retinamide in certain types of leukemia – lymphoblastic leukemias. Nowadays, samples from the Hospital de Cruces in Bilbao are used in order to get these types of leukemia cells.

Lymphoblastic leukemias are, as their name indicates, a type of leukemia that affects lymphoblasts. Lymphoblasts are large cells, precursors of lymphocytes. Malign lymphoblasts are constantly dividing and they accumulate in the bone marrow impeding the formation of blood cells. In the analyses undertaken in the laboratory, it was seen that 95 % of these malign lymphoblasts died after application of retinamide. But what is the mechanism that really triggers this death?

To explain the process, the researchers analysed the action mechanism of the retinamide at a molecular level. From the analyses it was observed that the retinamide accelerated the oxidative stress within the malign cells and that this stress triggered the mechanisms leading to apoptosis. This death is normally clean and programmed death, and, to this end, a group of enzymes cut the protein inside the cell at certain sites, leading to the death of the cell in question. The death has no effect on healthy adjacent cells, does not result in swelling and the side effects are minimal.

Thus, according to what has been shown, retinamide has great potential to eliminate the lymphoblastic cells without affecting healthy lymphocytes nor the rest of the normal cells.

Made-to-measure treatment

With the molecular action mechanism understood, researchers investigated why retinamide did not affect healthy cells and they discovered other factors to explain the phenomena. So, apart from molecular mechanisms, other factors that affect the efficacy of retinamide could be clearly seen. These and others should be taken into account if a pharmaceutical to combat leukemias based on retinamide is to be marketed.

Moreover, according to the researchers, future treatment will be patient-specific. As is well known, not all patients suffering from the same illness respond in the same way to the same treatment. This is why lines of medical and pharmaceutical research increasingly mention the need to know the genetic characteristics of each patient in order to specify suitable treatment. In the case of retinamide, treatment will also be similarly specific but, before this, the trigger mechanism of the retinamide in the cells has to be known and this research will provide key data to this end.