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Extracellular Ca(2+)-dependent enhancement of cytocidal potency of zoledronic acid in human oral cancer cells
- Source :
- European journal of pharmacology. 761
- Publication Year :
- 2015
-
Abstract
- Direct antitumor effects of bisphosphonates (BPs) have been demonstrated in various cancer cells in vitro. However, the effective concentrations of BPs are typically much higher than their clinically relevant concentrations. Oral cancers frequently invade jawbone and may lead to the release of Ca(2+) in primary lesions. We investigated the effects of the combined application of zoledronic acid (ZA) and Ca(2+) on proliferation and apoptosis of oral cancer cells. Human oral cancer cells, breast cancer cells, and colon cancer cells were treated with ZA at a wide range of concentrations in different Ca(2+) concentration environments. Under a standard Ca(2+) concentration (0.6mM), micromolar concentrations of ZA were required to inhibit oral cancer cell proliferation. Increasing extracellular Ca(2+) concentrations greatly enhanced the potency of the ZA cytocidal effect. The ability of Ca(2+) to enhance the cytocidal effects of ZA was negated by the Ca(2+)-selective chelator EGTA. In contrast, the cytocidal effect of ZA was less pronounced in breast and colon cancer cells regardless of whether extracellular Ca(2+) was elevated. In oral cancer cells incubated with 1.6mM Ca(2+), ZA up-regulated mitochondrial Bax expression and increased mitochondrial Ca(2+) uptake. This was associated with decreased mitochondrial membrane potential and increased release of cytochrome c. We suggest that ZA can specifically produce potent cytocidal activity in oral cancer cells in an extracellular Ca(2+)-dependent manner, implying that BPs may be useful for treatment of oral squamous cell carcinoma with jawbone invasion leading to the hypercalcemic state.
- Subjects :
- Colorectal cancer
Antineoplastic Agents
Apoptosis
Breast Neoplasms
Zoledronic Acid
chemistry.chemical_compound
Cell Line, Tumor
medicine
Extracellular
Potency
Humans
Calcium Chelating Agents
Cell Proliferation
bcl-2-Associated X Protein
Pharmacology
Membrane Potential, Mitochondrial
Diphosphonates
Dose-Response Relationship, Drug
Squamous Cell Carcinoma of Head and Neck
Imidazoles
Cytochromes c
medicine.disease
In vitro
Mitochondria
EGTA
Zoledronic acid
Biochemistry
chemistry
Head and Neck Neoplasms
Cancer cell
Colonic Neoplasms
Cancer research
Carcinoma, Squamous Cell
MCF-7 Cells
Calcium
Mouth Neoplasms
medicine.drug
Subjects
Details
- ISSN :
- 18790712
- Volume :
- 761
- Database :
- OpenAIRE
- Journal :
- European journal of pharmacology
- Accession number :
- edsair.doi.dedup.....612fcc0295a98b8902ebe2e61a4bb9df