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© 2005 The American Society for Nutritional Sciences J. Nutr. 135:1510-1514, June 2005

Nutrition and Cancer

Increased Carnitine-Dependent Fatty Acid Uptake into Mitochondria of Human Colon Cancer Cells Induces Apoptosis

Uwe Wenzel1, Alexander Nickel and Hannelore Daniel

Molecular Nutrition Unit, Department of Food and Nutrition, Technical University of Munich, Hochfeldweg 2, D-85350 Freising, Germany

1To whom correspondence should be addressed. E-mail: uwenzel{at}wzw.tum.de.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
Carnitine-dependent fatty acid import into mitochondria and ß-oxidation seem to be impaired in tumor cells. In the present study we show that a supply of palmitoylcarnitine together with L-carnitine potently induces apoptosis in HT-29 human colon cancer cells as a consequence of accelerated fatty acid oxidation. Caspase-3-like activities, measured by the cleavage rate of a fluorogenic tetrapeptide substrate and nuclear fragmentation determined after DNA labeling in fixed cells by fluorescence microscopy, served as indicators of apoptosis. Neither L-carnitine nor palmitoylcarnitine alone were able to increase caspase-3-like activities and DNA fragmentation, but when provided together, apoptosis occurred. That exogenous carnitine was indeed able to enhance fatty acid uptake into mitochondria was demonstrated by an increased influx of a fluorescent palmitic acid analog. Enhanced fatty acid availability in mitochondria led to an increased generation of O2–·, as detected by a O2–·-sensitive fluorogenic dye, indicating oxidation of delivered substrates. Benzoquinone, an O2–· scavenger, blocked O2–· generation and prevented apoptosis as initiated by the combination of palmitoylcarnitine and carnitine. The lack of effect of the ceramide synthesis inhibitor fumonisin on palmitoylcarnitine/carnitine-induced apoptosis further supports the notion that apoptotic cell death is specifically due to fatty acid oxidation. In contrast to HT-29 cells, nontransformed human colonocytes did not respond to exogenous palmitoylcarnitine/carnitine and no apoptosis was observed. In conclusion, our studies provide evidence that a limited mitochondrial fatty acid import in human colon cancer cells prevents high rates of mitochondrial O2–· production and protects colon cancer cells from apoptosis that can be overcome by an exogenous carnitine supply.

KEY WORDS: • HT-29 human colon cancer cells • carnitine • apoptosis • mitochondrial substrate oxidation • superoxide anions

Tumor cells possess an altered metabolism that is characterized by a high rate of glycolysis associated with an increased rate of glucose transport, a lowered pyruvate oxidation rate, increased production of lactic acid, decreased activities of the glycerol-3-phosphate and malate-aspartate shuttles, increased glycerol and fatty acid turnover, and a diminished fatty acid oxidation rate (1). This all limits the ability of cells to use pyruvate and fatty acids for mitochondrial oxidation, which in turn is thought to minimize oxidative stress during DNA replication and phases of high biosynthetic activity (2). We demonstrated previously that the rate of apoptosis in HT-29 human colon cancer cells is closely linked to an increased mitochondrial O2–· production rate when lactate or pyruvate uptake into mitochondria and substrate availability for oxidative metabolism are increased (3). Here, we investigated whether an increased supply of fatty acids for mitochondrial ß-oxidation is also able to induce the generation of O2–· that then leads to apoptosis. To assess whether these metabolic effects on the execution of apoptosis are specific for colonic tumor cells, the nontransformed human colonocyte cell line NCOL-1 (4) served as a control.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
    Cell cultures. HT-29 cells (passage 106) were provided by American Type Culture Collection and used between passage 150 and 200. HT-29 cells were cultured and passaged in RPMI-1640 supplemented with 10% fetal calf serum (FCS)2 and 2 mmol/L glutamine. Antibiotics added to the media were 100 kU/L penicillin and 100 mg/L streptomycin. NCOL-1 cells (passage 50) were a kind gift of Prof. Clifford W. Deveney and Dr. Michael J. Rutten, School of Medicine, Oregon Health Sciences University, Portland, OR. Cells were cultured and passaged in DMEM:Hepes:glutamine supplemented with 10% FCS, MEM amino acids, Basal Medium Eagle vitamin solution, and 1 nmol/L human recombinant epidermal growth factor. Antibiotics added to the media were 200 kU/L penicillin, 100 mg/L streptomycin, 12.5 mg/L gentamicin, and 1 mg/L fungizone. All cultures were maintained in a humidified atmosphere of 95% air and 5% CO2 at 37°C. Cells were passaged at preconfluent densities by the use of a solution containing 0.05% trypsin and 0.5 mmol/L EDTA (all materials for cell culture were from Invitrogen).

