THE ROLE OF ALPHA-LIPOIC ACID ON CANCER CELLS – BIOCHEMISTRY, CELL MEMBRANE TRANSPORT AND INDICATIONS/CONTRAINDICATIONS FOR CANCER, AND THE ROLE IN OTHER SERIOUS HEALTH CONDITIONS
What is Alpha lipoic acid?
Alpha lipoic acid (ALA) also known as thioctic acid (TA) or 1,2-dithiolane-3-pentanoic acid is a naturally occurring anti-oxidant synthesized enzymatically in plant and animal mitochondria including humans. ALA is an essential for aerobic metabolism. ALA is also absorbed intact from dietary sources, and it transiently accumulates in many tissues. It is present in many foods in small concentrations like liver, kidney, heart, spinach, broccoli, potatoes and yeast extract.
ALA has gained increased medical and scientific and there is growing evidence that when orally used as a supplement, instead of acting as a metabolic co-factor, it prompts a set of unique biochemical activities of significant pharmacologically and physiologically. Consumption of lipoic acid from food has not yet been found to result in detectable increases of free lipoic acid in human plasma or cells. In contrast, high oral doses of free lipoic acid (≥50 mg) significantly, yet transiently, increase the concentration of free lipoic acid in plasma and cells.
Biochemistry: α-lipoic acid (C8 H14 O2 S2) is an organosulfur compound, derived from octanoic acid (caprylic acid) and cysteine (as a sulfur source). α-Lipoic acid (ALA) contains a chiral carbon and exists as two enantiomers (R-α-lipoic acid (RLA) and S-α-lipoic acid (SLA)). The 6th carbon in ALA is chiral
carbon and thus the two enantiomers have different potencies. The RLA acid is more potent than SLA in insulin stimulated glucose uptake.
ALA is soluble in both water and ethanol. It has a very low molecular weight of 206 g/mol and has both hydrophilic (absorbs in water) and lipophilic (also absorbs in the fats of the body) properties which is why it is quickly absorbed from the gastrointestinal track.
ALA being a small molecule has two functional groups. It is found in two forms in human body, the oxidized form known as α-lipoic acid and the reduced form called dihydrolipoic acid (DHLA). It is a potent redox active compound having a -0.29V of midpoint redox potential. The two thiol groups in the oxidized form of α-Lipoic acid are separated by three carbon atoms and a five membered ring structure. This property of ALA makes it particularly more reactive than other biologically significant disulphide compounds.
It has a functional role in metabolism as it acts as a naturally occurring co-factor in various multi-enzyme complexes such as or pyruvate dehydrogenase and α-keto-glutarate dehydrogenase. In physiological condition, LA is present in the form of lipoate with the proton of the hydroxyl functional group substituted by remains of an organic alcohol or with an inorganic ion. LA (in the form of lipoate) acts as a cofactor in reactions of aerobic metabolism. It is essential for aerobic processes of life and serves as a coenzyme in the Krebs cycle.
DHLA, the reduced form of ALA, acts as a driving force in maintaining high concentrations of reduced antioxidant (potent) forms of the major cellular antioxidants such as glutathione, thioredoxin and ascorbic acid in the aqueous phase, and vitamin E and ubiquinol in membranes or lipoproteins.
Having anti-oxidant properties is what makes ALA so significant in today’s medical research. How anti-oxidants work? Anti-oxidants work by attacking the “free radicals” formed in the body as waste products resulting from catabolism. These free radicals if remain in the body can damage cells and cause harmful chemical reactions. Antioxidants are in the body are used up as they react with free radicals. Various anti-oxidants work either in water medium (ascorbate, glutathione, thiporedoxin and vitamin C) or in fatty tissues (vitamin E and ubiquinols).
ALA however is unique in way that it is a dihydrolipoate and has both the hydrophilic (water soluble) and lipophilic (fat soluble) properties which makes it possible for it to work throughout the body. ALA in its both oxidized as well as reduced form performs powerful anti-oxidant functions such as; reduction of reactive oxygen species, helps in regeneration of glutathione, vitamin C and E from their oxidized forms, repairs oxidative stress induced protein damage, chelation of metal ions and gene transcription regulation.
α-lipoic acid has been found and claimed to treat and help control symptoms in various medical illnesses like diabetic neuropathy, ischemia-reperfusion injury, hypertension, vascular disease, multiple sclerosis and neurodegenerative diseases. There also has been immense research about its effectiveness in preventing cataracts and cancer, also treating cancers of different kinds.
ALA and its role in treating cancers
Immense research has taken place to access the role of ALA in preventing and treating many kinds of cancers.
We know that the gene mutation in any cell of a living being that can turn a normal cell into cancer cell. Normally when a cell divides, it makes copies of itself and the older or damaged cells die through natural mechanism called cell apoptosis. These gene mutations may be inherited, developed with time as we grow older, or take place due to environmental factors such as UV rays, contact with carcinogenic compounds or personal habits like smoking and alcohol addiction.
Now when we talk about ALA’s potential in preventing and treating cancers, we take into account on molecular level how this works.
To understand its mechanisms, first we need to learn what biochemical properties of ALA makes it a promising candidate as an anti-cancer.?
