Senogles Susan E
Department of Molecular Sciences, The University of Tennessee Health Science Center, 858 Madison Avenue, Memphis, TN 38163, USA.
Anticancer Drugs. 2007 Aug;18(7):801-7. doi: 10.1097/CAD.0b013e3280b10d36.
The D2 dopamine receptor agonist bromocriptine has been used clinically for reducing tumor mass of pituitary adenomas arising from lactotroph origins. As well, bromocriptine has been shown to have an antiproliferative effect on primary lactotrophs and lactotroph-derived cell lines. The presence of D2 dopamine-like receptors on NCI-H69 cells was previously established by the use of [(125)I]iodosulpride binding and has been confirmed in this study by use of reverse transcription PCR with receptor-specific primers. The reverse transcription PCR analysis of NCI-H69 cells demonstrates that both the D2s and D2l are expressed in NCI-H69 cells, with D2s having the higher relative expression. The activation of the D2R results in an inhibition of growth of NCI-H69 cells as assessed by the incorporation of [(3)H]thymidine; a process not sensitive to pertussis toxin. In NCI-H69 cells, the D2 dopamine-like receptor is coupled to the inhibition of forskolin-stimulated cAMP accumulation and to the stimulation of phospholipase D. The receptor-mediated inhibition of cAMP accumulation is ablated by overnight treatment with pertussis toxin but the stimulation of phospholipase D mediated by dopaminergic agonists is not. These data suggest that the phospholipase D pathway is responsible for the antiproliferative effects of D2 dopamine-like receptors agonists in small cell lung cancer cells. In support of this hypothesis, the inhibition of [(3)H]thymidine incorporation mediated by dopaminergic agonists was shown to be sensitive to the presence of ethanol. Taken together, these data suggest that the D2 dopamine-like receptor activates phospholipase D, which ultimately leads to an inhibition of growth of this small cell lung cancer cell line.
D2多巴胺受体激动剂溴隐亭已在临床上用于缩小源自催乳素细胞的垂体腺瘤的肿瘤体积。此外，溴隐亭已被证明对原代催乳素细胞和催乳素衍生的细胞系具有抗增殖作用。先前通过使用[（125）I]碘舒必利结合确定了NCI-H69细胞上存在D2多巴胺样受体，并且在本研究中通过使用受体特异性引物的逆转录PCR得到了证实。对NCI-H69细胞的逆转录PCR分析表明，D2s和D2l在NCI-H69细胞中均有表达，其中D2s的相对表达较高。通过[（3）H]胸苷掺入评估，D2R的激活导致NCI-H69细胞生长受到抑制；该过程对百日咳毒素不敏感。在NCI-H69细胞中，D2多巴胺样受体与福司可林刺激的cAMP积累的抑制以及磷脂酶D的刺激偶联。受体介导的cAMP积累的抑制通过百日咳毒素过夜处理而消除，但多巴胺能激动剂介导的磷脂酶D的刺激则不受影响。这些数据表明，磷脂酶D途径负责D2多巴胺样受体激动剂在小细胞肺癌细胞中的抗增殖作用。为支持这一假设，已证明多巴胺能激动剂介导的[（3）H]胸苷掺入的抑制对乙醇的存在敏感。综上所述，这些数据表明D2多巴胺样受体激活磷脂酶D，最终导致该小细胞肺癌细胞系的生长受到抑制。
