BIOCHEMICAL MODULATION OF DOXORUBICIN USING AN ISOPRENOID DERIVATIVE,N-1379 - PLASMA TRANSMEMBRANE POTENTIAL AS A TARGET SITE

A new isoprenoid derivative, N-1379, was evaluated as a modulating age nt of doxorubicin (DOX)-induced anticancer efficacy. The level of plas ma transmembrane potential, measured using DiOC6(3), correlated with c ellular sensitivity to DOX in K562 myelogenous leukemia, SH101 stomach , and PH101 pancreatic cancer cells. Non-toxic N-1379 increased the ce llular transmembrane potential and DOX efficacy for three cell lines. The modulation of membrane function was accompanied by increases of DO X accumulation and S/G(2)M phase population in these cells. Overexpres sion of a 170 kD plasma membrane glycoprotein (GP-170) was not observe d in any cells examined. We suggest therefore that interaction between electronegative transmembrane potential and positive charge of DOX ma y be linked to intracellular DOX accumulation. N-1379 may augment DOX efficacy through its increasing effect on plasma membrane potential in dependently of GP-170 overexpression.