    Apoptosis assays. Caspase-3-like activity was measured as described previously (5). In brief, colonocytes were seeded at a density of 5 x 105/well onto 6-well plates (Renner) and allowed to adhere for 24 h. Cells were then exposed for 24 h to the test compounds. Subsequently, cells were trypsinized, cell numbers were determined, and then the cells were centrifuged at 2500 x g for 10 min. Cytosolic extracts were prepared by adding 750 µL of a buffer containing 2 mmol/L EDTA, 0.1% CHAPS, 5 mmol/L dithiothreitol (DTT), 1 mmol/L phenylmethylsulfonyl fluoride, 10 mg/L pepstatin A, 20 mg/L leupeptin, 10 mg/L aprotinin, and 10 mmol/L Hepes:KOH, pH 7.4, to each pellet and homogenizing by 10 strokes. The homogenate was centrifuged at 100,000 x g at 4°C for 30 min and the cytosolic supernatant was incubated with the fluorogenic caspase-3 tetrapeptide-substrate Ac-DEVD-AMC (Calbiochem) at a final concentration of 20 µmol/L. Cleavage of the caspase-3 substrate was followed by determination of emission at 460 nm after excitation at 390 nm using a fluorescence microtiter plate reader (Fluoroskan Ascent, Thermo Electron).

Nuclear fragmentation as a late marker of apoptosis was assayed by staining of DNA with Hoechst 33258 (Sigma). Colonocytes (3 x 104) were grown on glass slides placed into Quadriperm wells (Merck) and then incubated with the test compounds for 36 h. Thereafter, cells were washed with PBS, allowed to air-dry for 30 min, and then fixed with 2% paraformaldehyde before staining with 1 mg/L Hoechst 33258 and visualization under an inverted fluorescence microscope (DMIRBE, Leica). Photographs were made from at least 3 independent cell batches, and apoptotic cell numbers were determined by the number of the total cells that displayed nuclear fragmentation.

    Confocal laser scanning microscopy (CLSM). CLSM (TCS SP2 microscope, Leica) was used for quantification of mitochondrial uptake of the fluorescent 16-(9-anthroyloxy)-analog of palmitic acid (Bioprobes) and mitochondrial O2–· generation. For staining of mitochondria, cells were grown on glass slides placed into Quadriperm wells and loaded with 500 nmol/L MitoTracker Red CMXRos (Bioprobes) for the last 30 min of incubation. For detection of 16-(9-anthroyloxy)-palmitic acid uptake into mitochondria, cells were incubated with 100 µmol/L of the fatty acid analog for 4 h. For detection of mitochondrial O2–·, cells were loaded with 50 µmol/L proxylfluorescamine (Bioprobes) for the last 2 h of incubation. Cysteine (200 µmol/L) was added to the incubation media to yield an increase in the emission of proxylfluorescamine fluorescence due to the reduction of the fluorophore nitroxide to its corresponding hydroxylamine in the presence of superoxide (6). Detection of 16-(9-anthroyloxy)-palmitic acid and O2–· occurred after excitation with the UV laser at emissions of 440–480 nm, and mitochondria were detected after excitation at 543 nm at emissions of 590–650 nm, respectively. The fluorescence ratios of 16-(9-anthroyloxy)-palmitic acid and proxylfluorescamine over MitoTracker were determined only for the mitochondrial areas using the Leica Confocal Software, Version 2.5.

