Nicotine and Cancer: The Research

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1. The Papers
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The Papers (18)

Newest first. Study types on this page — Human trial: 1 · Review: 5 · Animal study: 3 · Cell study: 8 · Other: 1. Each summary is written from the paper’s own abstract; follow the PubMed link for the full record.

The Distinct Biological Effects of 6-Hydroxy-L-Nicotine in Representative Cancer Cell Lines

Cell study, 2024. Researchers tested 6-hydroxy-L-nicotine, a compound made from nicotine, on three kinds of cancer cells grown in the lab (lung, breast and brain-tumour cells) and on two kinds of normal lung and breast cells. Computer modelling suggested the compound may bind to nicotinic receptors, the same receptor family nicotine acts on. In the lab dishes it made the brain-tumour (glioblastoma) cells grow more, held back the breast cancer cells, and had no effect on the lung cancer cells. The normal cells stayed alive at the same rate, but all of these results come from cells in dishes and computer models, not from animals or people.

Postu PA, Boiangiu RS, Mihasan M et al. (2024). The Distinct Biological Effects of 6-Hydroxy-L-Nicotine in Representative Cancer Cell Lines. Molecules. — PubMed PMID: 39683752 · doi:10.3390/molecules29235593

Nicotine Ingestion Reduces Heart Rate Variability in Young Healthy Adults

Human trial, 2022. This randomized controlled trial gave 4 mg of nicotine by mouth to 80 young, healthy non-smokers (40 men and 40 women) and measured heart rate variability, a marker of how flexibly the heart's rhythm adjusts. Nicotine reduced heart rate variability in both men and women, and the size of the effect did not differ between the sexes. The authors concluded that nicotine at doses of 4 mg or more is harmful to the heart of young people.

Guo QN, Wang J, Liu HY et al. (2022). Nicotine Ingestion Reduces Heart Rate Variability in Young Healthy Adults. Biomed Res Int. — PubMed PMID: 35028314 · doi:10.1155/2022/4286621

Low-Dose Nicotine Activates EGFR Signaling via α5-nAChR and Promotes Lung Adenocarcinoma Progression

Cell study, 2020. Researchers studied how low doses of nicotine, like those from secondhand smoke, affect lung adenocarcinoma, a type of lung cancer common in non-smokers. Lung cancer cell lines and tumor tissue from patients had high levels of a nicotine receptor called alpha5. In the cells, this receptor worked with a growth signal called EGFR, and low-dose nicotine needed the receptor to make the cancer cells grow, move and invade more. When the receptor was switched off, tumors grown in animals grew less, and patients whose tumors had more of the receptor had poorer survival. Most of these findings come from cells and animals, not from treating people.

Wang ML, Hsu YF, Liu CH et al. (2020). Low-Dose Nicotine Activates EGFR Signaling via α5-nAChR and Promotes Lung Adenocarcinoma Progression. Int J Mol Sci. — PubMed PMID: 32957649 · doi:10.3390/ijms21186829

Nicotine promotes brain metastasis by polarizing microglia and suppressing innate immune function

Animal study, 2020. Researchers looked at 281 lung cancer patients whose cancer had spread, and found that smokers had a much higher rate of the cancer spreading to the brain. In mice, nicotine increased the spread of lung cancer to the brain by shifting the brain's immune cells (microglia) into a state that releases growth signals helping tumors grow and weakens those cells' ability to engulf and clear cancer cells. Removing the microglia blocked this effect, and a plant compound called parthenolide reduced the spread to the brain by blocking this shift. The authors say the results point to a possible risk of using nicotine to help people quit smoking.

