Endocrine Abstracts

Adrenocortical carcinoma (ACC) is a rare, heterogeneous malignancy with aggressive behavior and poor prognosis, particularly when metastatic at diagnosis. To date, radical surgery, possibly associated to mitotane adjuvant therapy, is considered the best option for ACC treatment. However, the mean 5-year survival rate diminishes dramatically in metastatic ACC and chemo-resistance often develops. Thus, more specific and effective drugs for ACC treatment are urgently required. The use of metformin, a well-established and effective agent for the management of type 2 diabetes mellitus, has been associated with decreased cancer incidence and mortality in several human malignancies, leading to increasing interest in its potential use as an anticancer agent.

In our study, we evaluate the potential in vitro anti-cancer effect of metformin on the adrenocortical cancer cell line H295R, looking for an alternative therapeutic approach to ACC treatment.

We observed that increasing doses of metformin (0.5–250 mM), administered to H295R cells for 1, 2, 3 and 7 days, inhibit cell viability and proliferation in a dose- and time-dependent manner, as demonstrated by MTS, cell counting and [³H]thymidine incorporation assay. This anti-proliferative effect seems to be mediated by metformin-induced apoptosis, as investigated by cytofluorimetric assay. Western blot analysis of cell lysates after 6- and 24-h metformin treatment (20, 50 and 100 mM) was used to identify the molecular pathways involved in mediating the drug effect: it revealed a dose-dependent increase in phosphorylated AMPK, which associates with a decreased mTOR phosphorylation, and a reduction in IGF1R expression and ERK1/2 phosphorylation, suggesting that metformin may exert its effect through these signaling pathways.

In conclusion, our data demonstrate that metformin is particularly effective in inhibiting proliferation in H295R adrenocortical cancer cells in a manner that depends on the drug concentration and treatment duration.

Further studies are necessary to validate these findings in vivo, to assess direct and indirect anti-cancer effects of metformin and to better elucidate the intracellular mechanisms involved in metformin action.