Antisense oligonucleotides against aldehyde dehydrogenase 3 inhibit hepatoma cell proliferation by affecting MAP kinases.

The increased activity of enzymes that eliminate anti-tumour drugs or their metabolites is one of the important limiting factors in therapeutic protocols. Among these enzymes, aldehyde dehydrogenase 3 (ALDH3) is considered a mechanism by which tumour cells evade the cytotoxic effects exerted by cyclophosphamide and drugs acting by free radical generation. It is also important in metabolising cytostatic aldehydes derived from lipid peroxidation. Therefore, ALDH3 may play a role in regulating cell proliferation in tumour cells with high activity of this enzyme. We previously reported that antisense oligonucleotides (AS-ODN) against ALDH3 strongly inhibit hepatoma cell growth, suggesting that this effect could be due to the accumulation of cytostatic aldehydes in the cells. In this research we demonstrate that AS-ODN against ALDH3 increase the quantity of malondialdehyde in the cells, and inhibit cell proliferation by affecting the MAPK pathway: a reduction of pRaf-1 and pERK1,2 was observed. These results confirm the importance of aldehydes derived from lipid peroxidation and of ALDH3 in regulating hepatoma proliferation. Moreover, the results indicate the use of AS-ODN against ALDH3 as a possible strategy to reduce growth in tumours overexpressing this enzyme.