Metformin, Oral Diabetes Treatment, Limits Growth of Tumors That Cause Cushing’s in Early Study

Metformin, an oral type 2 diabetes medicine, can promote cell death in tumors that cause Cushing’s disease and reduce the excessive production of the adrenocorticotroph hormone (ACTH) that underlies it, a study in mice cells reports.

These findings suggest that metformin, a tablet, may offer a new way of treating the pituitary tumors that produce excess ACTH and cause Cushing’s disease.

The research, “Metformin suppresses growth and adrenocorticotrophic hormone secretion in mouse pituitary corticotroph tumor AtT20 cells,” was published in Molecular and Cellular Endocrinology. The work was developed at The First Affiliated Hospital of Chongqing Medical University in China.

The most common cause of Cushing’s disease is pituitary adenoma — a benign tumor in the pituitary gland, found behind the nose and near the underside of the brain — which leads to overproduction of a hormone called ACTH.

ACTH causes the adrenal glands, located on top of the kidneys, to make too much cortisol. Known as the stress hormone, cortisol has an ability to increase blood-sugar levels, inhibit digestion, and halt immune activities — all processes crucial to the body in times of stress.

Cushing’s effects include metabolic and cardiovascular complications, bone alterations, kidney stones, autoimmune diseases, and susceptibility to opportunistic infections.

Signifor (pasireotide, by Novartis) is the only medicine approved by the European Medicines Agency and the U.S. Food and Drug Administration to treats adults with Cushing’s disease for whom surgery is not an option or whose disease failed to respond to surgery.

While effective at reducing tumor size and ACTH secretion, 73 percent of patients in a Phase 3 trial experienced high blood sugar levels after taking Signifor. Some developed uncontrolled diabetes due to this side effect.

“Recently, European experts in pituitary disease and diabetes mellitus recommend that the medical treatment for managing pasireotide-induced hyperglycemia [high blood sugar] should begin with metformin,” the researchers wrote.

Metformin lowers blood sugar levels, and is used to treat type 2 diabetes — and, as the study noted, to “manage” blood sugar levels and weight in Cushing’s patients. But evidence also shows that metformin can have direct effects against many tumor cell lines.

Researchers in China sought to investigate if metformin has an anti-tumor effect in lab-grown pituitary adenoma cells from mice by directly targeting them, and if so, to determine its underlying mechanisms.

They reported that metformin inhibited cell proliferation, promoted cell death, and lowered ACTH production.

While many treatments induce cell death by stopping cell division, this was not the case with metformin. Instead, the medicine activated the programmed cell death pathway, which initiates with the mitochondrial release of caspase-3.

Metformin also activated AMPK/mTOR, and blocked IGF-1R/AKT/mTOR pathways in the pituitary adenoma cells, inhibiting their growth. These are all molecular mechanisms known to be altered in cancer.

Results suggested that metformin can have a direct anti-tumor effect on pituitary adenomas.

“Based on these findings, metformin is not only an antidiabetic drug for the management of CD [Cushing’s disease], but it also has the potential to act as a novel therapeutic agent targeting pituitary corticotropn tumors,” the researchers concluded.