    Immunoblotting. HT-29 and NCOL-1 cells were incubated in 6-well cell culture plates (Renner) with or without palmitoylcarnitine plus carnitine (PC/C) for 24 h and scraped off in Laemmli equilibration buffer containing 50 mmol/L Tris, 100 mmol/L DTT, 10% glycerin, 2% SDS, and 0.1% bromphenol blue. Samples were centrifuged at 2500 x g for 5 min, and the protein content in the supernatant was determined by the Bradford reaction (Bio-Rad). The samples were resolved by SDS-PAGE according to the method described by Schagger and von Jagow (7) and were electroblotted onto polyvinylidene difluoride membranes (Roth). Control of protein transfer and identification of the molecular weight marker proteins were achieved by Ponceau Red staining. Thereafter, the blotting membranes were blocked for 1 h with TBST and then incubated with the primary antibody (anti-bcl-XL, sc-7195; anti-actin, sc-1615; Santa Cruz) for 1 h in a 1:1000 dilution in TBST. Bound antibodies were detected after 1 h incubation with horseradish peroxidase–conjugated secondary reagents (sc-2020 for anti-actin and sc-2004 for bcl-XL; Santa Cruz) using enhanced chemiluminescence Western blotting detection reagents (Amersham) according to the manufacturer’s instructions.

    Statistical analysis. Data were evaluated by 1-way ANOVA and post-hoc Tukey’s Multiple Comparison tests (GraphPadPrism). A Student’s t test was used for comparisons when the experiment consisted of only 2 groups. For each variable, at least 3 independent experiments were carried out. Data are means ± SEM. Differences were considered significant at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
    PC/C induces apoptosis in colon cancer cells but not in nontransformed colonocytes. When HT-29 cells were exposed to a combination of 100 µmol/L palmitoylcarnitine and 2 mmol/L carnitine (PC/C), caspase-3-like activities were increased by 700% compared with control cells (Fig. 1A). Execution of apoptosis beyond activation of caspase-3 was demonstrated by a pronounced chromatin condensation and nuclear fragmentation in cells treated with PC/C (Fig. 1B) but neither PC nor C alone affected apoptosis in HT-29 cells (Fig. 1A and B). Although nontransformed NCOL-1 colonocytes are apoptosis sensitive in general as indicated by the occurrence of apoptosis in response to the classical apoptosis-inducing drug camptothecin, apoptosis was not induced in NCOL-1 cells by PC/C (Fig. 1C and D).



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  		FIGURE 1 Effects of PC and C on apoptosis in HT-29 and NCOL-1 cells. Panel A: Caspase-3-like activity was assessed in HT-29 cells incubated for 24 h in the absence (control) or presence of 100 µmol/L PC, 2 mmol/L C or with PC plus C. Caspase-3-like activity of cells treated with medium alone was set as 100%. Values are means ± SEM, n = 4. ***Different from control, P < 0.001. Panel B: Effects of treatments on nuclear fragmentation (arrows) were assessed after 36 h in HT-29 cells. Panel C: Caspase-3-like activities were assessed in NCOL-1 cells after 24 h incubation with PC/C or with 25 µmol/L camptothecin (campto), used as an apoptosis-inducing positive control. Values are means ± SEM, n = 4. ***Different from control, P < 0.001. (D) Nuclear fragmentation in NCOL-1 cells exposed for 36 h to medium only (control), or to PC/C or campto.

 
    Carnitine (C) increases mitochondrial uptake of a fluorescent palmitic acid analog. HT-29 cells exposed to the fluorescent palmitic acid analog 16-(9-anthroyloxy)-palmitic acid showed a low mitochondrial uptake of the fluorophore but this was drastically increased by the addition of C (Fig. 2A). In contrast, NCOL-1 cells displayed an intrinsically higher mitochondrial uptake of the fatty acid analog, whereas the addition of C in these cells did not increase palmitic acid influx significantly (Fig. 2B).



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  		FIGURE 2 Uptake of a fluorescent palmitic acid analog into mitochondria of HT-29 cells (Panel A) and NCOL-1 cells (Panel B). Cells were treated for 4 h with 100 µmol/L 16-(9-anthroyloxy)-palmitic acid in the absence (control) or presence of 2 mmol/L carnitine. Mitochondria of cells were stained by MitoTracker. The fluorescence ratios of 16-(9-anthroyloxy)-palmitic acid (a) over MitoTracker (b) were determined for the mitochondrial areas only. Values are means ± SEM, n = 3. **Different from control, P < 0.01.

