Induction of apoptosis by natural agents through mitochondrial cell death pathway, Part 3

September 22, 2010, Featured in Cancer and Natural Medicines, 0 Comments

Mitochondrial fatty acid beta-oxidation is one of the main sources for energy production, particularly at times of stress or fasting. Fatty acids are oxidized inside the mitochondrial matrix but the fatty acids to be oxidized come from the cytosol. Fatty acids are activated in the cytosol by esterification with Coenzyme A (CoA) to form acyl-CoA (RCO-CoA, where R is the fatty acid acyl group).

Activated medium-chain fatty acids (C8 fatty acid and C10 fatty acid) freely diffuse into mitochondria to be oxidized but long chain fatty acids do not diffuse into mitochondria so they must be transported in. Palmitoylcarnitine is a well-known intermediate in mitochondrial fatty acid oxidation. The transport of long chain fatty acids into mitochondria for oxidation is accomplished by the carnitine palmitoyltransferase system (CPTI and CPTII). CPTI exchanges carnitine for the CoA attached to long chain fatty acids to form a fatty acid-carnitine conjugate (RCO-carnitine).

The fatty acid-carnitine is transported into the matrix by a transporter protein in the inner mitochondrial membrane. Once the fatty acid-carnitine is inside the matrix, CPTII exchanges CoA for carnitine to produce fatty acid-CoA once again, ready to enter fatty acid oxidation in the matrix to produce energy. The free carnitine is transported back out to renew the cytoplasmic pool of carnitine and allow the transfer process to continue. Acyl-CoA dehydrogenases (ACADs) are mitochondrial enzymes that catalyze the initial rate-limiting step in the beta-oxidation of fatty acyl-CoA.

Carnitine-dependent fatty acid import into mitochondria and beta-oxidation seem to be impaired in tumor cells. Studies show that a supply of palmitoylcarnitine together with L-carnitine induces apoptosis in colon cancer cells as a consequence of accelerated fatty acid oxidation. Enhanced fatty acid availability in mitochondria led to an increased generation of O(2)(-) that finally leads to apoptosis. Similarly, a supply of palmitoylcarnitine in combination with carnitine induces apoptosis in colon cancer cells by increasing the mitochondrial respiration rate. In contrast to cancer cells, nontransformed human colonocytes did not respond to exogenous palmitoylcarnitine/carnitine and no apoptosis was observed.

Cancer cell metabolism is characterized by limited cellular respiration (oxidative phosphorylation) in order to minimize oxidative stress. The subsequent metabolic generation of O(2)(-) in mitochondria is the initiating factor for the execution of apoptosis. Palmitoylcarnitine is synthesized through the action of palmitoylcarnitine transferase I – an enzyme. An increase of the intracellular content of palmitoylcarnitine in cancer cells, i.e. administration of carnitine lead to inhibition of cell proliferation and a concomitant promotion of differentiation processes.

In addition, the antioxidant alpha-lipoic acid (ALA) has been shown to affect a variety of biological processes associated with oxidative stress including cancer. Alpha-lipoic acid is an antioxidant that is made by the body and is found in every cell, where it helps turn glucose into energy. Unlike other antioxidants, which work only in water (such as vitamin C) or fatty tissues (such as vitamin E), alpha-lipoic acid is both fat- and water-soluble. That means it can work throughout the body. In the cells of the body, alpha-lipoic acid (ALA) is converted into dihydrolipoic acid (DHLA). Alpha-lipoic acid is not the same as alpha linolenic acid, which is an omega-3 fatty acid that may help heart health (Confusion can arise because both are sometimes abbreviated ALA).

Study shows that ALA and DHLA can effectively induce apoptosis in human colon cancer cells by a pro-oxidant mechanism that is initiated by an increased uptake of oxidizable substrates into mitochondria. Exposure of colon cells to ALA or 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 O(2)(-) in colon cancer cells whereas both compounds increased O(2)(-)-generation inside mitochondria. Increased mitochondrial O(2)(-)-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-X(L). Mitochondrial O(2)(-)-generation and apoptosis induced by ALA and DHLA could be prevented by the O(2)(-)-scavenger, antioxidants.

When you start cancer treatment, take L-carnitine and alpha-lipoic acid (ALA). But, don’t take a group of antioxidants together.

Increased carnitine-dependent fatty acid uptake into mitochondria of human colon cancer cells induces apoptosis.

Increased mitochondrial palmitoylcarnitine/carnitine countertransport by flavone causes oxidative stress and apoptosis in colon cancer cells.

Palmitoylcarnitine, a surface-active metabolite.

Dietary flavone is a potent apoptosis inducer in human colon carcinoma cells.

alpha-Lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O2-*-generation.

Antrodia camphorata is a polypore mushroom. This orange-red to brown-red colored mushrooms are very bitter in taste with a camphor aroma. The mushroom grows only on one species of rainforest tree that is native only to Taiwan, Cinnamomum kanehirai, usually in hollow areas of the trunks of mature trees. The host tree is related to the Camphor tree and contains highly aromatic oils. In Traditional Taiwanese Medicine, Antrodia is commonly used as an anti-cancer, anti-itching, anti-allergy, and liver protective drug. Scientific research have also shown that the mushroom can be useful in the treatment of diabetes, cardiovascular diseases such as hypertension, hepatitis, and many types of cancers including liver, lung, cervical, colon, and breast cancers and also leukemia and adenoma.

Recent studies show that antcin A, antcin C, and methyl antcinate A (MAA) isolated from Antrodia camphorate induces apoptosis in oral cancer and liver cancer cells through oxidant-mediated cofilin- and Bax-triggered mitochondrial pathway. MAA triggered the mitochondrial apoptotic pathway by an increase in expression of Bax, Bak, and PUMA, as well as a decrease in Bcl-(XL) and Bcl-2 and disruption of mitochondrial membrane potential and promotion of mitochondrial cytochrome c release, as well as activation of caspases-2, -3, and -9.

Methylantcinate A induces tumor specific growth inhibition in oral cancer cells via Bax-mediated mitochondrial apoptotic pathway.

Methyl antcinate A from Antrodia camphorata induces apoptosis in human liver cancer cells through oxidant-mediated cofilin- and Bax-triggered mitochondrial pathway.

Effects of Antrodia camphorata extracts on the viability, apoptosis, [Ca2+]i, and MAPKs phosphorylation of OC2 human oral cancer cells.

Effects of antrodia camphorata on viability, apoptosis, and [Ca2+]i in PC3 human prostate cancer cells.

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