Cancer destruction in vivo through disrupted energy metabolism. Part II. Lipid peroxidation and cell death; drug resistance as a consequence of reversible cellular injury.
In the second part of this review of autoxidative cellular injury and death in tumor cells, the presence of saturated or polyunsaturated fatty acids, vitamin E, and free or esterified cholesterol in whole cells and organelles is discussed in the context of enhancing or attenuating lipid peroxidation. The disposition of unsaturation within polyunsaturated fatty acid molecules is critical for tumor promotion, but the situation appears ambivalent with regard to inflicting cellular injury. Increases in lipid peroxidation and phospholipase A2 activity following on from the administration of hormones or non-cytotoxic drugs are considered from the viewpoint of generating hydroperoxyfatty acids and lysophosphatides, both of which disrupt mitochondrial energy production by uncoupling oxidative phosphorylation. The metabolic fate of lysophosphatides is thought to be a crucial factor both in determining whether cancer cells survive or not, and in furnishing protection for surviving cells against subsequent attack. Both energy-dependent and energy-independent mechanisms for acylating lysophosphatides are reviewed. The emergence of an unstable form of drug resistance during the recovery phase is interpreted in terms of the chemical identity of the new acyl groups on the acylated lysophospholipid. Resistance to further free radical challenge can be conferred by the regeneration of phospholipids bearing saturated or monoenoic 2-substituents which are unable to undergo peroxidation.
Jones
G R
GR
Department of Biochemistry, University of Surrey, Guildford, U.K.
D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D004351:Drug Resistance; D004734:Energy Metabolism / Q000187:drug effects*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology