Highlights
- •Metformin has been shown to inhibit tumour growth by inducing apoptosis in various cancers.
- •In the present study we validated the association between metformin and sorafenib in hepatocellular carcinoma (HCC) patients.
- •Our findings show a lower response to sorafenib whilst undergoing chronic therapy with metformin.
- •Our findings also reveal different tumour biology among the various aetiologies of HCC.
- •We hypothesise that SIRT-3 could play a fundamental role in the resistance to sorafenib.
Abstract
Purpose
In 2015, we published a study on a small series of patients with hepatocellular carcinoma
(HCC) treated chronically with metformin for type II diabetes mellitus (DM2) who showed
a poorer response to sorafenib. The aim of the present study was to validate the prognostic
significance of metformin in HCC patients treated with sorafenib, providing a biological
rationale for the mechanism of resistance to sorafenib in patients on chronic metformin
therapy, and to clarify the role of sirtuin-3 (SIRT-3), a protein involved in metabolic
diseases and acknowledged as a tumour suppressor in HCC, in this resistance.
Patients and methods
We analysed 279 patients consecutively treated with sorafenib for the clinical analysis.
Of the 86 (30%) patients with DM2, 52 (19%) were on chronic treatment with metformin
and 34 (12%) with insulin. We included 43 patients with HCC for the biological study:
19 (44.1%) were diabetic and 14 (73.7%) of these received metformin for DM2. SIRT-3
expression was investigated by immunohistochemistry (IHC) in formalin-fixed and paraffin-embedded
(FFPE) samples.
Results
In HCC patients undergoing chronic treatment with metformin, the use of sorafenib
was associated with poor progression-free survival (PFS) and overall survival (OS)
(1.9 and 6.6 months, respectively) compared to 3.7 months and 10.8 months, respectively,
for patients without DM2 and 8.4 months and 16.6 months, respectively, for patients
on insulin (P < .0001). We also observed that SIRT-3 protein expression was significantly higher
in patients treated with metformin than in those not taking this medication (65% versus
25%, respectively) (P = .013).
Conclusions
Our findings could be attributed to increased tumour aggressiveness and resistance
to sorafenib caused by chronic treatment with metformin.
Keywords
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Article info
Publication history
Published online: October 03, 2017
Accepted:
September 4,
2017
Received in revised form:
August 28,
2017
Received:
July 3,
2017
Identification
Copyright
© 2017 Elsevier Ltd. All rights reserved.