 
    Generation of mitochondrial O2–· but not ceramide synthesis is crucial for PC/C-induced apoptosis in HT-29 cells. Uptake of fatty acids into the mitochondria of HT-29 cells was followed by an enhanced generation of O2–· inside the mitochondria, whereas in NCOL-1 cells, mitochondrial O2–· generation did not differ significantly between cells treated with PC/C and control cells (Fig. 3A). Scavenging of O2–· by the use of the tissue-permeable benzoquinone (8,9) in HT-29 cells potently inhibited the PC/C-induced generation of mitochondrial O2–· (Fig. 3A) and blocked caspase-3 activation (Fig. 3B) and DNA-fragmentation (Fig. 3C). Because ceramide is an efficient apoptosis-inducing molecule that contains 2 long-chain fatty acids, it was plausible to conclude that PC could provide excess substrate for de novo synthesis of ceramide, thereby stimulating ceramide-mediated apoptosis. The ceramide synthesis inhibitor, fumonisin, however, did not exert any effect on the PC/C-mediated increase in caspase-3-like activities (Fig. 3B) nor on nuclear fragmentation (Fig. 3C), thus strengthening the importance of PC/C-induced oxidative metabolism for the triggering of apoptosis in HT-29 cells.



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  		FIGURE 3 Scavenging of mitochondrial O2–· but not blockade of ceramide synthesis prevents PC/C-mediated apoptosis in HT-29 cells. Panel A: Cells were exposed to medium alone (control), or to 100 µmol/L PC:2 mmol/L C (PC/C) with or without 10 µmol/L benzoquinone (benzo) for 6 h. O2–· (a) were visualized by proxylfluorescamine and mitochondria (b) by MitoTracker. The fluorescence ratios of a over b were determined for the mitochondrial areas only. Values are means ± SEM, n = 3. *Different from control, P < 0.05, #Different from PC/C, P < 0.05. Panel B: Caspase-3-like activities were determined in HT-29 cells exposed for 24 h to medium alone (control), or to PC/C in the presence of either 10 µmol/L benzo or 1 µmol/L fumonisin (fumo). Values are means ± SEM, n = 4. ***Different from control, P < 0.001. Panel C: Nuclear fragmentation (arrows) in HT-29 control cells or cells treated with PC/C/benzo, or PC/C/fumonisin.

 
    The antiapoptotic protein bcl-XL is downregulated by PC/C in HT-29 but not in NCOL-1 cells. It was shown previously that several compounds that lead to the generation of mitochondrial O2–· in HT-29 cells diminish the levels of bcl-XL, which was associated with the induction of apoptosis. To test whether PC/C also lowered the levels of this antiapoptotic protein in HT-29 cells, Western blot analysis was performed. Although bcl-XL levels in HT-29 cells were greatly diminished after 24 h of exposure to PC/C (Fig. 4A), those compounds did not affect the levels of bcl-XL in NCOL-1 cells (Fig. 4B).



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  		FIGURE 4 Determination of bcl-XL and actin levels in HT-29 cells (Panel A) or NCOL-1 cells (Panel B) by Western blotting after incubation for 24 h either in medium alone (control) or in 100 µmol/L PC/2 mmol/L C (PC/C).

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
A diminished mitochondrial oxidation of acetyl-CoA from glucose and fatty acid breakdown is a hallmark of cancer cell metabolism (1). Because a low mitochondrial respiration also reduces the ROS burden, tumor cells appear to be particularly well protected from oxidative stress (2). Redirecting cancer cell metabolism toward a normal phenotype could therefore result in specific apoptosis induction by an increased ROS production. We demonstrated recently that when lactate/pyruvate uptake into mitochondria is increased and in turn substrate availability for oxidative metabolism is specifically enhanced in HT-29 human colon cancer cells, mitochondrial O2–· generation is drastically accelerated and in turn cells undergo apoptosis (3).

In the present study, we investigated whether an increased delivery of fatty acids for mitochondrial ß-oxidation could similarly induce apoptosis in colon cancer cells. Providing a combination of PC and C to cells indeed initiated apoptosis in the transformed but not in the nontransformed colonic cell line. Interestingly, neither PC nor C alone was able to elicit apoptosis in HT-29 cells. In the absence of exogenous fatty acids, C appears to be without any effect that might be due to the lack of or insufficient endogenous production of FFA for uptake into mitochondria. NCOL-1 cells, in contrast to HT-29 cells, possess an intrinsically higher mitochondrial uptake rate of the fluorescent fatty acid, suggesting also a sufficient availability of carnitine. Because cytoplasmic acylcarnitines such as palmitoylcarnitine are exchanged for mitochondrial free carnitine via the acylcarnitine/carnitine-translocase for mitochondrial uptake of fatty acids (10), it appears that HT-29 cells lack efficient free carnitine for this antiport reaction. Indeed, human colonic tumor cells were shown to have low levels of free carnitine (1,11). Moreover, concentration ratios of free carnitine and carnitine esters also were shown to be altered in cancer patients compared with healthy controls (12,13), suggesting a cancer-associated metabolic dysfunction related to carnitine availability.

