Kahalalide F, a new marine-derived compound, induces oncosis in human prostate and breast cancer cells.
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.
Suárez
Yajaira
Y
Pharma Mar S.A., Madrid, Spain.
González
Laura
L
Cuadrado
Ana
A
Berciano
Maite
M
Lafarga
Miguel
M
Muñoz
Alberto
A
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D002471:Cell Transformation, Neoplastic; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D047630:Depsipeptides; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008978:Mollusk Venoms / Q000737:chemistry*; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D047630:Depsipeptides; D008978:Mollusk Venoms; D009842:Oligopeptides; D010455:Peptides; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C097897:kahalalide F; D020169:Caspases