Article

Palm D, Lang K, Niggemann B, et al. The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by beta-blockers

Institute of Immunology, Witten/Herdecke University, Witten, Germany.
International Journal of Cancer (Impact Factor: 5.09). 06/2006; 118(11):2744-9. DOI: 10.1002/ijc.21723
Source: PubMed

ABSTRACT

The development of metastases is a decisive step in the course of a cancer disease. The detection of metastases in cancer patients is correlated with a poor prognosis, and over 90% of all deaths from cancer are not due to the primary tumor, which often can be successfully treated, but are due to the metastases. Tumor cell migration, a prerequisite for metastasis development, is not merely genetically determined, but is distinctly regulated by signal substances of the environment including chemokines and neurotransmitters. We have shown previously that the migration of breast, prostate, and colon carcinoma cells is enhanced by the stress-related neurotransmitter norepinephrine in vitro, and that this effect can be inhibited by the beta-blocker propranolol. We now provide for the first time evidence for the in vivo relevance of this neurotransmitter-driven regulation using PC-3 prostate carcinoma cells. The development of lumbar lymph node metastases in athymic BALB/c nude mice increased with the application of norepinephrine via microosmotic pumps, while propranolol inhibited this effect. However, the growth of the primary tumor was not affected by either treatment. Additionally, experiments using human tissue microarrays showed that 70-90 percent of breast, colon, and prostate carcinoma tissues express the relevant beta2-adrenoceptor. Thus, our work contributes to the understanding of the basic cellular mechanisms of metastasis development, and furthermore delivers a rationale for the chemopreventive use of clinically established beta-blockers for the inhibition of metastases.

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Available from: Kerstin Lang, Nov 27, 2014
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    • "To date, the by far most striking discovery in the context of drug repurposing in oncology is the anti-metastatic function of beta-blockers [8]. Stimulated by results provided by in vitro drug testing systems91011, and confirmed by mice experiments [12], several retrospective patient studies have delivered proof for an anti-metastatic effect in various types of solid tumors, i.e., breast, ovarian, prostate, colorectal, lung, liver, melanoma1314151617181920212223242526272829. The in vitro drug testing systems that initially led to this development were migration analyses, which are currently not a standard drug screening method in oncology, but may constitute such a new model as requested by the EMA. "
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    • "The microosmotic pumps implanted in the body could keep functional and pump drugs contained continuously for up to 4 weeks. The pumps were filled with 100 μL normal saline containing 56 mM NE, 56 mM propranolol or both of them at a dose of 1 μmol/100 g/day [14]. Ascorbic acid (0.2%) was added as a preservative into every pump. "
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    • "Multicenter clinical trials on large samples are needed to confirm existing scientific evidence in this field. Some clinical trials are currently underway to confirm positive effects of paravertebral analgesia on outcome of breast cancer patients, and epidural analgesia on those of colon cancer patients [84–86]. Finally, it is undoubtedly important to verify if local anesthetics can decrease metastatic progression in humans. "
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