N-Acetyl Cysteine, NAC, a cheap over-the-counter decongestant, can be used ‘off-label' to reduce a tumour’s ability to feed off the surrounding environment by blocking the ‘transporter protein’ MCT4; however. it's general use in cancer treatment may be a double edged sword as it acts by increasing levels of glutathione. (Ed. article updated by Chris Woollams from previous 2020 article).
N-acetylcysteine as a drug
N-acetylcysteine, or NAC, is used as a drug to break up mucus. It is a dietary supplement sold in the UK in chemist's without the need for a prescription. It is made from the amino acid L-cysteine, which is found in nature and is semi-essential. NAC is also is used as a drug for acetaminophen overdose, cystic fibrosis or in cases of COPD (Chronic obstructive pulmonary disease).
N-Acetylcysteine and cancer
i) Breast cancer
Clinical trials with breast cancer patients awaiting surgery in America have shown that NAC can help starve a primary cancer tumour. The research was conducted by The Sidney Kimmel Cancer Center at Thomas Jefferson University, in Philadelphia.
There’s a long held theory that cancer cells in a tumour ‘stroma’ are being maintained and strengthened by the presence of MCT4, a ‘transporter’ protein which transports lactate (a source of energy) to them from adjacent cells.
Most host cells in a healthy stroma possess certain tumour-suppressing abilities but the stroma changes during malignancy and eventually promotes growth, invasion, and metastasis. A tumour stroma mainly consists of the membrane, fibroblasts, extracellular matrix, immune cells, and blood vessels
High levels of stromal MCT4 are linked to aggressive cancer behaviour and poor overall survival.
In the research, cancer patients taking high doses of NAC recorded an 80% fall in MCT4 which reduced the ability of the cancer cells in the tumour to feed off their neighbours’ lactate.
The research team, which included Professor Michael Lisanti, of the University of Salford and Dr. Ubaldo Martinez-Outschoorn, in the USA, conducted a 'window trial' on only 12 patients, but the results were consistent. Patients were given maximum daily doses of NAC for three weeks between diagnosis and surgery. Tumour tissue biopsies were taken before and during surgery and MCT4 and K167, were measured post-surgery.
MCT4 levels were reduced by approximately 80%. K167, a cancer cell antigen often used as a marker for breast cancer growth, fell by 25%.
The results were published in Seminars in Oncology (1).
NAC and glutathione production
Glutathione is made from three amino acids: cysteine, glycine and glutamic acid (glutamate) and is the body's second largest self-produced antioxidant after Melatonin.
When Melatonin is made by the mitochondria under the influence of Infra Red sunlight, it cleans up the free radicals and Reactive Oxygen Species (ROS) made by your cellular power stations (mitochondria) during energy production in the microenvironment of cells. It cannot perform the job fully on its own and so calls up other antioxidants such as glutathione, Coenzyme Q10 and vitamin E. We have a review on Glutathionw HERE.
Glutathione is sometimes called 'The Master Antioxidant'. It is usually made from ingredients in foods such as greens, garlic, onions and flaxseed. Unfortunately, few people eat enough ingredients and so do not make enough glutathione. The same goes for melatonin (people typically damage their night time production through blue light (computers, phones, TVs) and day time production (by not spending enough time outdoors).
The important point about glutathione is that you should allow your body to both make it and regulate its production. In this way it can manage free radicals but not overproduce. We make 10% less glutathione at the age of 40 and 30% less at the age of 60 showing its anti-illness and anti-aging powers. Research has shown that L-cysteine (even in the form of NAC) does increase production. You would not want to supplement with glutamate as it can be a fuel for cancer cells, and research shows that glycine supplementation hardly prompts glutathione production at all. The production volume is still regulated by the body. NAC is akin to a 'quick fix' for those not providing enough daily raw materials.
The breast cancer research above did not appear to measure women's levels of glutathione before or after the study.
Is NAC's action really that of Glutathione?
ii) Triple Negative Breast Cancer -
The beneficial effect of NAC may depend on whether the type of cancer relies slightly or heavily on ROS signaling for its survival and metastasis. For example, Basal-like TNBC cells, characterised by inactivated BRCA1 and mutated p53, produce high ROS levels and rely on ROS signaling for their survival and malignant progression. High ROS levels in TNBC cells can also trigger the recruitment and conversion of stromal cells and induce hypoxic (low oxygen) responses, leading to an increased cancer aggression. In a separate research study (2) NAC has been shown to play an important role in reducing ROS production and ROS-mediated signaling that would have contributed to cell survival, metastasis, and drug resistance in TNBC cells.