ALA is an eight carbon acid with 2 sulfhydryl groups in position 6 and 8 and is thus considered to be oxidized. It is an anti-oxidant present in every cell of the body, synthesized in the mitochondria and is essential in aerobic metabolism, where it helps converting glucose into energy.
The use of ALA in cancer treatment aims at inhibition of aerobic glycolysis. From various researches it is evident that cancer cells preferentially use aerobic glycolysis for ATP generation even in the presence of oxygen. Aerobic glycolysis converts glucose into lactate that the cancer cell uses for proliferation. A lot of studies have been designed to assess the roles of ALA in inhibiting the aerobic glycolysis.
How this works:
Pyruvate dehydrogenase is an enzyme that converts pyruvate into Acetyl CoA thus preventing lactate formation. A study conducted to check the activity of ALA help activate this enzyme showed that ALA has significant role in reducing 1. cancerous cell viability/proliferation and 2. Lactate production thus increasing the apoptosis in all investigated cell lines. (Feuerecker et al., 2012)
Role in treating breast cancer:
A study conducted by (Dozio et al., 2010) examined if and how α-Lipoic acid can induce p27kip1– dependent cell cycle arrest and apoptosis in MCF-7 human breast cancer. It was observed that ALA was able to scavenge reactive oxygen species in MCF-7 cells followed by cell growth arrest at the G1 phase of the cell cycle.
It is evident from a recent study that ALA inhibits the proliferation and Akt and ERK signaling pathways for several breast cancer cells. The IGF-1R expression was lost upon ALA exposure because ALA the convertase, furin, which is found to be involved in maturation of IGF-1R. (Farhat et al., 2020)
Another research by (Kuban-Jankowska, Gorska-Ponikowska, & Wozniak, 2017) has shown that ALA in both its forms, oxidized and reduced, decreases the viability of breast cancer cells. It is well known that tumor proliferates as a result of overexpression of tyrosine kinase receptors. Here ALA was tested to check the effect on protein tyrosine phosphatases PTP1B and SHP2 (they are overexpressed in breast cancer cells). ALA proved to reduce their activity and thus inhibiting the viability and proliferation of cancer cells.
Role in treating thyroid cancer
Thyroid cancer is a cancer originating from follicular or parafollicular thyroid cells. These cells give rise to both well-differentiated cancers (i.e. papillary and follicular) and analastic thyroid cancer.
ALA suppresses the thyroid cancer by suppressing tumor growth through activation of adenosine monophosphate activated protein kinase (AMPK) and inhibiting the transforming growth factor-β (TGFβ) pathway. This resultantly inhibits the migration and invasion along with epithelial mesenchymal transition of thyroid cancer cells. (Jeon et al., 2016).
ALA is also evident in limiting lung cancer growth in xenograft mice and reduced lung cancer A549 cell viability (Peng et al., 2020).
Role in colon cancer:
The third most diagnosed cancer in the world is the colon cancer. It occurs due to uncontrolled cell growth in the colon or rectum. ALA has shown to 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 (Wenzel, Nickel, & Daniel, 2005).
Role in gastric cancer:
In an in vitro study conducted to check ALA’s effect on gastric cancer cells showed that ALA inhibits both the proliferation and invasion of gastric cancer cells by suppressing the MUC4 gene which is found to be overexpressed in gastric cancer tissues (Yang et al., 2019).
ALA with a combination of hydroxycitrate along with chemotherapy has also shown to be effective against pancreatic tumor development (Guais et al., 2012). In Liver cancer, ALA induces apoptosis hepatoma cells via the PTEN/Akt pathway (Shi, Liu, Stern, Yu, & Liu, 2008). However, ALA didn’t had any effect on cell proliferation in case of prostate cancer.
Role in other serious health conditions.
- Pharmacologically, ALA has been found to have beneficial role in treating patients with type-2 diabetes. One, it enhances the body cell’s ability to take up glucose, reducing the blood sugar level. Second, it may reduce effects of peripheral neuropathy that is secondary to diabetes (Taliyan et al., 2004).
- In patients with multiple sclerosis, ALA has been reported to help reduce the relapse frequency and also decrease corticosteroid uptake (Odinak et al.) Another study implies that a dose 1200mg of lipoic acid once a day resulted in decreased inflammatory cytokines in patients with Multiple sclerosis (Shamsizadeh, Roohbakhsh, Ayoobi, & Moghaddamahmadi, 2017).
- Although inconsistent and sparse research is available to check effect of ALA supplements on hypertension control/prevention, a recent study conducted on rats showed that due to its anti-oxidant properties, ALA was found to be effective in preventing the development of hypertension in them (El Midaoui, Fantus, Ait Boughrous, & Couture, 2019).
- A study by (Koh et al., 2011) reported that 1800mg/d of Alpha-lipoic acid led to a modest weight loss in obese subjects and that it to be considered as a therapy for treating obesity.
- ALA has also reported to show protective effects on renal tissue damage caused by abdominal ischemia-reperfusion injury (Gultekin, Tuncer, & Burat, 2020). Another study shows reduction in inflammatory markers preventing ischemia-reperfusion injury when preconditioned with ALA (Ambrosi et al., 2016).
These diverse actions of ALA suggest that it has significant importance pharmacologically as well as physiologically in treatment of various serious illnesses particularly cancer. However, further research and targeted uses in-vivo are required to access about its potential. ALA might be a breakthrough in cancer treatments in near future.
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