The effect of a novel irreversible inhibitor of aldehyde dehydrogenases 1 and 3 on tumour cell growth and death

Aldehyde dehydrogenases (ALDHs) are a family of several isoenzymes expresse d in various tissues and in all subcellular fractions. In some tumours, the re is an increase of ALDH activity, especially that of class 1 and 3. The i ncrease in the activity of these isoenzymes is correlated with cell growth and drug resistance shown by these cells. It has been observed that hepatom a cells expressing low ALDH3 activity are more susceptible to growth inhibi tion by low concentration of lipid peroxidation products than hepatoma cell s expressing high ALDH3 activity. The products of lipid peroxidation are go od substrates for ALDH, but when their intracellular levers are increased i n hepatoma cells treated repeatedly with prooxidants, they inhibit ALDH3 an d bring about growth inhibition or cell death. As a follow up to the work p reviously reported on S-methyl 4-amino-4-methylpent-2-ynethioate, a synthet ic suicide inhibitor of ALDH1, which induced bcl2 overexpressing cells into apoptosis and exhibited an ED50 of 400 muM, a novel broad spectrum inhibit or of ALDH1 and ALDH3 was synthesised. This new compound (ATEM) is a suicid e inhibitor of ALDH1, an irreversible inhibitor of ALDH3 and exhibits an ED 50 of 10-25 muM on rat cultured hepatoma cells. Four hours after treatment with 25 muM ATEM, ALDH activity using benzaldehyde or propionaldehyde in he patoma cells was decreased by 40% and cell number by 15% compared with cont rols. As cell growth did not resume when the inhibitor was removed from the culture medium, it suggested strongly that. ALDHs play a pivotal role in m ediating cell death. (C) 2001 Elsevier Science Ireland Ltd. All rights rese rved.