Modulation of doxorubicin activity in cancer cells by conjugation with fatty acyl and terpenyl hydrazones

Doxorubicin N-acylhydrazones derived from saturated, unsaturated and terpene-terminated fatty acids were tested for anticancer activity in cells of human HL-60 leukaemia, 518A2 melanoma, MCF-7/Topo breast and KB-V1/Vbl cervix carcinomas. In the latter, the N-heptadecanoyl hydrazone was more cytotoxic than its unsaturated C18-fatty acyl analogues and even three times more than doxorubicin. The (menthoxycarbonyl)undecanoyl hydrazone was twice as active as doxorubicin in these multidrug resistant KB-V1/Vbl and in the 518A2 cells and also more efficacious in KB-V1 and MCF-7 cells that had been desensitised for doxorubicin. All hydrazones induced apoptosis albeit by slightly different mechanisms. While apoptosis induction by the menthoxymalonyl hydrazone was characterized by an upfront increase in caspase-8 activity, all other hydrazones elicited a hike in caspase-9 activity. Treatment of HL-60 and 518A2 cells with doxorubicin or its heptadecanoyl, linolenoyl, (menthoxycarbonyl)undecanoyl or menthoxymalonyl hydrazones also led to diverging increases of the ratio of bax to bcl-2 mRNA expression, of reactive oxygen species and of mitochondrial membrane damage.