Inhibition of growth and migration of cholangiocarcinoma cells by pamidronate

Buranrat,Benjaporn; Prawan,Auemduan; Senggunprai,Laddawan; Kukongviriyapan,Veerapol

doi:10.3892/etm.2019.8041

Inhibition of growth and migration of cholangiocarcinoma cells by pamidronate

Authors:
- Benjaporn Buranrat
- Auemduan Prawan
- Laddawan Senggunprai
- Veerapol Kukongviriyapan
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Affiliations: Faculty of Medicine, Mahasarakham University, Muang, MahaSarakham 44000, Thailand, Department of Pharmacology, Faculty of Medicine, KhonKaen University, KhonKaen 40002, Thailand
Published online on: September 23, 2019 https://doi.org/10.3892/etm.2019.8041
Pages: 3977-3983
Copyright: © Buranrat et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pamidronate has been hypothesized to effectively inhibit cancer cell growth and metastasis in bone tissue. Furthermore, pamidronate (Pami) exerts various direct effects against several cancer cell types, including growth and migration. The present study aimed to determine the underlying mechanism of Pami's effect on the proliferation and migration of cholangiocarcinoma (CCA) cells. KKU‑100 cells were used to determine the effects of Pami on cell death and migration. The following were assessed: Sulforhodamine B, colony formation, apoptosis via flow cytometry, reactive oxygen species (ROS) production and caspase‑3 activity. In addition, the effects of the test compound on the mevalonate (MVA) signaling pathway were determined via western blotting and reverse transcription‑quantitative PCR. Cell migration was observed via wound healing, Matrigel and gelatin zymography. The results indicated that Pami induced CCA cell death and inhibited colony formation in a dose‑dependent manner, with IC50 values of 444.67±44.05 µM at 24 h and 147.33±17.01 µM at 48 h. Furthermore, Pami treatment suppressed colony formation at a lower concentration than growth inhibition with IC50 values of 5.36±0.31 µM. The mechanism of growth inhibition was determined to potentially be associated with increased ROS generation and stimulated caspase‑3 enzyme activity, leading to the induction of apoptosis. Furthermore, Pami treatment interfered with the MVA signaling pathway by reducing Rac1 protein levels and modulating the gene and protein expression of RhoA. Furthermore, Pami suppressed CCA cell migration by decreasing matrix metalloproteinase (MMP)2 and MMP9 levels. Additionally, Pami treatment activated CCA cell death and inhibited CCA migration at low concentrations. Pami significantly decreased the protein expression levels of Rac1 in the MVA signaling pathway and may therefore be beneficial for developing a novel chemotherapeutic method for CCA.

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