The issue seems to be to 'know your cancer' - using NAC as a glutathione-precursor to reduce ROS-dependent 'aggressive' cancers in glutathione-deficient situations might be a powerful treatment option..
iii) NAC and Colorectal cancer -
Other cancers can run out of control too. Colorectal cancer is one. And NAC has been suggested for treatment use with this cancer.
NAC has been shown to be important in intestinal health (3). NAC is rapidly metabolized by the small intestine to produce glutathione. A number of studies using small pigs show that NAC reduces inflammation, alleviates oxidative stress, improves energy status, and ameliorates tissue damage in the intestines. Another finding was that dietary supplementation with NAC reduced acetic acid-induced colitis. NAC was also shown to be linked to certain cell signaling pathways (e.g. EGFR, TLR4, including cancer apoptosis).
Other studies suggest it may reduce liver toxicity and neuropathy (4).
N Acetylcysteine - the bottom line: It's complicated!
NAC is often referred to as an antioxidant. It might be more accurate to say that it is the precursor to an antioxidant - the active GSH form of Glutathione. In providing cysteine, it should promote production of glutathione in glutathione-deficient situations, and that is still regulated in the body. Why do I keep on about this 'regulation' point? Because too much glutathione can help cancers survive.
Cancer cell development and metastases go hand in hand with free radicals (ROS). 'Moderate ROS levels can support survival and proliferation by activating signaling pathways that can contribute to tumour growth in stressful tumor microenvironments'. So glutathione can restrict this. Good news.
But high levels of free radicals actually can kill cancer cells. 'Excessive ROS accumulation, failure of proper scavenging mechanisms, or antioxidant scarcity results in severe damage to cancer cells, triggering cell death'. So technically, by preventing high levels of ROS, glutathione can theoretically come to cancer cells' rescue. Bad news.
This could be the case when having chemotherapy or radiotherapy where the aim was to generate high levels of free radicals to kill the cells (5).
Just to complicate matters, there is research on Lung cancer showing that NAC can prevent chemotherapy damage to healthy tissue (6).
This is why at CANCERactive, we like to keep things simple. People with cancer have built a body conducive to cancer. We aim to rebuild these people - we aim to build them a body conducive to health. This is why we give patients green juices and flaxseed but rarely NAC and never if they are on chemo, or radiotherapy. We like to keep processes as natural as possible.
We do use NAC where there is a job to do, and research to support it - in primary tumours and cancers that are out of control. In other cases (especially in the use of supplements of glutathione or IV glutathione) we urge caution.
NAC is potentially a double edged sword. A quick fix, or a cancer aid?
NAC's use might also be most appropriate in older people who eat low levels of glutathione-producing foods and who are not having chemotherapy or radiotherapy.
Go to: N-Acetyl cysteine, Covid, cancer and respiratory illness
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References
- Pilot study demonstrating metabolic and anti-proliferative effects of in vivo anti-oxidant supplementation with N-Acetylcysteine in Breast Cancer - Seminars in Oncology, Daniel Monti, Federica Sotgia, Diana Whitaker- Menezes, Madalina Tuluc, Ruth Birbe, Adam Berger, Melissa Lazar, Paolo Cotzia, Rossitza Draganova-Tacheva, Zhao Lin, Marina Domingo-Vidal, Andrew Newberg, Michael P. Lisanti, Ubaldo Martinez-Outschoorn.
- Possible Beneficial Effects of N-Acetylcysteine for Treatment of Triple-Negative Breast Cancer -Youngjoo Kwon; Antioxidants (Basel); 2021 Jan 24;10(2):169.
- N-acetylcysteine and intestinal health: a focus on its mechanism of action; Yongqing Hou et al; Front Biosci (Landmark Ed), 2015 Jan 1;20(5):872-91
- Memorial Sloan Kettering; NAC - https://www.mskcc.org/cancer-care/integrative-medicine/herbs/n-acetylcysteine#references-57
- Glutathione metabolism in cancer progression and treatment resistance; Ankita Bansal, M. Celeste Simon; Journal of Cell Biology, 2018 Jul 2;217(7):2291-2298
- Chemopreventive properties of N-acetylcysteine and other thiols, De Flora S, Izzotti A, D'Angostini F et al. CRC Press, Boca Raton, Fla:1992: 183-194
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