Multidrug-resistance (MDR) is largely caused by the efflux of
therapeutics from the
tumor cell by means of
P-glycoprotein (P-gp), resulting in reduced efficacy of the
chemotherapy. In order to overcome MDR, substances, such as
verapamil and
cyclosporin A (CsA), were employed. As these P-gp modulating agents did not seem promising in clinical practice, new compounds with a low degree of undesirable side effects, were introduced. In this study, bisindolic
alkaloid voacamine was examined for its possible capability of enhancing the cytotoxic effect of
doxorubicin (DOX) on
drug resistant cells. Two different pairs of tumor cell lines were analyzed: the parental lymphoblastoid cell line CEM-WT and its MDR derivative CEM-R, the parental
osteosarcoma cell line U-2 OS-WT and its resistant counterpart U-2 OS-R. These cell lines were characterized for their morphological features by scanning electron microscopy (SEM) and for the expression of the main
drug transporters by flow cytometric analysis. The effects of
voacamine on the cell survival and on both accumulation and efflux of DOX were then investigated. The intracellular distribution of DOX, given alone or in association with CsA or
voacamine, was observed by
laser scanning confocal microscopy. A differential effect of
voacamine between sensitive and resistant cells on the intracellular DOX concentration and distribution was shown. In particular,
voacamine induced a significant increase of
drug retention and intranuclear location in resistant cells. The results of cell survival experiments revealed an enhancement of the cytotoxic effect of DOX induced by
voacamine, confirmed by evident morphological changes observed by SEM. These findings suggest promising applications of this natural substance against MDR
tumors.