Diabetes therapy metformin may slow common skin cancer in RDEB

Study: Medication inhibited processes used by cancer cells to generate energy

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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The diabetes medication metformin slowed tumor growth and prolonged survival in a mouse model of aggressive squamous cell carcinoma (SCC), the most common type of cancer seen in people with recessive dystrophic epidermolysis bullosa (RDEB), in a recent study. 

It did so by inhibiting cellular processes used by cancer cells to generate energy, which were found to be increased in SCC cells from RDEB patients relative to healthy skin cells.

Researchers believe that topical administration of metformin to RDEB skin wounds at high risk for SCC could help to slow the progression of this cancer, which often has an aggressive course in RDEB.

The study, “Metformin shows anti-neoplastic properties by inhibition of oxidative phosphorylation and glycolysis in epidermolysis bullosa-associated aggressive cutaneous squamous cell carcinoma,” was published in The Journal of the European Academy of Dermatology and Venereology.

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A subtype of epidermolysis bullosa (EB), RDEB is characterized by easily damaged skin, inflammation, and painful wounds, as well as an elevated risk for SCC, a type of skin cancer. It is the most commonly reported type of cancer among people with EB.

In the general population, SCC is usually not life-threatening and is treatable with surgery to remove the lesions, but it is particularly aggressive and more difficult to treat in certain populations, including RDEB patients.

In fact, RDEB patients have about a 68% chance of developing life-threatening SCC by age 35, and the cancer is the leading cause of death for these patients, according to the researchers. 

For cancer cells to grow, they require a large amount of energy. In general, they switch between two major metabolic pathways to produce this energy — glycolysis and oxidative phosphorylation. The latter process takes place in mitochondria, the cellular organelles used for the majority of energy production in cells.

Evidence suggests that SCCs, as well as other types of cancer, undergo metabolic reprogramming to alter their energy usage in ways that promote their growth. Such alterations could contribute to the initiation and maintenance of aggressive SCC.

In the study, the scientists aimed to more closely examine the metabolic alterations in cancer cells from RDEB patients. 

They leveraged information from a publicly available database, which contained information about gene expression, or gene activity, from SCC cells and normal skin cells called keratinocytes taken from RDEB patients. Genes with higher activity in the SCC cells tended to be related to oxidative phosphorylation and mitochondria function.

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Skin cells from RDEB patients show altered gene activity

Moreover, keratinocytes from RDEB patients showed higher gene activity related to both glycolysis and oxidative phosphorylation compared with cells from healthy people. On the other hand, SCC cells from RDEB patients and from non-EB patients both exhibited a strong profile associated with oxidative phosphorylation compared with keratinocytes from healthy people. 

“Together, … analyses demonstrated an altered cell energetics program in RDEB-SCC characterised by high [oxidative phosphorylation] activity,” the scientists wrote. 

Consistently, when grown in lab cultures, RDEB-SCC cells exhibited signs of increased oxidative phosphorylation and mitochondrial stress compared with keratinocytes from healthy people, as well as higher levels of glycolysis.

The two energy production processes were found to compensate for one another. When oxidative phosphorylation was inhibited, glycolysis increased, and the reverse was also true, suggesting the SCC cells have some “adaptability to metabolic stresses,” the scientists wrote. 

That also means that to effectively target metabolic processes in SCC, inhibiting both processes will be important, the team noted. 

Given these findings, the scientists evaluated whether the diabetes medication metformin, which is known to modulate mitochondrial activity and has garnered interest as an anti-cancer treatment, would alter these metabolic processes in the SCC cells.

At a high concentration, metformin was able to shut down oxidative phosphorylation and inhibit glycolysis in these cancer cells. Long-term treatment for more than two weeks led to significant death of the SCC cells and inhibited tumor growth.

Treatment with metformin in a mouse model of SCC was well tolerated and both delayed the formation of tumors and slowed tumor growth. This was accompanied by significantly increased overall survival in mice given the treatment (median 27 days) compared with untreated animals (median 21 days). 

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Ketogenic diet could boost metformin’s anti-cancer effects

The scientists believe these anti-cancer effects of metformin could be even greater when combined with classic approaches to target tumor metabolism, such as the ketogenic diet.

While the properties of metformin make it an interesting therapeutic candidate for RDEB-SCC, “additional investigation into its impact on wound healing in this disease context is highly warranted if it is to be considered for long-term use, especially given the significant overlap in the cellular processes that drive wound healing and tumour progression,” the scientists wrote.

They also noted that metformin is linked to significant gastrointestinal side effects. This could be a concern for RDEB patients, who often have nutritional issues and are underweight. 

Nevertheless, “local topical application of metformin in an adjuvant setting, or as a preventative measure in at-risk wounds or pre-malignant [precancerous] lesions, may represent a favourable option for RDEB patients that is worthwhile investigating in future studies,” the team concluded.