Disease relevance of AFMID

• EXPERIMENTAL DESIGN: Adult patients with advanced or metastatic androgen refractory prostate cancer received KF as an i.v. infusion over 1 hour, during five consecutive days every 3 weeks [1].
• In line with previous reports, we show that KF caused rapid and potent cytotoxicity in the breast cancer cell lines SKBR3 and BT474, characterized by cytoplasmic swelling and DNA clumping [2].
• The sensitivity to KF in a panel of human tumor cell lines derived from breast (SKBR3, BT474, and MCF7), vulval (A431), non-small-cell lung (H460, A549, SW1573, and H292), and hepatic (Skhep1, HepG2, and Hep3B) carcinomas positively correlated with ErbB3 (HER3) protein levels [2].
• We investigated the cytotoxicity of KF in cell lines from breast, ovary, prostate and colon cancers, but focused on hepatoma cell lines, performing mechanistic studies in HepG2 (IC50 = 0.3 microM) and PLC/PRF/5C (IC50 = 5 microM) [3].

High impact information on AFMID

• Kahalalide F (KF) is a novel marine-derived antitumor agent that is currently undergoing phase II clinical trials [2].
• Altogether, these data indicate that KF-induced cell death is a necrosis-like process [2].
• Furthermore, the pharmacokinetics after KF administration and preliminary antitumor activity were evaluated [1].
• On the other hand, stable transfection of an ErbB3-expressing plasmid increased the KF sensitivity of H460 cells, the most resistant cell line in our panel [2].
• PURPOSE: The purpose is to determine the maximum tolerated dose, profile of adverse events, and dose-limiting toxicity of Kahalalide F (KF) in patients with androgen refractory prostate cancer [1].

Chemical compound and disease context of AFMID

• Kahalalide F (KF) is a novel cyclic depsipeptide anticancer drug, which has shown anticancer activity both in vitro and in vivo especially against human prostate cancer cell lines [4].

Biological context of AFMID

• Recombinant casein kinase II phosphorylated the 63F and 63 delta KF fusion proteins in vitro but did not phosphorylate the 63 delta NF fusion protein, implying that phosphorylation occurred between amino acids 142 and 210 [5].
• Flow cytometry analysis revealed that KF induced neither cell-cycle arrest nor apoptotic hypodiploid peak [6].

Anatomical context of AFMID

• The pattern of cell permeability is similar to maitotoxin, another small cytotoxic peptide, but the differential effects on the cell membrane induced by KF in HepG2 and PLC/PRF/5C suggest specific interactions with membranes or proteins [3].
• 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 [6].
• 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 [6].
• Under the conditions of this study, NT files used with the BF technique were significantly less likely to change canal curvature than either FR or KF files when instrumenting curved root canals [7].

Associations of AFMID with chemical compounds

• Following KF exposure, HepG2 cells demonstrated profound ATP depletion, associated with cell swelling and cell blebbing, and increased permeability to propidium iodide (PI), annexin V (AV) and release of lactate dehydrogenase (LDH) [3].
• A butyric acid analogue of KF was used as the internal standard [4].
• Microbore reversed-phase liquid chromatography (LC) performed with mobile phases containing trifluoroacetic acid, an additive commonly used for separating peptides, resulted in substantial suppression of the signal for KF on ESI-MS/MS [4].
• Results showed statistically less reduction in canal curvature with nickel-titanium (NT) files compared with either Flex-R (FR) (p < 0.05) or K-Flex (KF) files (p < 0.0021) [7].
• Neither a general caspase inhibitor (Z-VAD-fmk) nor transcription or translation inhibitors (actinomycin D, cycloheximide) blocked KF action [6].

References