Partha Sarathi Dasgupta

The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor

Angiogenesis has an essential role in many important pathological and physiological settings. It has been shown that vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), a potent cytokine expressed by most malignant tumors, has critical roles in vasculogenesis and both physiological and pathological angiogenesis. We report here that at non-toxic levels, the neurotransmitter dopamine strongly and selectively inhibited the vascular permeabilizing and angiogenic activities of VPF/VEGF. Dopamine acted through D2 dopamine receptors to induce endocytosis of VEGF receptor 2, which is critical for promoting angiogenesis, thereby preventing VPF/VEGF binding, receptor phosphorylation and subsequent signaling steps. The action of dopamine was specific for VPF/VEGF and did not affect other mediators of microvascular permeability or endothelial-cell proliferation or migration. These results reveal a new link between the nervous system and angiogenesis and indicate that dopamine and other D2 receptors, already in clinical use for other purposes, might have value in anti-angiogenesis therapy.

Dopamine, a neurotransmitter, influences the immune system

Dopamine (DA) is a monoamine neurotransmitter of both central and peripheral nervous system. Its role in the neural-immune communication has been discussed in the present review. Results reveal that in vivo damage or stimulation of specific central dopaminergic system suppresses or enhances functional activities of the immune effector cells. The possible influences of other immunomodulators of the brain by altering brain DA may be the underlying mechanism. Direct effects of DA on the immune effector cells are also contradictory, it is suppressive in vitro, while in pharmacological doses, it is mostly stimulatory in vivo. The possible mechanisms have been discussed. Lastly, future areas of relevance on DA and immunity have been highlighted to advance our knowledge regarding DA as an immune regulator.

Catecholamines regulate tumor angiogenesis.

Among the regulators of angiogenesis, catecholamine neurotransmitters are of recent interest because of their opposite roles in the regulation of tumor neovascularization. Norepinephrine and epinephrine by acting through specific adrenoceptors increase the synthesis of proangiogenic factors, and thereby, promote tumor growth. In contrast, dopamine acting via its specific D(2) receptors inhibits tumor growth by suppressing the actions of vascular permeability factor/vascular endothelial growth factor-A on both tumor endothelial and bone marrow-derived endothelial progenitor cells. These reports identify novel endogenous regulators of tumor angiogenesis and also indicate a new and an inexpensive class of antiangiogenic drugs for the treatment of cancer.

Dopamine regulates endothelial progenitor cell mobilization from mouse bone marrow in tumor vascularization

Mobilization of endothelial progenitor cells (EPCs) from the bone marrow and their subsequent participation in neovessel formation are implicated in tumor growth and neovascularization. As the neurotransmitter dopamine (DA) modulates adult endothelial cell function, we hypothesized that DA might have a regulatory role in mobilization of EPCs from the bone marrow niche. We show that there was a significant decrease in bone marrow DA content and an increase in EPC mobilization in tumor-bearing mice associated with tumor neovascularization. DA treatment of tumor-bearing mice inhibited EPC mobilization and tumor growth through its D2 receptors, as DA treatment failed to inhibit EPC mobilization in tumor-bearing mice treated with a specific DA D2 receptor antagonist and in tumor-bearing mice lacking the D2 receptor. In addition, we found that DA, through D2 receptors, exerted its inhibitory effect on EPC mobilization through suppression of VEGFA-induced ERK1/ERK2 phosphorylation and MMP-9 synthesis. These findings reveal a new link between DA and EPC mobilization and suggest a novel use for DA and D2 agents in the treatment of cancer and other diseases involving neovessel formation.

Dopamine inhibits cytokine release and expression of tyrosine kinases, Lck and Fyn in activated T cells

The effect of dopamine (DA) on the release of cytokines from activated human T cells has been evaluated to analyze the mechanism by which physiological concentration of dopamine inhibits T cell proliferation. Dopamine inhibited anti-CD3 mAb-induced release of both Th1 and Th2 cytokines, IL2, IFN-gamma and IL4 from T cells by specific class of dopamine receptors. This action of dopamine was mediated by a new mechanism. Dopamine suppressed non-receptor tyrosine kinases, Lck and Fyn expression which are the initial and pivotal signaling steps in T cell receptor (TCR) mediated different down stream signaling cascades, leading to cytokine release and subsequent clonal expansion of these immune effector cells.

Ablation of Peripheral Dopaminergic Nerves Stimulates Malignant Tumor Growth by Inducing Vascular Permeability Factor/Vascular Endothelial Growth Factor-Mediated Angiogenesis

Many important physiological and pathological processes are modulated by angiogenesis. It has been shown that initiation of this angiogenic process is an essential early step in the progression of malignant tumors. We report here that ablation of peripheral dopaminergic nerves markedly increased angiogenesis, microvessel density, microvascular permeability, and growth of malignant tumors in mice. Endogenous peripheral dopamine acted through D2 receptors as significantly more angiogenesis and tumor growth was observed in D2 dopamine receptor knockout mice in comparison with controls. The vascular endothelial growth factor receptor 2 phosphorylation, which is critical for promoting angiogenesis, was also significantly more in tumor endothelial cells collected from the dopamine-depleted and D2 dopamine receptor knockout animals. These results reveal that peripheral endogenous neurotransmitter dopamine might be an important physiological regulator of vascular endothelial growth factor-mediated tumor angiogenesis and growth and suggest a novel link between endogenous dopamine, angiogenesis, and tumor growth.

