Thomas H. Porter

Inhibition of coenzyme Q10-enzymes, succinoxidase and NADH-oxidase, by adriamycin and other quinones having antitumor activity.

Summary Adriamycin, carminomycin, and daunorubicin inhibit the coenzyme Q 10 -enzymes, succinoxidase and NADH-oxidase. Adriamycin 14-octanoate, which is more lipoidal than adriamycin, was the most effective inhibitor of the anthracyclines for both enzymes, and was 1/12 as effective as the standard inhibitor, 6-ω-cyclohexylpentyl-5-hydroxy-2,3-dimethoxy-1,4-benzoquinone, of coenzyme Q 10 for NADH-oxidase. Lapachol and dichloroallyl lawsone inhibited succinoxidase, and the latter of all quinones was second only to the standard for inhibition. These data indicate that the antitumor activities of adriamycin could possibly be partly due to inhibition of CoQ 10 -enzymes in electron transfer processes of cell respiration in addition to intercalation within DNA helices.

The site of inhibition of mitochondrial electron transfer by coenzyme Q analogues

Abstract The effects of 33 quinone derivatives on mitochondrial electron transfer in yeast were examined. Twenty-two of the compounds were also tested for their effects on the growth of yeast cells. Four strong inhibitors of electron transfer were identified: 5-n-undecyl-6-hydroxy-4, 7-dioxobenzothiazole, 7-ω-cyclohexyloctyl-6-hydroxy-5,8-quinolinequinone, 7-n-hexadecyl-mercapto-6-hydroxy-5, 8-quinolinequinone, and 3-n-dodecylmercapto-2-hydroxy-1, 4-naphthoquinone. They inhibit the growth of yeast with ethanol as an energy source, but not when glucose is the energy source. The NADH oxidase activity of isolated mitochondria is 50% inhibited by these quinone derivatives at about 10−8 m , or 0.5 μmol/g mitochondrial protein; 1000-fold higher concentrations do not affect electron transfer from NADH or succinate to coenzyme Q2. The effects of the inhibitors on cytochrome spectra indicate that they block electron transfer between cytochromes b and c1. A possible antagonism between these compounds and coenzyme Q at a site between cytochromes b and C1 is discussed in terms of Mitchells “protonmotive Q cycle” hypothesis (Mitchell, P. (1976) J. Theor. Biol. 62, 327–367). 6-β-naphthylmercapto-5-chloro-2,3-dimethoxy-1,4-benzoquinone inhibits electron transfer between succinate and coenzyme Q2 or phenazine methosulfate, suggesting a site in the succinate-coenzyme Q reductase complex with a different quinone specificity from that of the site in the cytochrome bc1 complex. Seven of the quinone derivatives inhibit growth on both glucose and ethanol media, indicating that their effect is not the result of inhibition of respiration.

Inhibition by adriamycin of the mitochondrial biosynthesis of coenzyme Q10 and implication for the cardiotoxicity of adriamycin in cancer patients

Summary Steps were standardized as a control system for the mitochondrial biosynthesis of coenzyme Q 10 from radioactive p-hydroxybenzoic acid. In this system, adriamycin inhibited the biosynthesis. Adriamycin and the reference inhibitor of the functionality of CoQ 10 -enzymes at the same concentration gave the same inhibition of biosynthesis. Whatever the mechanism(s) may be for this inhibition by adriamycin of biosynthesis of CoQ 10 , in conjunction with the known inhibition by adriamycin of the functionality of CoQ 10 -enzymes, the net result could partially account for the cardiotoxicity of adriamycin in cancer patients. Administration of CoQ 10 to such patients could circumvent depressed biosynthesis and the inhibition of CoQ 10 -enzymes with some possible reduction of cardiotoxicity.

New quinolinequinone inhibitors of mitochondrial reductase systems and reversal by coenzyme Q

Summary 3-ω-Cyclohexyloctyl-2-hydroxy-1,4-naphthoquinone and 7-ω-cyclohexyloctyl-6-hydroxy-5,8-quinolinequinone inhibit the succinate-cytochrome c reductase and the succinate-coenzyme Q reductase in beef heart submitochondrial systems. These inhibitions could be reversed by coenzyme Q 6 . These analogs of coenzyme Q also inhibit the succinate-coenzyme Q reductase of intact mitochondria from the human heart.

Synthesis, enzyme inhibition, and antitumor activity of new 1,4-benzoquinone analogs of coenzyme Q10

Abstract A rationale based upon coenzyme Q 10 (CoQ 10 , ubiquinone) for the synthesis of potential antitumor agents constitutes a new approach in the search toward chemotherapy of cancer. The antitumor activities of 38 alkyl-1,4-benzoquinones, analogs of coenzyme Q, 24 of which are new compounds, are described. The 10 best antitumor analogs of CoQ all showed long-term cures of Walker carcinosarcoma 256 in rats. Particularly impressive were the 6- n -octylmercapto-5-chloro-2,3-dimethoxy-1,4-benzoquinone (NSC 252188), which cured six out of six rats with % T C = 584 at 3.13 mg/kg , 6-phytyl-5-hydroxy-2,3-dimethoxy-1,4-benzoquinone (NSC 277818) (four out of four cures, % T C = 923 at 50 mg/kg ), and 5-phytyl-2,3-dimethoxy-1,4-benzoquinone (NSC 276371) (three out of six cures, % T C = 789 at 0.78 mg/kg ). In general, a 5-chloro or 5-hydroxy group on the quinone nucleus or a side chain with unsaturation and branching, such as the phytyl side chain of NSC 277818 and NSC 276371, seemed to increase antitumor activity. Although a perfect correlation was not to be expected, many of the most potent antitumor analogs were also among the best in vitro inhibitors of the mitochondrial CoQ 10 -enzymes, succinoxidase, and NAD oxidase.

Inhibition of valine utilization by cyclobutaneglycine.

Abstract dl -Cyclobutaneglycine formed by basic hydrolysis of 5-cyclobutylhydantoin prevents the growth of Escherichia coil W in an inorganic salts-glucose medium. This inhibitory effect of the amino acid analog is reversed in a competitive manner over a wide range of concentrations specifically by l -valine. Studies with valyl-tRNA synthetase indicate that cyclobutaneglycine not only prevents the formation of valyl-tRNA but also is transferred to tRNA val . The cellular uptake as well as incorporation into protein of valine is inhibited by cyclobutaneglycine.

Inhibition of nucleic acid synthesis in leukemia 1210 cells by antimetabolites of coenzyme Q10.

Abstract Thirteen diversified antimetabolites of coenzyme Q10 which have antitumor activity in vivo were tested for inhibition of uptake of tritiated thymidine and uridine into DNA and RNA, respectively, of L1210 cells grown in tissue culture. Eight of these antimetabolites have inhibitory activities of the same order of magnitude as the used anticancer drugs, rubidazone and ellipticine. 5-ω-Phenylpropylmercapto-2,3-dimethoxy-1,4-benzoquinone was particularly potent to inhibit nucleic acid synthesis; ED50 for DNA = 2.1 μM and ED50 for RNA = 4.0 μM.