ALA induces aptosis in colon cancer (???!!!!???)

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http://www.ingentaconnect.com/content/klu/appt/2005/00000010/00000002/

00000810

Abstract:

The antioxidant -lipoic acid (ALA) has been shown to affect a variety

of biological processes associated with oxidative stress including

cancer. We determined in HT-29 human colon cancer cells whether ALA

is able to affect apoptosis, as an important parameter disregulated

in tumour development. Exposure of cells to ALA or its reduced form

dihydrolipoic acid (DHLA) for 24 h dose dependently increased caspase-

3-like activity and was associated with DNA-fragmentation. DHLA but

not ALA was able to scavenge cytosolic O2-. in HT-29 cells whereas

both compounds increased O2- .-generation inside mitochondria.

Increased mitochondrial O2- .-production was preceded by an increased

influx of lactate or pyruvate into mitochondria and resulted in the

down-regulation of the anti-apoptotic protein bcl-XL. Mitochondrial

O2-.-generation and apoptosis induced by ALA and DHLA could be

prevented by the O2- .-scavenger benzoquinone. Moreover, when the

lactate/pyruvate transporter was inhibited by 5-nitro-2-(3-

phenylpropylamino) benzoate, ALA- and DHLA-induced mitochondrial ROS-

production and apoptosis were blocked. In contrast to HT-29 cells, no

apoptosis was observed in non-transformed human colonocytes in

response to ALA or DHLA addition. In conclusion, our study provides

evidence that ALA and DHLA can effectively induce apoptosis in human

colon cancer cells by a prooxidant mechanism that is initiated by an

increased uptake of oxidizable substrates into mitochondria.

Keywords: HT-29 human colon cancer cells; mitochondrial apoptosis

pathway; monocarboxylate transporter; superoxide anion generation

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Conclusion

In conclusion, our studies demonstrate that the antioxidants

ALA and DHLA do effectively induce apoptosis in

HT-29 human colon cancer cells via an increased ROSproduction

in mitochondria. Although at least DHLA acts as

a potent O & #8722;.

2 -scavenger in the cytosol, both compounds

increase substantially mitochondiral O & #8722;.

2 -production that

can obviously not be quenched or detoxified. The underlying

mechanism seems to be an enhancement of the

uptake of monocarboxylates (pyruvate/lactate) from glycolysis

into mitochondria followed by their oxidation in

the citric acid cycle with increased delivery of reduction

equivalents to the respiratory chain which in turn drastically

increases mitochondrial O & #8722;.

2 -production. This high

O & #8722;.

2 -burden appears to overcome the intrinsically high antioxidative

capacity of antiapoptotic proteins and allows

apoptosis in tumor cells to be executed.

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>

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http://www.ingentaconnect.com/content/klu/appt/2005/00000010/00000002/

> 00000810

>

> Abstract:

>

> The antioxidant -lipoic acid (ALA) has been shown to affect a

variety

> of biological processes associated with oxidative stress including

> cancer. We determined in HT-29 human colon cancer cells whether ALA

> is able to affect apoptosis, as an important parameter disregulated

> in tumour development. Exposure of cells to ALA or its reduced form

> dihydrolipoic acid (DHLA) for 24 h dose dependently increased

caspase-

> 3-like activity and was associated with DNA-fragmentation. DHLA but

> not ALA was able to scavenge cytosolic O2-. in HT-29 cells whereas

> both compounds increased O2- .-generation inside mitochondria.

> Increased mitochondrial O2- .-production was preceded by an

increased

> influx of lactate or pyruvate into mitochondria and resulted in the

> down-regulation of the anti-apoptotic protein bcl-XL. Mitochondrial

> O2-.-generation and apoptosis induced by ALA and DHLA could be

> prevented by the O2- .-scavenger benzoquinone. Moreover, when the

> lactate/pyruvate transporter was inhibited by 5-nitro-2-(3-

> phenylpropylamino) benzoate, ALA- and DHLA-induced mitochondrial

ROS-

> production and apoptosis were blocked. In contrast to HT-29 cells,

no

> apoptosis was observed in non-transformed human colonocytes in

> response to ALA or DHLA addition. In conclusion, our study provides

> evidence that ALA and DHLA can effectively induce apoptosis in

human

> colon cancer cells by a prooxidant mechanism that is initiated by

an

> increased uptake of oxidizable substrates into mitochondria.

> Keywords: HT-29 human colon cancer cells; mitochondrial apoptosis

> pathway; monocarboxylate transporter; superoxide anion generation

>