Metformin enhances the chemosensitivity of hepatocarcinoma cells to cisplatin through AMPK pathway

Dong, Hao; Huang, Jianghua; Zheng, Kang; Tan, Dong; Chang, Qi; Gong, Genqiang; Zhang, Qing; Tang, Hanqiu; Sun, Jianping; Zhang, Shaoyu

doi:10.3892/ol.2017.7198

Cited by 12 publications

(8 citation statements)

References 20 publications

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“…Combined application of metformin and cisplatin had shown controversial results in the treatment of various tumors. It has been reported that metformin could promote the anticancer effect of cisplatin in breast cancer ( 18 ), NSCLC ( 26 ), nasopharyngeal carcinoma ( 20 ), liver cancer ( 27 ). On the contrary, metformin reduced the anti-proliferative effects of cisplatin through mTOR/AKT signaling pathways in the MKN-45 cells ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

Metformin-induced AMPK activation promotes cisplatin resistance through PINK1/Parkin dependent mitophagy in gastric cancer

Xiao

Wang

et al. 2022

Front. Oncol.

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Gastric cancer (GC) is one of the most common tumors worldwide, and cisplatin is a standard chemotherapeutic reagent for GC treatment. However, chemoresistance is an inherent challenge which limits its application and effectiveness in clinic. This study aims to investigate the mechanism of metformin-induced cisplatin resistance in GC. Intriguingly, the upregulation of mitophagy markers, mitochondrial fission, autophagy and mitophagosome were observed in SGC-7901/DDP cells compared to those in the SGC-7901 cells. Treatment with metformin significantly increased mitochondrial fission and mitophagy in both AGS and SGC-7901 cells, resulting in decreased ATP production, which unexpectedly protected GC cells against the cytotoxicity of cisplatin. In contrast, application of Chloroquine and 3-methyladenine, two inhibitors of autophagy, significantly alleviated the protective effect of metformin on SGC-7901 and AGS cells against cytotoxicity of cisplatin. Moreover, metformin also stimulated the phosphorylation of AMPK (Thr172) and increased the expression of mitophagy markers including Parkin and PINK1 in the AMPK signaling-dependent manner. Consistently, the cell viability and cell apoptosis assay showed that metformin-induced cisplatin resistance was prevented by knockdown of AMPKα1. Taken together, all data in this study indicate that metformin induced AMPK activation and PINK1/Parkin dependent mitophagy, which may contribute to the progression of cisplatin resistance in GC.

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Section: Discussionmentioning

confidence: 99%

Metformin-induced AMPK activation promotes cisplatin resistance through PINK1/Parkin dependent mitophagy in gastric cancer

Xiao

Wang

et al. 2022

Front. Oncol.

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“…[28–31] In addition, various preclinical studies have found that metformin enhances the anti-tumor effects of platinum and increases their sensitivity by regulating multiple signaling pathways including AMPK-mTOR, ERK1/2, NF-κB. [32–34] Thus, we hypothesized that metformin might benefit lung cancer patients who received platinum-based chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Impact of metformin use on survival outcomes in non-small cell lung cancer treated with platinum

Xin

Xiao²,

Ding³

et al. 2018

Medicine

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Preclinical evidence suggests that metformin, a widely used antidiabetic drug, may have a sensitizing effect on platinum. The purpose of this study was to evaluate the survival outcomes for non-small cell lung cancer (NSCLC) patients with type 2 diabetes mellitus (T2DM) using metformin during platinum-based chemotherapy.The clinicopathological parameters and survival data of 75 NSCLC patients with T2DM from January 2008 to December 2011 were collected and analyzed retrospectively. Patients were divided into 2 groups: metformin exposure group (n = 27) and non-metformin group (patients using other hypoglycemic agents or no drug for controlling n = 48). Univariate and multivariate analyses were performed to assess the association of metformin usage with overall survival (OS).Mean follow-up time was 58.7 months. The mean survival time was 36.74 months in the metformin group and 40.21 months in the non-metformin group. There was no significant difference in survival time between the 2 groups (P = .661). After adjusting gender, age, smoking status, tumor stage, tumor histology, and differentiation, multivariate analysis showed that metformin was not associated with the OS in NSCLC patients treated with concurrent platinum-based chemotherapy (hazard ratio: 1.071, 95% confidence interval: 0.577–1.986, P = .828).Our results indicated that metformin exposure had no significant effect on OS in NSCLC patients treated with platinum-based chemotherapy. Further studies are warranted to evaluate whether metformin could affect the survival of NSCLC patients treated with platinum-based chemotherapy.

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“…Wide differences in its effectiveness also stems from the variety of clinical approaches used for drug delivery [8][9][10]. Thus, optimisation of cisplatin efficiency [11,12] and minimisation of cisplatin chemoresistance [13] are the most important approaches that could improve patient treatment and prognosis.…”

Section: Introductionmentioning

confidence: 99%

Membrane Association of the Short Transglutaminase Type 2 Splice Variant (TG2-S) Modulates Cisplatin Resistance in a Human Hepatocellular Carcinoma (HepG2) Cell Line

Meshram¹,

Fanutti²,

Pike³

et al. 2023

Preprint

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Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with complex carcinogenesis. Although there has been significant progress in the treatment of HCC over the past decades, drug resistance to chemotherapy remains a major obstacle in its successful management. In this study we were able to reduce chemoresistance in cisplatin-resistant HepG2 cells by either silencing the expression of transglutaminase type 2 (TG2) using siRNA or by pre-treatment of cells with the TG2 enzyme inhibitor cystamine. Further analysis revealed that, whereas the full-length TG2 isoform (TG2-L) was almost completely cytoplasmic in its distribution, the majority of the short TG2 isoform (TG2-S) was membrane-associated in both parental and chemoresistant HepG2 cells. Following induction of cisplatin toxicity in non-chemoresistant parental cells, TG2-S together with cisplatin quickly relocated to the cytosolic fraction. Conversely, no cytosolic relocalisation of TG2-S or nuclear accumulation cisplatin was observed following identical treatment of chemoresistant cells, where TG2-S remained predominantly membrane-associated. This suggests that deficient subcellular relocalisation of TG2-S from membranous structures into the cytoplasm may limit the apoptic response to cisplatin toxicity in chemoresistant cells. Structural analysis of TG2 revealed the presence of binding motifs for interaction of TG-S with the membrane scaffold protein LC3/LC3 homologue that could contribute to a novel mechanism of chemotherapeutic resistance in HepG2 cells.

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Metformin enhances the chemosensitivity of hepatocarcinoma cells to cisplatin through AMPK pathway

Cited by 12 publications

References 20 publications

Metformin-induced AMPK activation promotes cisplatin resistance through PINK1/Parkin dependent mitophagy in gastric cancer

Metformin-induced AMPK activation promotes cisplatin resistance through PINK1/Parkin dependent mitophagy in gastric cancer

Impact of metformin use on survival outcomes in non-small cell lung cancer treated with platinum

Membrane Association of the Short Transglutaminase Type 2 Splice Variant (TG2-S) Modulates Cisplatin Resistance in a Human Hepatocellular Carcinoma (HepG2) Cell Line

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