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Updated: Aug 8, 2026
An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 19, 2013
Inhibition of human prostate cancer proliferation in vitro and in a mouse model by a compound synthesized to block
D M Haverstick1, T N Heady, T L Macdonald
1Department of Pathology, University of Virginia, Charlottesville 22908, USA.
Abstract:
Accelerated Ca2+ entry may be one component of the pathway regulating the proliferative phenotype of some types of cancer. Thus, a pharmacological agent with the ability to retard Ca2+ influx in susceptible cancers might inhibit proliferation of them by a cytostatic mechanism rather than by inducing cytotoxicity. We have developed a chemical synthetic scheme that has produced a small library of novel compounds that block Ca2+ entry induced by occupancy of the P2 receptor in two prostate cancer cell lines and inhibit proliferation of these cells in vitro. One of the agents, named TH-1177, was used to treat severe combined immunodeficient mice inoculated with the human prostate cancer line PC-3. Although the doses used and treatment schedule were chosen arbitrarily, treatment extended the mean life span of mice bearing tumors by up to 38%. Treatment of mice without cancer at doses 18 times that used in mice with tumors was not associated with any obvious toxicity, either grossly or on histological examination. These results suggest that novel cytostatic agents with efficacy against human prostate cancer cells can be developed by chemical synthesis of agents directed at the Ca2+ entry pathway.
Insights
Novel compounds blocking calcium (Ca2+) influx inhibit prostate cancer cell proliferation. One agent, TH-1177, extended lifespan in mice with tumors by 38% without toxicity, suggesting potential cytostatic cancer therapies.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Accelerated calcium (Ca2+) influx is implicated in the proliferation of certain cancers.
- Targeting Ca2+ entry could offer cytostatic mechanisms for cancer treatment, distinct from cytotoxic approaches.
Purpose of the Study:
- To develop novel compounds that inhibit Ca2+ entry and prostate cancer cell proliferation.
- To evaluate the efficacy and safety of a lead compound (TH-1177) in a preclinical cancer model.
Main Methods:
- Chemical synthesis of novel compounds targeting Ca2+ entry via P2 receptor.
- In vitro testing of compounds on prostate cancer cell lines for proliferation inhibition.
- In vivo efficacy and toxicity assessment of TH-1177 in mice bearing human prostate cancer xenografts.
Main Results:
- A library of compounds was synthesized, with several blocking P2 receptor-induced Ca2+ entry and inhibiting prostate cancer cell proliferation.
- The compound TH-1177 significantly extended the mean lifespan of tumor-bearing mice by up to 38%.
- TH-1177 demonstrated no obvious toxicity in non-tumor-bearing mice, even at high doses.
Conclusions:
- Novel cytostatic agents targeting the Ca2+ entry pathway can be developed through chemical synthesis.
- TH-1177 shows promise as a potential therapeutic agent for human prostate cancer.
- Targeting Ca2+ influx represents a viable strategy for developing new cancer treatments.
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