Depleted dopamine in gastric cancer tissues: dopamine treatment retards growth of gastric cancer by inhibiting angiogenesis.
OBJECTIVE
It has been recently shown that the catecholamine neurotransmitter dopamine (DA) strongly and selectively inhibits vascular permeability factor/vascular endothelial growth factor (VPF/VEGF)-induced angiogenesis. Gastric cancer is highly angiogenic and is dependent on VEGF for its growth and progression. Because substantial amounts of DA present in normal stomach tissues has been implicated in several gastric functions, we therefore investigated the role, if any, of this neurotransmitter in the growth and progression of gastric cancer.


METHODS
Initially, the status of DA and tyrosine hydroxylase, the rate-limiting enzyme required for DA synthesis, were determined in human gastric cancer tissues and in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric cancer tissues of rats. On the basis of our observation of inverse correlation between stomach DA and gastric cancer growth, we determined the effect of pharmacological dose of DA on the angiogenesis and growth of MNNG induced gastric cancer in rats and Hs746T human gastric cancer in nude mice.


RESULTS
DA and tyrosine hydroxylase were absent in both human and rat gastric cancer tissues. On the contrary, a low nontoxic pharmacological dose of DA significantly retarded tumor angiogenesis by inhibiting VEGFR-2 phosphorylation in tumor endothelial cells, which expressed DA D(2) receptors. This action of DA was associated with the growth inhibition of both MNNG-induced rat malignant gastric tumors and xenotransplanted human gastric cancer in nude mice.


CONCLUSIONS
Our study demonstrates that there is an inverse correlation between endogenous stomach DA and gastric cancer and indicates that DA already in clinical use for other purposes might have a role as an antiangiogenic agent in the treatment of gastric cancer.
Chakroborty
Debanjan
D
Signal Transduction and Biogenic Amines Laboratory, Chittaranjan National Cancer Institute, Calcutta, India.
Sarkar
Chandrani
C
Mitra
Rita Basu
RB
Banerjee
Samir
S
Dasgupta
Partha Sarathi
PS
Basu
Sujit
S
D000230:Adenocarcinoma / Q000378:metabolism; D000328:Adult; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002851:Chromatography, High Pressure Liquid; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D018377:Neurotransmitter Agents / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D002316:Cardiotonic Agents; D018377:Neurotransmitter Agents; D042461:Vascular Endothelial Growth Factor A; D008769:Methylnitronitrosoguanidine; D014446:Tyrosine 3-Monooxygenase; D040301:Vascular Endothelial Growth Factor Receptor-2; D004298:Dopamine