Limits...
Metformin reverses multidrug resistance in human hepatocellular carcinoma Bel‑7402/5‑fluorouracil cells.

Ling S, Tian Y, Zhang H, Jia K, Feng T, Sun D, Gao Z, Xu F, Hou Z, Li Y, Wang L - Mol Med Rep (2014)

Bottom Line: Metformin exhibits anti‑proliferative effects in tumor cells in vitro and in vivo.The results demonstrated that metformin had a synergistic anti‑proliferative effect with 5‑Fu in the Bel/Fu cells.Metformin targeted the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, suppressed the expression of hypoxia‑inducible factor‑1α (HIF‑1α) and transcriptionally downregulated the expression of multidrug resistance protein 1/P‑glycoprotein (P‑gp) and multidrug resistance‑associated protein 1 (MRP1).

View Article: PubMed Central - PubMed

Affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China.

ABSTRACT
Metformin exhibits anti‑proliferative effects in tumor cells in vitro and in vivo. The present study investigated the ability of metformin to reverse multidrug resistance (MDR) in human hepatocellular carcinoma Bel‑7402/5‑fluorouracil (5‑Fu; Bel/Fu) cells. The synergistic anti‑proliferative effect of metformin combined with 5‑Fu was evaluated using a Cell Counting kit‑8 assay. The variation in apoptotic rates and cell cycle distribution were evaluated using a flow cytometric assay and variations in target gene and protein expression were monitored using reverse transcription‑polymerase chain reaction and western blot analysis. The results demonstrated that metformin had a synergistic anti‑proliferative effect with 5‑Fu in the Bel/Fu cells. The variations in the number of apoptotic cells and distribution of the cell cycle were consistent with the variability in cell viability. Metformin targeted the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, suppressed the expression of hypoxia‑inducible factor‑1α (HIF‑1α) and transcriptionally downregulated the expression of multidrug resistance protein 1/P‑glycoprotein (P‑gp) and multidrug resistance‑associated protein 1 (MRP1). Collectively, these findings suggested that metformin may target the AMPK/mTOR/HIF‑1α/P‑gp and MRP1 pathways to reverse MDR in hepatocellular carcinoma.

Show MeSH

Related in: MedlinePlus

Met treatment increases phosphorylation of AMPK and decreases phosphorylation of mTOR. (A) Phosphorylation of AMPK was upregulated and phosphorylation of mTOR was downregulated in a dose-dependent manner. (B and C) Band intensities were quantified using Image Lab 5.0 software and were normalized to β-actin (**P<0.01, compared with the control). AMPK, AMP-activated protein kinase; mTOR, mammalian target of rapamycin; pAMPK, phosphorylated AMP-activated protein kinase; pmTOR, phosphorylated mammalian target of rapamycin; Met, metformin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4227430&req=5

f4-mmr-10-06-2891: Met treatment increases phosphorylation of AMPK and decreases phosphorylation of mTOR. (A) Phosphorylation of AMPK was upregulated and phosphorylation of mTOR was downregulated in a dose-dependent manner. (B and C) Band intensities were quantified using Image Lab 5.0 software and were normalized to β-actin (**P<0.01, compared with the control). AMPK, AMP-activated protein kinase; mTOR, mammalian target of rapamycin; pAMPK, phosphorylated AMP-activated protein kinase; pmTOR, phosphorylated mammalian target of rapamycin; Met, metformin.

Mentions: To evaluate the specific effect of metformin on the AMPK/mTOR pathway, which is widely considered to be the most common target of metformin, western blot analysis was used to evaluate the AMPK/mTOR pathway in Bel/Fu cells. Metformin treatment resulted in enhanced AMPK phosphorylation and reduced mTOR phosphorylation in a dose-dependent manner (Fig. 4).


Metformin reverses multidrug resistance in human hepatocellular carcinoma Bel‑7402/5‑fluorouracil cells.

Ling S, Tian Y, Zhang H, Jia K, Feng T, Sun D, Gao Z, Xu F, Hou Z, Li Y, Wang L - Mol Med Rep (2014)

Met treatment increases phosphorylation of AMPK and decreases phosphorylation of mTOR. (A) Phosphorylation of AMPK was upregulated and phosphorylation of mTOR was downregulated in a dose-dependent manner. (B and C) Band intensities were quantified using Image Lab 5.0 software and were normalized to β-actin (**P<0.01, compared with the control). AMPK, AMP-activated protein kinase; mTOR, mammalian target of rapamycin; pAMPK, phosphorylated AMP-activated protein kinase; pmTOR, phosphorylated mammalian target of rapamycin; Met, metformin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4227430&req=5

f4-mmr-10-06-2891: Met treatment increases phosphorylation of AMPK and decreases phosphorylation of mTOR. (A) Phosphorylation of AMPK was upregulated and phosphorylation of mTOR was downregulated in a dose-dependent manner. (B and C) Band intensities were quantified using Image Lab 5.0 software and were normalized to β-actin (**P<0.01, compared with the control). AMPK, AMP-activated protein kinase; mTOR, mammalian target of rapamycin; pAMPK, phosphorylated AMP-activated protein kinase; pmTOR, phosphorylated mammalian target of rapamycin; Met, metformin.
Mentions: To evaluate the specific effect of metformin on the AMPK/mTOR pathway, which is widely considered to be the most common target of metformin, western blot analysis was used to evaluate the AMPK/mTOR pathway in Bel/Fu cells. Metformin treatment resulted in enhanced AMPK phosphorylation and reduced mTOR phosphorylation in a dose-dependent manner (Fig. 4).

Bottom Line: Metformin exhibits anti‑proliferative effects in tumor cells in vitro and in vivo.The results demonstrated that metformin had a synergistic anti‑proliferative effect with 5‑Fu in the Bel/Fu cells.Metformin targeted the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, suppressed the expression of hypoxia‑inducible factor‑1α (HIF‑1α) and transcriptionally downregulated the expression of multidrug resistance protein 1/P‑glycoprotein (P‑gp) and multidrug resistance‑associated protein 1 (MRP1).

View Article: PubMed Central - PubMed

Affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China.

ABSTRACT
Metformin exhibits anti‑proliferative effects in tumor cells in vitro and in vivo. The present study investigated the ability of metformin to reverse multidrug resistance (MDR) in human hepatocellular carcinoma Bel‑7402/5‑fluorouracil (5‑Fu; Bel/Fu) cells. The synergistic anti‑proliferative effect of metformin combined with 5‑Fu was evaluated using a Cell Counting kit‑8 assay. The variation in apoptotic rates and cell cycle distribution were evaluated using a flow cytometric assay and variations in target gene and protein expression were monitored using reverse transcription‑polymerase chain reaction and western blot analysis. The results demonstrated that metformin had a synergistic anti‑proliferative effect with 5‑Fu in the Bel/Fu cells. The variations in the number of apoptotic cells and distribution of the cell cycle were consistent with the variability in cell viability. Metformin targeted the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, suppressed the expression of hypoxia‑inducible factor‑1α (HIF‑1α) and transcriptionally downregulated the expression of multidrug resistance protein 1/P‑glycoprotein (P‑gp) and multidrug resistance‑associated protein 1 (MRP1). Collectively, these findings suggested that metformin may target the AMPK/mTOR/HIF‑1α/P‑gp and MRP1 pathways to reverse MDR in hepatocellular carcinoma.

Show MeSH
Related in: MedlinePlus