Garle, M.J.; Middleton, B.; Hawkey, C.J.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA51
Academic Journal
Introduction: Sulindac (active metabolite: sulindac sulphide (SS)), is useful for the chemoprevention of colorectal cancer. Sulindac derivatives are active against COX-negative cancers by promoting apoptosis indicating that mechanisms unrelated to prostagland n synthesis are involved. We have shown that SS inhibits β-oxidation of long chain fatty acids. To explore precise mechanisms, we measured ADPstimulated oxygen consumption, proton transport (mitochondrial membrane potential (MMP)), and peroxide generation with different metabolic fuels: octanoate (OCT, C8 fatty acid), palmitoylcarnitine (PC, C16 fatty acid), pyruvate (PYR, glycolytic intermediate and succinate (SUC, TCA cycle intermediate. Methods: Rat liver mitochondria were prepared by differential centrifugation and ADP-stimulated oxygen uptake was measured using a Clark oxygen electrode. MMP andperoxide generation was determined in HCT-116 cells using JC-1 accumulation and dichlorofluorescin oxidation respectively. Results: SS (l00µM) inhibited octanoate and succinate but stimulated pyruvate, oxidation (see table). It enhanced MMP by 86% but suppressed peroxide generation. Conclusions: SS selectively inhibits fatty acid and succinate oxidation. Our data imply flavoproteins, eg succinate dehydrogenase, and medium chain acyl CoA dehydrogenase as possible targets. Suppression of peroxide formation may indicate an additional antioxidant action of SS.


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