Synergistic effect of metformin on sorafenib in <i>in vitro</i> study using hepatocellular carcinoma cell lines

Chung, Yong-Gyu; Tak, Eunyoung; Hwang, Shin; Lee, Jooyoung; Kim, Ji-Ye; Kim, Ye-Young; Song, Gi‐Won; Lee, Kyoung-Jin; Kim, Nayoung

doi:10.14701/ahbps.2018.22.3.179

Cited by 14 publications

(7 citation statements)

References 20 publications

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“…It is secreted in an unchanged form from these cells into the bile or urine, through multidrug and toxin extrusion protein transporter-1 (MATE1; SLC47A1 , Slc47a1 ) and MATE2 ( SLC47A2 ) [ 14 , 15 , 16 ]. In the last few years, a growing number of studies have investigated the anti-cancer properties of metformin and TKIs [ 17 , 18 , 19 , 20 ]. In vitro studies suggest that the addition of metformin may significantly decrease the dose of sorafenib needed to induce the equal inhibition of both the growth and colony and tumor formation of HT74 anaplastic thyroid carcinoma cells [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Interaction between Sorafenib and Atorvastatin, and Sorafenib and Metformin in Rats

et al. 2020

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The tyrosine kinase inhibitor sorafenib is the first-line treatment for patients with hepatocellular carcinoma (HCC), in which hyperlipidemia and type 2 diabetes mellitus (T2DM) may often coexist. Protein transporters like organic cation (OCT) and multidrug and toxin extrusion (MATE) are involved in the response to sorafenib, as well as in that to the anti-diabetic drug metformin or atorvastatin, used in hyperlipidemia. Changes in the activity of these transporters may lead to pharmacokinetic interactions, which are of clinical significance. The study aimed to assess the sorafenib−metformin and sorafenib−atorvastatin interactions in rats. The rats were divided into five groups (eight animals in each) that received sorafenib and atorvastatin (ISOR+AT), sorafenib and metformin (IISOR+MET), sorafenib (IIISOR), atorvastatin (IVAT), and metformin (VMET). Atorvastatin significantly increased the maximum plasma concentration (Cmax) and the area under the plasma concentration–time curve (AUC) of sorafenib by 134.4% (p < 0.0001) and 66.6% (p < 0.0001), respectively. Sorafenib, in turn, caused a significant increase in the AUC of atorvastatin by 94.0% (p = 0.0038) and its metabolites 2−hydroxy atorvastatin (p = 0.0239) and 4−hydroxy atorvastatin (p = 0.0002) by 55.3% and 209.4%, respectively. Metformin significantly decreased the AUC of sorafenib (p = 0.0065). The AUC ratio (IISOR+MET group/IIISOR group) for sorafenib was equal to 0.6. Sorafenib did not statistically significantly influence the exposure to metformin. The pharmacokinetic interactions observed in this study may be of clinical relevance in HCC patients with coexistent hyperlipidemia or T2DM.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Interaction between Sorafenib and Atorvastatin, and Sorafenib and Metformin in Rats

et al. 2020

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“… 28 , 29 Additionally, the combination has been shown to increase apoptotic cell death in HepG2.2.15 cells through alterations in the mTOR pathway, suggesting a promising approach for improving HCC treatment outcomes. 30 Given the outcomes of metformin‐SF combination therapies, the DDC‐SF combination could be another novel strategy to overcome resistance in HBV‐related HCC, potentially optimizing therapeutic outcomes. Moreover, considering the combined treatment of DDC and SF has increased cellular levels of lipid ROS, such as 4‐HNE, DDC‐SF combination therapy can modulate the inhibition of the diverse pathways including PI3K/Akt pathway, via modulating SOD1 and related cellular antioxidant mechanisms.…”

Section: Discussionmentioning

confidence: 99%

SOD1 inhibition enhances sorafenib efficacy in HBV‐related hepatocellular carcinoma by modulating PI3K/Akt/mTOR pathway and ROS‐mediated cell death

