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Nuclear Magnetic Resonance-visible Lipids Induced by Cationic Lipophilic Chemotherapeutic Agents Are Accompanied by Increased Lipid Droplet Formation and Damaged Mitochondria¹

Department of Cancer Medicine, The University of Sydney, New South Wales 2006, Australia [E. J. D., W. A. C., N. S.]; Central Sydney Area Health Service Electron Microscopy Unit, Concord Hospital, Concord, New South Wales 2139, Australia [S. B.]; and Darryl Rideout Structural Bioinformatics, Inc., San Diego, California [D. C. R.]

Proton nuclear magnetic resonance (NMR) spectroscopy, histological lipid staining, and electron microscopy were used to assess the biochemical and structural changes induced by treating the cultured human breast cell line HBL-100 with the cationic lipophilic phosphonium salts p-(triphenylphosphoniummethyl) benzaldehyde chloride (drug A) and [4-(hydrazinocarboxy)-1-butyl] tris-(4-dimethylaminophenyl) phosphonium chloride (drug B). The major biochemical change detected by ¹H NMR in drug-treated cells was a significant time- and concentration-dependent increase in lipid acyl chain resonances arising from mobile lipids. The amount of NMR-visible lipid strongly correlated with morphometric measurements of oil red O-staining lipid detected in the cytoplasm by light microscopy. Ultrastructural investigations revealed substantial damage to mitochondria and the progressive development of lipid droplets accompanied by end-stage autophagic vacuoles, in the form of densely staining myelinoid bodies, after treatment of HBL-100 cells with drug B at the IC₅₀. No apparent increase in acid phosphatase activity was observed using electron microscopy, indicating that the accumulation of phospholipids in myelinoid bodies may result from substrate inundation of the lysosome, rather than increased lysosomal activity. These results indicate a potential role for lysosomal lipid catabolism in the formation of NMR-visible lipids in models of cytotoxic insult.

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