Wu SY, Xing F, Sharma S et al. (2020). Nicotine promotes brain metastasis by polarizing microglia and suppressing innate immune function. J Exp Med. — PubMed PMID: 32496556 · doi:10.1084/jem.20191131

Cotinine, a major nicotine metabolite, induces cell proliferation on urothelium in vitro and in vivo

Animal study, 2020. Researchers tested cotinine, the main substance the body makes when it breaks down nicotine, along with two other nicotine breakdown products, on three lines of human bladder cancer cells in the lab and in rats that drank it in their water (13, 40 and 120 ppm). In the cells, cotinine (0.1 to 1 mM) made the cells multiply more than nicotine or the other breakdown products did. Blocking nicotinic receptors or a growth signal called Stat3 stopped this effect. In rats, cotinine also caused extra cell growth and thickening of the lining of the bladder and kidney, but less than nicotine (40 ppm). Only nicotine, not cotinine, damaged and killed bladder lining cells. The authors suggest that high levels of cotinine in urine may help bladder cancer develop, but these results come only from cells and rats.

Suzuki S, Cohen SM, Arnold LL et al. (2020). Cotinine, a major nicotine metabolite, induces cell proliferation on urothelium in vitro and in vivo. Toxicology. — PubMed PMID: 31678612 · doi:10.1016/j.tox.2019.152325

E-Cigarettes and Cancer Risk

Review, 2020. This review looks at how inhaling nicotine from e-cigarettes might be linked to cancer risk. The authors focus on nicotine's activation of the sympathetic nervous system, the body's 'fight or flight' stress system, and argue that this effect has been overlooked. Based on preclinical evidence, meaning laboratory and animal studies rather than studies in people, they report that this nervous-system activation by nicotine may help cancers start, grow and progress through several mechanisms. They note this may matter most for people with cancer, who may wrongly believe that e-cigarettes carry no risk compared with regular cigarettes.

Mravec B, Tibensky M, Horvathova L et al. (2020). E-Cigarettes and Cancer Risk. Cancer Prev Res (Phila). — PubMed PMID: 31619443 · doi:10.1158/1940-6207.CAPR-19-0346

In vitro effects of nicotine on the non-small-cell lung cancer line A549

Cell study, 2016. Researchers exposed a line of human non-small-cell lung cancer cells (A549), grown in the laboratory, to four concentrations of nicotine (0.01, 0.1, 1 and 10 µM) for 24 hours and compared them with untreated cells. The lowest dose had no significant effect on growth, but 0.1, 1 and 10 µM significantly held back the growth of the cancer cells, and the higher the dose, the stronger the effect. Fewer cells were seen on staining, and the cells changed in size and shape, with changes in their internal scaffolding and structures under the microscope. These results come only from cells in a dish, not from animals or people.

Gao T, Zhou XL, Liu S et al. (2016). In vitro effects of nicotine on the non-small-cell lung cancer line A549. J Pak Med Assoc. — PubMed PMID: 27122258

Mechanisms of growth-promoting and tumor-protecting effects of epithelial nicotinic acetylcholine receptors

Cell study, 2015. This laboratory study looked at how nicotine may help cancer cells grow and survive, using human oral cancer cells and lung cancer cells grown in dishes. Nicotine switched on nicotinic receptors both on the cell surface and inside the mitochondria, the cell's power plants. The surface receptors teamed up with receptors for growth signals, and the mitochondrial receptors linked up with enzymes that block a pathway cells use to self-destruct; together this was tied to faster cell growth and more resistance to cell death caused by hydrogen peroxide. These results come from cells only, and the authors suggest these receptors could become a target for slowing or preventing cancer.

Chernyavsky AI, Shchepotin IB, Grando SA (2015). Mechanisms of growth-promoting and tumor-protecting effects of epithelial nicotinic acetylcholine receptors. Int Immunopharmacol. — PubMed PMID: 26071223 · doi:10.1016/j.intimp.2015.05.033

Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR-mutated lung cancer via an EGFR signal

Cell study, 2015. Researchers grew two lines of lung cancer cells that carry EGFR mutations in a low dose of nicotine (1 μM) for 3 months, then tested how well EGFR-blocking cancer drugs worked on them. The nicotine-exposed cells resisted the drugs more than untreated cells did, because the drugs switched off the EGFR signal less fully, although a higher drug concentration lowered that signal further. The researchers also looked at patients with this type of lung cancer who were treated with gefitinib, and found that a history of smoking independently predicted a shorter time before the cancer progressed. The authors say smoking cessation is very important for these patients, and that higher-dose EGFR drugs may overcome the resistance; the nicotine findings come from cells only.