In addition to enhancing mitochondrial uptake of acylcarnitines and thus providing substrates for ß-oxidation, carnitine supplementation could also increase glucose oxidation. This can be accomplished by the removal of acetyl moieties from the mitochondrial acetyl-CoA pool via carnitine/acetyl-transferase delivering acetyl groups to the cytosol and free CoA to the matrix. The carnitine-dependent removal of mitochondrial acetyl-CoA then releases the inhibition of pyruvate-dehydrogenase and enables pyruvate utilization with the free mitochondrial CoA, allowing an increased oxidation rate. Such a mechanism was proposed for the effects of carnitine on increased glucose oxidation in the heart (14) and in peripheral tissues (15). However, because we did not observe an increased generation of mitochondrial O2–· nor any signs of apoptosis in the presence of carnitine and glucose (provided by the medium), it is unlikely that carnitine affects glucose oxidation rates significantly in the colon cancer cells.

The efficiency of the combination of PC and C in initiating apoptosis appears unique to the transformed colonocytes because we did not observe any indications of enhanced apoptosis in the nontransformed colonocytes. Because this was associated with a much lower production of ROS in NCOL-1 cells, it is suggested that these cells have a considerably higher antioxidative capacity than the transformed cells. Flavone and {alpha}-lipoic acid are 2 other compounds that showed such a selectivity of apoptosis induction, and for both agents, it was shown that mitochondrial ROS generation is crucial for their death-inducing effects (16,17). Moreover, for both compounds, it was shown that mitochondrial ROS production is strictly associated with the downregulation of the antiapoptotic protein bcl-XL and that increased levels of antioxidants can prevent the decline in bcl-XL levels and prevent the occurrence of apoptosis (16,17). As shown here, PC/C can also cause a similar decline of the bcl-XL levels as a key regulatory protein followed by apoptosis execution.

The specificity of the effects observed here for PC/C in cancer cells of the colon is substantiated by findings in Jurkat cells in which apoptosis was lowered by carnitine through an inhibitory effect on effector caspases (18). When breast cancer cells were treated with palmitic acid, apoptosis was induced but independently of changes in ROS status (19). In murine B-lymphoma cell lines, palmitate was shown to elicit apoptosis via an increase in the synthesis of the sphingolipid ceramide, which is a known apoptosis inducer (20), but ceramide synthesis does not play a role for PC/C-initiated apoptosis in HT-29 cells.

In conclusion, our study provides evidence that transformed colonocytes have a very low capacity for fatty acid uptake into mitochondria that may be linked to an intrinsically low level of carnitine. When both fatty acids and carnitine are supplied, efficient uptake of fatty acids can occur; these then undergo ß-oxidation with a concomitant rise in mitochondrial O2–· generation, which initiates the apoptosis program due to the low antioxidative capacity of the cells. Further studies, especially in vivo, are required to assess whether effects similar to those shown here in cell culture models also occur in solid tumors in which oxygen supply and ROS generation are limited by a lack of vascularization.


   ACKNOWLEDGMENTS
 
The authors acknowledge the expert technical assistance of Margot Siebler and Beate Rauscher.


   FOOTNOTES
 
2 Abbreviations used: Ac-DEVD-AMC, acetyl-aspartyl-glutamyl-valyl-aspartyl-amino-4-methyl-coumarine; C, carnitine; CLSM, confocal laser scanning microscopy; DTT, dithiothreitol; FCS, fetal calf serum; PC, palmitoylcarnitine; ROS, reactive oxygen species. Back

Manuscript received 3 February 2005. Initial review completed 22 February 2005. Revision accepted 18 March 2005.