Lee,

Kim,

Lee

et al. 2024

J Cellular Molecular Medi

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Hepatitis B Virus (HBV) infection significantly elevates the risk of hepatocellular carcinoma (HCC), with the HBV X protein (HBx) playing a crucial role in cancer progression. Sorafenib, the primary therapy for advanced HCC, shows limited effectiveness in HBV‐infected patients due to HBx‐related resistance. Numerous studies have explored combination therapies to overcome this resistance. Sodium diethyldithiocarbamate (DDC), known for its anticancer effects and its inhibition of superoxide dismutase 1 (SOD1), is hypothesized to counteract sorafenib (SF) resistance in HBV‐positive HCCs. Our research demonstrates that combining DDC with SF significantly reduces HBx and SOD1 expressions in HBV‐positive HCC cells and human tissues. This combination therapy disrupts the PI3K/Akt/mTOR signalling pathway and promotes apoptosis by increasing reactive oxygen species (ROS) levels. These cellular changes lead to reduced tumour viability and enhanced sensitivity to SF, as evidenced by the synergistic suppression of tumour growth in xenograft models. Additionally, DDC‐mediated suppression of SOD1 further enhances SF sensitivity in HBV‐positive HCC cells and xenografted animals, thereby inhibiting cancer progression more effectively. These findings suggest that the DDC‐SF combination could serve as a promising strategy for overcoming SF resistance in HBV‐related HCC, potentially optimizing therapy outcomes.

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“…Recently, Ling and colleagues evaluated the efficacy of the combination treatment of metformin and sorafenib in HCC and concluded that the combination treatment induces apoptosis and inhibits cell proliferation both in vitro and in vivo [ 54 ]. The synergistic effect of metformin and sorafenib seemed to induce AMPK signaling in HCC cells [ 55 , 56 ]. Harati and colleagues examined the effect of a clinically relevant dose of metformin (50 mg/kg/d) on the antitumoral effects of sorafenib (15 mg/kg/d) using different modes of administration (concomitant versus sequential).…”

Section: Discussionmentioning

confidence: 99%

Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma

Siddharth

Panjamurthy

et al. 2022

IJMS

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Hepatocellular carcinoma (HCC) incidence, as well as related mortality, has been steadily increasing in the USA and across the globe, partly due to the lack of effective therapeutic options for advanced HCC. Though sorafenib is considered standard-of-care for advanced HCC, it only improves median survival by a few months when compared to placebo. Sorafenib is also associated with several unpleasant side effects that often lead to early abatement of therapy. Here, we investigate whether a combination regimen including low-dose sorafenib and a non-toxic dose of anti-diabetic drug metformin can achieve effective inhibition of HCC. Indeed, combining metformin with low-dose sorafenib inhibited growth, proliferation, migration, and invasion potential of HCC cells. We observed a 5.3- and 1.9-fold increase in sub-G1 population in the combination treatment compared to sorafenib alone. We found that the combination of metformin enhanced the efficacy of sorafenib and inhibited the MAPK/ERK/Stat3 axis. Our in vivo studies corroborated the in vitro findings, and mice harboring HepG2-derived tumors showed effective tumor reduction upon treatment with low-dose sorafenib and metformin combination. This work sheds light on a therapeutic strategy aiming to augment sorafenib efficacy or dose-de-escalation that may prove beneficial in circumventing sorafenib resistance as well as minimizing related side effects.

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Synergistic effect of metformin on sorafenib in in vitro study using hepatocellular carcinoma cell lines

Cited by 14 publications

References 20 publications

Pharmacokinetic Interaction between Sorafenib and Atorvastatin, and Sorafenib and Metformin in Rats

Pharmacokinetic Interaction between Sorafenib and Atorvastatin, and Sorafenib and Metformin in Rats

SOD1 inhibition enhances sorafenib efficacy in HBV‐related hepatocellular carcinoma by modulating PI3K/Akt/mTOR pathway and ROS‐mediated cell death

Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma

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