Togashi Y, Hayashi H, Okamoto K et al. (2015). Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR-mutated lung cancer via an EGFR signal. Lung Cancer. — PubMed PMID: 25704955 · doi:10.1016/j.lungcan.2015.01.027

Connections of nicotine to cancer

Review, 2014. This opinion article reviews emerging evidence that nicotine itself may directly contribute to the start and growth of cancer. The authors list a growing number of cancers that have been reported to be connected to nicotine, including lung, head and neck, stomach, pancreas, gallbladder, liver, colon, breast, cervical, bladder and kidney cancers, and describe how nicotine may damage DNA, disrupt how cells use energy, and help abnormal cells grow and spread, partly by switching on nicotinic receptors. They also note that inherited differences in the genes for these receptors may affect how strongly a person is affected, and that these receptors might be targets for cancer treatment or prevention.

Grando SA (2014). Connections of nicotine to cancer. Nat Rev Cancer. — PubMed PMID: 24827506 · doi:10.1038/nrc3725

Long-term nicotine replacement therapy: cancer risk in context

Other, 2011. This is a short commentary, not a new study. It looks at whether using nicotine replacement therapy for a long time could raise cancer risk. The authors note that using it for up to 12 weeks is well established as safe and helps people stop smoking, and that some laboratory studies have suggested nicotine could cause cancer. They say two animal studies in the same journal issue add reassurance that it does not promote lung cancer, but very long-term human studies do not exist yet, and the risks should be weighed against the far greater risks of continuing to smoke.

Shields PG (2011). Long-term nicotine replacement therapy: cancer risk in context. Cancer Prev Res (Phila). — PubMed PMID: 22052338 · doi:10.1158/1940-6207.CAPR-11-0453

Intervention of nicotine on MNU-induced bladder cancer in rats

Animal study, 2011. Researchers gave rats bladder cancer with a chemical called MNU. Some of the rats were then fed nicotine at one of three doses (25, 15 or 5 mg/kg), three times a week for 8 weeks. By week 14, a mutant form of the p53 protein was found in 75.00%, 58.33% and 41.67% of the three nicotine groups, compared with 33.33% of rats that got MNU only, and higher doses and longer treatment went with higher rates. The authors concluded that nicotine may play a role in bladder cancer development, partly by raising mutant p53 levels; this result comes from rats only.

Liu D, Pan F, Li B et al. (2011). Intervention of nicotine on MNU-induced bladder cancer in rats. J Huazhong Univ Sci Technolog Med Sci. — PubMed PMID: 21336733 · doi:10.1007/s11596-011-0159-z

Nicotine and apoptosis

Review, 2007. This review looks at how nicotine affects apoptosis, the process by which the body's cells are programmed to die when they are damaged or no longer needed. Nicotine acts on many kinds of cells beyond the nervous system, including immune cells, by attaching to nicotinic acetylcholine receptors. The authors say that through these receptors nicotine disrupts apoptosis, the growth of new blood vessels and cell-based immunity. Nicotine is not usually called a cancer-causing substance, but the authors note an ongoing debate over whether it helps tumors grow, and they argue that its effects on apoptosis are directly involved in diseases such as cancer and obstructive diseases.

Zeidler R, Albermann K, Lang S (2007). Nicotine and apoptosis. Apoptosis. — PubMed PMID: 17846896 · doi:10.1007/s10495-007-0102-8

Nicotine-mediated cell proliferation and angiogenesis: new twists to an old story

Review, 2006. This review looks at how nicotine acts on the body's nicotinic acetylcholine receptors. These receptors are found in the brain and at nerve-muscle junctions, and also in other tissues such as the lung. The authors say nicotine does not cause cancer by itself. However, they describe research showing that when nicotine activates these receptors outside the brain, it can make cells multiply and help new blood vessels grow, and they explain the cell signals involved. They suggest that the steps in this pathway could become targets for new anti-cancer treatments.

