Kahalalide F (KF) is a novel
antitumor drug of marine origin under clinical investigation. KF showed a potent cytotoxic activity against a panel of human prostate and
breast cancer cell lines, with IC(50) ranging from 0.07 micro M (PC3) to 0.28 micro M (DU145, LNCaP, SKBR-3, BT474, MCF7). Importantly, nontumor human cells (MCF10A, HUVEC, HMEC-1, IMR90) were 5-40 times less sensitive to the
drug (IC(50) = 1.6-3.1 micro M). KF cytotoxicity did not correlate with the expression level of the multidrug resistance MDR1 and of the
tyrosine kinase HER2/NEU, and only slightly by the anti-apoptotic BCL-2
protein. KF action was triggered rapidly by short pulse treatments (15 min caused 50% maximum cytotoxicity). Neither a general
caspase inhibitor (
Z-VAD-fmk) nor transcription or translation inhibitors (
actinomycin D,
cycloheximide) blocked KF action. Flow cytometry analysis revealed that KF induced neither cell-cycle arrest nor apoptotic hypodiploid peak. Using mitochondrial (JC-1)- and lysosomal (
LysoTracker Green,
Acridine Orange)-specific fluorophores, we detected loss of mitochondrial membrane potential and of lysosomal integrity following KF treatment. Confocal
laser and electron microscopy revealed that KF-treated cells underwent a series of profound alterations including severe cytoplasmic swelling and vacuolization, dilation and vesiculation of the endoplasmic reticulum, mitochondrial damage, and plasma membrane
rupture. In contrast, the cell nucleus showed irregular clumping of
chromatin into small, condensed masses, while
chromatin disappeared from other nuclear domains, but the nuclear envelope was preserved and no
DNA degradation was detected. Together, these data indicate that KF induces cell death via oncosis preferentially in
tumor cells.