Circulating dopamine level, in lung carcinoma patients, inhibits proliferation and cytotoxicity of CD4+ and CD8+ T cells by D1 dopamine receptors: an in vitro analysis

Besides cardiovascular and renal functions, the role of dopamine in periphery as an endogenous regulator of immune functions is in the limelight. In human malignancy, depression of T cell functions is known. Interestingly, recent evidences indicate significant elevation of plasma dopamine in malignancy due to stress of the disease process. Therefore, this study evaluates whether this increased plasma dopamine exerts any influence on the proliferation and cytotoxicity of CD4+ and CD8+ T cells. Patients with lung carcinoma were selected for this study due to the high prevalence rate of this kind of cancer in developing countries and also due to strong positive biochemical and psychological criteria of stress in most of the patients. Results showed significant elevation of plasma dopamine (48.6 +/- 5.1 pg/ml) in lung cancer patients than normal controls (10.2 +/- 0.9 pg/ml). In vitro dopamine concentration, simulating the plasma concentration of the patients, significantly inhibited the proliferation and cytotoxicity of T cells of these patients and also of the normal volunteers, in presence of their respective serum. The mechanism has been attributed to be D1 class of dopamine receptor mediated elevation of intracellular cAMP in these cell populations. The results may be of significance in understanding the role of peripheral dopamine as an immunomodulator in human health and diseases.

Dopamine Increases the Efficacy of Anticancer Drugs in Breast and Colon Cancer Preclinical Models

Purpose: Because neurotransmitter dopamine inhibits vascular permeability factor/vascular endothelial growth factor (VEGF)–induced angiogenesis and as anti-VEGF agents act synergistically with anticancer drugs, we therefore investigated whether dopamine can increase the efficacies of these drugs. Experimental Design: The effect of dopamine was investigated in human breast cancer–(MCF-7) and colon (HT29) cancer–bearing mice. Experimental groups received either dopamine or doxorubicin or dopamine plus doxorubicin in MCF-7 tumor-bearing mice, and either dopamine or 5-fluorouracil or dopamine plus 5-fluorouracil in HT29-bearing mice. Thereafter, tumor growth, angiogenesis, tumor cell apoptosis, life span, and the effect of dopamine on the growth and survival of tumor cells in vitro were determined. Finally, the effects of dopamine on tumor vascular permeability; on VEGF receptor-2, mitogen-activated protein kinase, and focal adhesion kinase phosphorylation; and also on the proliferation and migration of tumor endothelial cells were investigated. Results: Dopamine, in combination with anticancer drugs, significantly inhibited tumor growth and increased the life span when compared with treatment with dopamine or anticancer drugs alone. Dopamine had no direct effects on the growth and survival of tumor cells. The antiangiogenic action of dopamine was mediated by inhibiting proliferation and migration of tumor endothelial cells through suppression of VEGF receptor-2, mitogen-activated protein kinase, and focal adhesion kinase phosphorylation. Conclusion: Our study shows that dopamine significantly enhances the efficacies of commonly used anticancer drugs and also indicates that an inexpensive drug like dopamine, which is being extensively used in the clinics, might have a role as an antiangiogenic agent for the treatment of breast and colon cancer.

Cutting Edge: Stimulation of Dopamine D4 Receptors Induce T Cell Quiescence by Up-Regulating Krüppel-Like Factor-2 Expression through Inhibition of ERK1/ERK2 Phosphorylation

The neurotransmitter dopamine (DA) is an important regulator of human T cell functions. Although it has been observed that DA, by acting through the D1/D5, D2, and D3 receptors, can activate resting T cells by stimulating the release of cytokines and the expression of surface integrins and also inhibit the proliferation of activated T cells by down-regulating nonreceptor tyrosine kinases, there is not yet a report indicating the functional significance of the D4 DA receptors present in these cells. The present work, for the first time, demonstrates that the stimulation of D4 DA receptors in human T cells induces T cell quiescence by up-regulating lung Krüppel-like factor-2 expression through the inhibition of ERK1/ERK2 phosphorylation. These results reveal a new link between the nervous system and T cell quiescence and indicate that D4 DA receptor agonists may have a therapeutic value in diseases with uncontrolled T cell proliferation.

Uptake and biodistribution of dopamine in bone marrow, spleen and lymph nodes of normal and tumor bearing mice

Significant labelled dopamine uptake was evident in bone marrow, spleen and lymph nodes of normal murine hosts in vivo. On the contrary animals bearing solid Ehrlich carcinoma, 3H-dopamine uptake was significantly reduced. The tumor tissue itself incorporated only insignificant amount of dopamine. Bone marrow cells, splenocytes and lymphocytes from lymph nodes showed specific uptake of this monoamine. At present the peripheral role of dopamine in the regulation of heart and kidney functions are well documented and utilized clinically for treatment of congestive heart and renal failure. The present result of specific dopamine uptake by bone marrow, spleen and lymph nodes and alterations following tumor growth where hematopoesis and immune functions are disrupted, strengthens our previous idea that dopamine might also influence the functions of these peripheral organs. Knowledge of this possible effect of DA on these peripheral organs may be of future clinical significance in the management of hematological and immune abnormalities.