Éñ¾­µÝÖÊÓ방ϸ°û£¨neurotransmitter and cancer£©

ScienceDaily (Dec. 5, 2011) ¡ª Doses of a neurotransmitter might offer a way to boost the effectiveness ofanticancer drugs and radiation therapy, according to a new study led by researchers at the Ohio State University Comprehensive Cancer Center -- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

The study also found that dopamine plays an important role in maintaining the structure of normal blood vessels, and that it does this by working through the D2 dopamine receptor, which is present in normal blood-vessel cells called endothelial cells and pericytes. Dopamine was absent in tumor blood-vessel cells.

The findings are published online in the Proceedings of the National Academy of Sciences.

"Our study indicates a use for dopamine in the treatment of cancer and perhaps other disorders in which normalizing abnormal and dysfunctional blood vessels might improve therapeutic responses," says principal investigator Dr. Sujit Basu, associate professor of pathology and a researcher in the OSUCCC -- James Experimental Therapeutics Program.

"Since dopamine and related agents are already used in the clinic for other disorders, these comparatively inexpensive drugs might be applied to the treatment of cancer to increase the therapeutic responses of chemotherapy and radiotherapy," he says.

The blood vessels that develop inside tumors are structurally abnormal, chaotic and leaky and do a poor job of supplying blood to the tumor, Basu notes. This hinders the delivery of chemotherapeutic agents, and it leaves tumors oxygen deprived. This oxygen deprivation makes tumor cells resistant to chemotherapy and radiation.

Basu and his colleagues found that the dopamine treatment normalizes the structure of abnormal tumor blood vessels, indicating an important role for a neurotransmitter in the remodeling of blood vessels. Other key findings include the following:

• The tumor tissue used in the study showed the absence of dopamine.
• After dopamine treatment, tumor blood vessels in both cases resembled normal vessels in regard to leakiness and architecture. Pretreatment with a dopamine receptor antagonist negated this effect.
• Subcutaneous human colon tumors in mice treated with dopamine and the chemotherapeutic drug 5-fluorouracil (5-FU) accumulated twice the amount of 5-FU as tumors in mice treated with the drug only, and the tumors were less than one-third the size of tumors in mice treated with 5-FU only.

"Overall, our findings suggest that the normalization of tumor blood vessels using the neurotransmitter dopamine might be an important approach for improving therapeutic efficacy in the treatment of cancer patients," Basu says.

Funding from the National Cancer Institute, U.S. Department of Defense Grant mainly supported this research; a grant from the American Heart Association partially supported one of the investigators.

The other researchers involved in this study were Debanjan Chakroborty, Chandrani Sarkar, Hongmei Yu, Jiang Wang and Zhongfa Liu of Ohio State University; and Partha Sarathi Dasgupta of Chittaranjan National Cancer Institute, Kolkata, India.

Story Source:

The above story is reprinted from materials provided by Ohio State University Medical Center.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

1. Debanjan Chakroborty, Chandrani Sarkar, Hongmei Yu, Jiang Wang, Zhongfa Liu, Partha Sarathi Dasgupta, Sujit Basu. Dopamine stabilizes tumor blood vessels by up-regulating angiopoietin 1 expression in pericytes and Kr¨¹ppel-like factor-2 expression in tumor endothelial cells. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1108696108

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  Cell, 24 May 2012
  Copyright 2012 Elsevier Inc. All rights reserved.
  10.1016/j.cell.2012.03.049

   

   Highlights

  • Neoplastic hPSCs provide a robust generalizable screening model for human CSCs
  • Compounds that induce hPSC differentiation selectively target somatic CSCs
  • Thioridazine selectively targets leukemic stem cells while sparing normal HSCs
  • Dopamine receptor pathway provides a candidate biomarker of human CSCs
    

  Summary

  Selective targeting of cancer stem cells (CSCs) offers promise for a new generation of therapeutics. However, assays for both human CSCs and normal stem cells that are amenable to robust biological screens are limited. Using a discovery platform that reveals differences between neoplastic and normal human pluripotent stem cells (hPSC), we identify small molecules from libraries of known compounds that induce differentiation to overcome neoplastic self-renewal. Surprisingly, thioridazine, an antipsychotic drug, selectively targets the neoplastic cells, and impairs human somatic CSCs capable of in vivo leukemic disease initiation while having no effect on normal blood SCs. The drug antagonizes dopamine receptors that are expressed on CSCs and on breast cancer cells as well. These results suggest that dopamine receptors may serve as a biomarker for diverse malignancies, demonstrate the utility of using neoplastic hPSCs for identifying CSC-targeting drugs, and provide support for the use of differentiation as a therapeutic strategy.
  

Pancreatic ductal adenocarcinoma (PDAC) has a near 100% mortality because it is generally detected at an advanced stage and responds poorly to existing therapeutics. This review summarizes current evidence suggesting important roles of neurotransmitter receptors in the regulation of this malignancy. Experimental evidence indicates that the ¦Á7-nicotinic acetylcholine receptor (¦Á7nAChR) stimulates PDAC via stress neurotransmitter-mediated activation of ¦Â-adrenergic signaling while the ¦Á4¦Â2nAChR inhibits PDAC via GABA-mediated inhibition of adenylyl cyclase activation. In analogy to molecular mechanisms that govern nicotine addiction, chronic exposure to nicotine or its nitrosated derivative nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone render the stimulatory ¦Á7nAChR hyperactive while desensitizing the inhibitory ¦Á4¦Â2nAChR. Accordingly, PDAC intervention strategies should include the diagnosis of unphysiological neurotransmitter levels and aim to restore any imbalance in stimulatory and inhibitory neurotransmitters.

http://www.futuremedicine.com/doi/abs/10.2217/fon.09.171

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1. Summary

Cyclin-dependent kinase 5 is activated by small subunits, of which p35 is the most abundant. The functions of cyclin-dependent kinase 5 signalling in cognition and cognitive disorders remains unclear. Here, we show that in schizophrenia, a disorder associated with impaired cognition, p35 expression is reduced in relevant brain regions. Additionally, the expression of septin 7 and OPA1, proteins downstream of truncated p35, is decreased in schizophrenia. Mimicking a reduction of p35 in heterozygous knockout mice is associated with cognitive endophenotypes. Furthermore, a reduction of p35 in mice results in protein changes similar to schizophrenia post-mortem brain. Hence, heterozygous p35 knockout mice model both cognitive endophenotypes and molecular changes reminiscent of schizophrenia. These changes correlate with reduced acetylation of the histone deacetylase 1 target site H3K18 in mice. This site has previously been shown to be affected by truncated p35. By restoring H3K18 acetylation with the clinically used specific histone deacetylase 1 inhibitor MS-275 both cognitive and molecular endophenotypes of schizophrenia can be rescued in p35 heterozygous knockout mice. In summary, we suggest that reduced p35 expression in schizophrenia has an impact on synaptic protein expression and cognition and that these deficits can be rescued, at least in part, by the inhibition of histone deacetylase 1.

http://brain.oxfordjournals.org/content/early/2011/07/11/brain.awr155