Sirolimus and metformin synergistically inhibit hepatocellular carcinoma cell proliferation and improve long-term survival in patients with HCC related to hepatitis B virus induced cirrhosis after liver transplantation

Abstract

Immunosuppressive agents used postoperatively after liver transplantation (LT) for hepatocellular carcinoma (HCC) favor recurrence and metastasis. Therefore, new effective immunosuppressants are needed. This retrospective study assessed combined sirolimus and metformin on survival of HCC patients after LT. In 2001-2013, 133 HCC patients with LT were divided into four groups: sirolimus and metformin combination (Sir+Met), sirolimus monotherapy (Sir), other immunosuppressants in diabetes mellitus (DM) patients without metformin (No Sir with DM), and other immunosuppressants in patients without DM (No Sir without DM). Kaplan-Meier and Log-rank tests were used to assess survival. Cell proliferation and tumor xenograft assays were performed to disclose the mechanisms underlying the sirolimus and metformin effects. The Sir+Met group showed significantly prolonged survival compared to the other groups. The most significant cytotoxicity was seen in the Sir+Met group, with significantly decreased levels of phosphorylated PI3K, AKT, AMPK, mTOR, 4EBP1 and S6K, compared with the other groups. In agreement, Sir+Met had the highest suppressive effect on tumor growth among all groups (P<0.01). In summary, Sir+Met treatment significantly prolonged survival, likely by suppressing cell proliferation. Therefore, this combination could represent a potential routine-regimen for patients post LT.

Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma

“…In line with our observation, metformin treatment was associated with reduced tumour recurrence and improvement of OS in patients who underwent hepatic resection for HCC . Another retrospective study in patients undergoing LT for HCC could show that OS was improved in patients receiving sirolimus and metformin . In a small propensity score matched cohort of 76 patients receiving radiotherapy for HCC, medication with metformin was also associated with a prolonged survival .…”

“…[14][15][16][17] Another retrospective study in patients undergoing LT for HCC could show that OS was improved in patients receiving sirolimus and metformin. 18 In a small propensity score matched cohort of 76 patients receiving radiotherapy for HCC, medication with metformin was also associated with a prolonged survival. 19 Another study showed a favourable outcome for metformin in a cohort of 135 patients treated with RFA for HCC.…”

“…However, there are several studies that have investigated the influence of metformin in specific treatment subgroups. Accordingly, treatment with metformin has been associated with reduced tumour recurrence and a prolonged survival in patients who underwent hepatic resection, liver transplantation (LT), radiotherapy and radiofrequency ablation (RFA) for HCC . The potential anticancer mechanisms of metformin include interference with pivotal oncogenic signalling pathways such as the mammalian target of rapamycin (mTOR) signalling pathway, activation of AMP‐activated protein kinase (AMPK), p53‐dependent and ‐independent pro‐apoptotic activities and cell cycle arrest .…”

Metformin attenuates albumin‐induced alterations in renal tubular cells in vitro

“…Our findings also demonstrate that 1 mM of metformin could significantly reduce mTOR activity induced by albumin. A similar inverse association between AMPK and mTOR pathway was shown in many cell types such as hepatocytes (Shen et al, ), airway smooth muscle cells (Liu, Pan et al, ), and cellular models of cancer (Rios et al, ; White‐Al Habeeb, Garcia, Fleshner, & Bapat, ). Comparably, data from renal injury models further indicate the inhibitory effects of metformin on mTOR pathway.…”

Systematic review with meta‐analysis: sirolimus‐ or everolimus‐based immunosuppression following liver transplantation for hepatocellular carcinoma

“…One further study had an intervention arm containing mTOR‐inhibitors and another experimental anti‐oncogenic agent, and was excluded due to the potential confounding effect. Therefore, 23 studies were included in the quantitative analysis …”