Tubastatin A Small Molecule Shows Early Promise as Cushing’s Therapy

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Using a mouse model, scientists have found that the small molecule tubastatin A may be a potential treatment for Cushing’s disease.

Tubastatin A was shown to reduce the activity of genes encoding the precursor of the adrenocorticotropic hormone (ACTH), and to lessen the growth of ACTH-producing tumor cells isolated from the pituitary gland of the mice.

“These findings suggest that tubastatin A may have applications as a novel therapy for Cushing’s disease,” the researchers wrote.

The study, “Effects of tubastatin A on adrenocorticotropic hormone synthesis and proliferation of AtT-20 corticotroph tumor cells,” was published in the Endocrine Journal.

The presence of non-cancerous, or benign tumors in the brain’s pituitary gland causes most cases of Cushing’s disease. These tumors trigger the excessive production of ACTH, which in turn signals the adrenal glands, sitting atop the kidneys, to overproduce cortisol, leading to a variety of Cushing’s symptoms.

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Histone deacetylases (HDACs) are enzymes that modulate the production of ACTH and the growth of ACTH-producing cells.

Recent studies suggest that blocking one type of HDAC enzyme — HDAC6 — with the small molecule tubastatin A decreases tumor cell growth. However, whether inhibiting HDAC6 with tubastatin A lowers ACTH production and cell growth in ACTH-producing tumor cells is unknown.

Now, investigators at the Hirosaki University Graduate School of Medicine, in Japan, examined the effects of blocking HDAC6 in AtT-20 cells, which are ACTH-producing tumor cells isolated from the pituitary gland of mice.

First, researchers showed that incubating AtT-20 cells with tubastatin A led to a time- and dose-dependent reduction in Hdac6 messenger RNA (mRNA) — the molecule that carries instructions for making the HDAC6 enzyme. At the same time, there was a time- and dose-dependent decrease in the mRNA encoding proopiomelanocortin (Pomc), which is ACTH’s precursor molecule.

Further, with tubastatin A, there also was a time- and dose-dependent decrease in Pttg1 mRNA, a biomarker for pituitary tumor cell growth in AtT-20 cells, as well as a dose-dependent decrease in the growth of AtT-20 cells.

In comparison, the team conducted the same set of experiments using dexamethasone, a man-made steroid similar to cortisol that is often used to test for the presence of Cushing’s. Dexamethasone suppresses ACTH and thus cortisol production in people without Cushing’s, but not to the same extent as in those with the disease who produce excess ACTH.

Like tubastatin A, dexamethasone also reduced Hdac6 and Pttg1 mRNA levels in a time- and dose-dependent manner.

Treating AtT-20 cells with a combination of tubastatin A and dexamethasone lowered Pomc mRNA levels even more, showing “the combined treatment showed additive effects on the Pomc mRNA level,” the researchers wrote. In contrast, combined treatment did not reduce Pttg1 mRNA levels beyond reductions seen with tubastatin A alone.

Lastly, tests showed tubastatin A activated the Akt pathway, a potential therapeutic target for cancer, after two hours. The same signaling cascade was activated after six hours with dexamethasone, but a combined treatment had no effect. The Akt pathway is thought to regulate Pttg1. Thus, the growth of ACTH-producing tumor cells “may be regulated through the Akt-Pttg1 pathway,” the researchers noted.

“We found that the selective HDAC6 inhibitor tubastatin A decreased Pomc and Pttg1 mRNA levels in and blocked the [growth] of AtT-20 murine [ACTH-producing] tumor cells,” the authors wrote.

The results support further research into this small molecule as a potential new treatment, the team concluded.