Dasgupta P, Chellappan SP (2006). Nicotine-mediated cell proliferation and angiogenesis: new twists to an old story. Cell Cycle. — PubMed PMID: 17102610 · doi:10.4161/cc.5.20.3366

Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin

Cell study, 2006. Researchers tested whether nicotine changes how well three chemotherapy drugs (gemcitabine, cisplatin and taxol) kill human non-small cell lung cancer cells grown in the lab. Nicotine protected the cancer cells from being killed by these drugs, and it did so by raising two survival proteins in the cells, XIAP and survivin. When those proteins were removed, the protective effect went away. The effect ran through a type of nicotinic receptor and the Akt signaling pathway. This was only shown in cells, and the authors suggest nicotine exposure might weaken how well chemotherapy works.

Dasgupta P, Kinkade R, Joshi B et al. (2006). Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin. Proc Natl Acad Sci U S A. — PubMed PMID: 16601104 · doi:10.1073/pnas.0509313103

Carcinogenic effect of nicotine on normal mammary ductal epithelial cells and the protective role of beta-carotene

Cell study, 2003. Researchers exposed normal breast duct lining cells to nicotine in the laboratory to see whether nicotine acts on them directly. Nicotine significantly increased how fast the cells multiplied and how much estrogen receptor they made, and it also raised colony formation; the effect was stronger at the lower concentration tested (650 micrograms per millilitre), while a higher dose damaged the cells. Adding beta-carotene, an antioxidant, significantly reduced the faster multiplication caused by the lower nicotine dose and prevented the cell damage from the higher dose, but it did not significantly change the rise in estrogen receptor, although that showed a downward trend. These results come only from cells grown in the laboratory, not from people or animals.

Mazhari NJ, Mandal AK, Thusoo TK (2003). Carcinogenic effect of nicotine on normal mammary ductal epithelial cells and the protective role of beta-carotene. Indian J Pathol Microbiol. — PubMed PMID: 15027713

Nicotine inhibition of apoptosis suggests a role in tumor promotion

Cell study, 1993. Researchers tested in laboratory cell cultures whether nicotine affects apoptosis, the built-in self-destruct process that helps the body get rid of damaged cells before they can turn into tumors. Nicotine blocked apoptosis triggered by several different stresses, including an immune signaling protein, UV light, chemotherapy drugs and a calcium-raising chemical. This happened in normal and cancer-like cells from several species and tissues, including tumor cell types linked to tobacco use. Cotinine, nicotine's main breakdown product, also blocked apoptosis, but a cancer-causing chemical found in tobacco did not. The authors suggest this effect could contribute to tobacco-related cancers and make cancer treatments work less well. The findings come from cells only, not from animals or people.

Wright SC, Zhong J, Zheng H et al. (1993). Nicotine inhibition of apoptosis suggests a role in tumor promotion. FASEB J. — PubMed PMID: 8370474

Nicotine and smokeless tobacco

Review, 1988. This review looked at nicotine in smokeless tobacco. It reports that people who use smokeless tobacco absorb about as much nicotine into the body as cigarette smokers, and the few studies so far suggest they become dependent in a similar way. The authors say regular smokeless tobacco use is expected to carry the health hazards that are known to come from smoking and are suspected to come from long-term nicotine exposure, with faster-developing heart artery disease in young men as a major concern. They also raise concern that smokeless tobacco use in young people may lead to later cigarette dependence, and they call for better ways to help users quit.

Benowitz NL (1988). Nicotine and smokeless tobacco. CA Cancer J Clin. — PubMed PMID: 3135084 · doi:10.3322/canjclin.38.4.244

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PubMed Topic Searches

1. PubMed: Cancer Research and nicotine (the search this page is built from)

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Connections

• Nicotine: The Research
• The Nicotine Patch, animated
• Nicotinic Acetylcholine Receptors
• Cigarette Smoke — what burnt tobacco adds that nicotine alone does not
• Brain and Memory
• Mood and Mental Health
• Inflammation and Immunity
• Heart and Blood Vessels
• Metabolism and Weight
• Addiction and Withdrawal
• Patches, Gum and Delivery
• Toxicity and Safety

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