   LITERATURE CITED
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 

1. Peluso, G., Nicolai, R., Reda, E., Benatti, P., Barbarisi, A. & Calvani, M. (2000) Cancer and anticancer therapy-induced modifications on metabolism mediated by carnitine system. J. Cell. Physiol. 182:339-350.[Medline]

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3. Wenzel, U., Schoberl, K., Lohner, K. & Daniel, H. (2005) Activation of mitochondrial lactate uptake by flavone induces apoptosis in human colon cancer cells. J. Cell. Physiol. 202:379-390.[Medline]

4. Deveney, C. W., Rand-Luby, L., Rutten, M. J., Luttropp, C. A., Fowler, W. M., Land, J., Meichsner, C. L., Farahmand, M., Sheppard, B. C., Crass, R. A. & Deveney, K. E. (1996) Establishment of human colonic epithelial cells in long-term culture. J. Surg. Res. 64:161-169.[Medline]

5. Wenzel, U., Kuntz, S., Brendel, M. D. & Daniel, H. (2000) Dietary flavone selectively induces apoptosis in human colon carcinoma cells. Cancer Res. 60:3823-3831.[Abstract/Free Full Text]

6. Pou, S., Huang, Y. I., Bhan, A., Bhadti, V. S., Hosmane, R. S., Wu, S. Y., Cao, G. L. & Rosen, G. M. (1993) A fluorophore-containing nitroxide as a probe to detect superoxide and hydroxyl radical generated by stimulated neutrophils. Anal. Biochem. 212:85-90.[Medline]

7. Schagger, H. & von Jagow, G. (1987) Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 100 kDa. Anal. Biochem. 166:368-379.[Medline]

8. Li, B., Gutierrez, P. L. & Blough, N. V. (1997) Trace determination of hydroxyl radical in biological systems. Anal. Chem. 69:4295-4302.[Medline]

9. Oshitani, N., Kitano, A., Okabe, H., Nakamura, S., Matsumoto, T. & Kobayashi, K. (1993) Location of superoxide anion generation in human colonic mucosa obtained by biopsy. Gut 34:936-938.[Abstract/Free Full Text]

10. Indiveri, C., Tonazzi, A. & Palmieri, F. (1994) The reconstituted carnitine carrier from rat liver mitochondria: evidence for a transport mechanism different from that of the other mitochondrial translocators. Biochim. Biophys. Acta 1189:65-73.[Medline]

11. Willson, J., Weese, J., Wolberg, W. & Shug, A. (1983) Differences between normal and cancerous human colon in carnitine (C) and CoA levels. American Association of Cancer Research Annual Meeting, May 25–28 1983 San Diego, CA.

12. Yazdanpanah, M., Luo, X., Lau, R., Greenberg, M., Fisher, L. J. & Lehotay, D. C. (1997) Cytotoxic aldehydes as possible markers for childhood cancer. Free Radic. Biol. Med. 23:870-878.[Medline]

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14. Broderick, T. L., Quinney, H. A. & Lopaschuk, G. D. (1992) Carnitine stimulation of glucose oxidation in the fatty acid perfused isolated working rat heart. J. Biol. Chem. 267:3758-3763.[Abstract/Free Full Text]

15. Capaldo, B., Napoli, R., Di Bonito, P., Albano, G. & Sacca, L. (1991) Carnitine improves peripheral glucose disposal in non-insulin-dependent diabetic patients. Diabetes Res. Clin. Pract. 14:191-195.[Medline]

16. Wenzel, U., Nickel, A., Kuntz, S. & Daniel, H. (2004) Ascorbic acid suppresses drug-induced apoptosis in human colon cancer cells by scavenging mitochondrial superoxide anions. Carcinogenesis 25:703-712.[Abstract/Free Full Text]

17. Wenzel, U., Nickel, A. & Daniel, H. (2005) {alpha}-lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O2–·-generation. Apoptosis 10:359-368.[Medline]

18. Mutomba, M. C., Yuan, H., Konyavko, M., Adachi, S., Yokoyama, C. B., Esser, V., McGarry, J. D., Babior, B. M. & Gottlieb, R. A. (2000) Regulation of the activity of caspases by L-carnitine and palmitoylcarnitine. FEBS Lett. 478:19-25.[Medline]

19. Hardy, S., El-Assaad, W., Przybytkowski, E., Joly, E., Prentki, M. & Langelier, Y. (2003) Saturated fatty acid-induced apoptosis in MDA-MB-231 breast cancer cells. A role for cardiolipin. J. Biol. Chem. 278:31861-31870.[Abstract/Free Full Text]

20. Paumen, M. B., Ishida, Y., Muramatsu, M., Yamamoto, M. & Honjo, T. (1997) Inhibition of carnitine palmitoyltransferase I augments sphingolipid synthesis and palmitate-induced apoptosis. J. Biol. Chem. 272:3324-3329.[Abstract/Free Full Text]




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