RA synthetic derivative 4-HPR's ability to induce tumour cell death

Retinoic acid (RA), a natural derivative of vitamin A, is the basis of a number of treatments against cancer. Nevertheless, it has certain disadvantages, such as the possibility of the appearance of retinoic acid syndrome, present in 25 % of cases and which can lead to death. The development of 4-HPR, a synthetic derivative of RA, has meant a considerable advance due to its greater efficacy compared to its predecessor. It is able to induce the death of tumour cells as the method for reducing their proliferation, in a precise manner and without serious damage to surrounding tissue. Moreover, it halts the referred-to retinoic acid syndrome and even functions with cells that resist RA. In vitro studies corroborate its effectiveness as a chemopreventive agent and also as a chemotherapeutic agent, both with leukaemias and with ovary, breast or brain tumour cells.

Biologist Ms Aintzane Apraiz studied the 4-HPR in depth, focusing on the causes that, according to previous research, give rise to this ability to induce cell death. To this end, she applied this synthetic derivative to acute lymphoblastic leukaemia T cells (LLA-T). Her PhD thesis, defended at the University of the Basque Country (UPV/EHU), is entitled "Role of sphingolipids and oxidative stress in the antineoplasic activity of 4-HPR: study in a leucemia model".

Not such a direct relation

Amongst the various processes that can induce cell death, in the case of 4-HPR, apoptosis is outstanding; a precise mechanism and without inflammatory processes or serious damage to surrounding tissue. According to Ms Apraiz, previous research on LLA-T undertaken by the team of which she is a member, showed that 4-HPR induced a massive accumulation of ceramides (lipids of the cell membrane) and of reactive oxygen species (ROS), both of which can cause cell death. However, the PhD thesis shows that the cause-effect relation is not so direct.

To start with, thanks to new technological advances, Ms Apraiz has been able to show that it is not the ceramides that are accumulated due to the 4-HPR effect, but their precursors - dihydroceramides, these latter thought to date to be biologically inactive. Moreover, the thesis concludes that the accumulation of these dihydroceramides does not cause cell death, as it occurs in cells both resistant and sensitive to 4-HPR. If such accumulation was a key to cell death, it would not occur in the same way in resistant cells.

As regards the relation between the accumulation of ROS and cell death, the PhD thesis concludes that there is a direct connection in this case, but this in itself does not explain the whole process. In fact, Ms Apraiz observed that, even using antioxidants such as NDGA in order to neutralise the accumulation of ROS, the 4-HPR continued to be able to induce cell death.

Compatible with alternative therapies

Ms Apraiz also showed that, in the case of failure of treatment with 4-HPR, the possible effectiveness of alternative therapies is not affected. That is, the researcher observed that, unlike what happens with other treatments, the LLA-T cells that become resistant to 4-HPR continue to be sensitive to other compounds, and so alternative therapies based on these latter compounds may well continue to be effective even though the 4-HPR has failed.