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Pamidronate induced anti-proliferative, apoptotic, and anti-migratory effects in hepatocellular carcinoma
Akira Wada1, Koji Fukui, Yoshiyuki Sawai
1Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Background/Aims:
The small GTPase of Ras and Rho families are widely involved in human tumorgenesis and metastasis. It has recently been reported that pamidronate inhibits the mevalonate pathway, which is required for the prenylation of the small GTPase. We demonstrated a possible beneficial use of pamidronate in the treatment of hepatocellular carcinoma (HCC).
Methods:
The effect of pamidronate on cell proliferation was analyzed with five hepatoma cell lines using MTT assay. Apoptosis was evaluated by staining with DAPI and a histon ELISA assay. A cell migration assay was performed using the Modified Boyden Chamber. To analyze anti-proliferation effect of pamidronate in vivo, tumor volumes were monitored with the intraperitoneal injection of pamidronate after subcutaneous inoculation of PLC/PRF/5 cells into nude mice.
Results:
Pamidronate inhibited cell growth for all hepatoma cell lines. The amount of membrane associated Ras and phosphorylated extracellular signal-regulated kinase 2 (ERK 2) were reduced after pamidronate treatment. Pamidronate increased apoptosis and cleavage of Caspase-3, and -9. Pamidronate suppressed membrane associated RhoA and cell motility. In vivo, tumor volumes were significantly suppressed by pamidronate at three weeks (P<0.03).
Conclusions:
We conclude that pamidronate has therapeutic potential in inducing anti-proliferative, apoptotic, and anti-migratory effects in HCC.
Insights
Pamidronate effectively inhibits hepatocellular carcinoma (HCC) cell growth and metastasis by targeting small GTPases. This study shows pamidronate
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Small GTPases (Ras and Rho families) are crucial in human tumorgenesis and metastasis.
- Pamidronate inhibits the mevalonate pathway, essential for GTPase prenylation.
Purpose of the Study:
- To investigate the therapeutic potential of pamidronate in treating hepatocellular carcinoma (HCC).
Main Methods:
- In vitro: MTT assay for proliferation, DAPI/histon ELISA for apoptosis, Modified Boyden Chamber for migration in five hepatoma cell lines.
- In vivo: Tumor volume monitoring in nude mice after pamidronate injection.
Main Results:
- Pamidronate inhibited proliferation and motility, reduced membrane-associated Ras and RhoA, and increased apoptosis in HCC cell lines.
- In vivo studies showed significant tumor volume suppression after pamidronate treatment.
- Reduced levels of phosphorylated ERK 2 and increased Caspase-3/-9 cleavage were observed.
Conclusions:
- Pamidronate exhibits significant anti-proliferative, apoptotic, and anti-migratory effects.
- Pamidronate demonstrates therapeutic potential for hepatocellular carcinoma treatment.
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