Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
J Clin Endocrinol Metab. 2017 Oct 1;102(10):3692-3703. doi: 10.1210/jc.2017-00627.
The dopamine agonist cabergoline (CAB) has been used widely in the treatment of prolactinomas and other types of pituitary adenomas, but its clinical use is hampered by intolerance in some patients with prolactinoma and lack of effectiveness in other pituitary tumor types. Chloroquine (CQ) is an old drug widely used to treat malaria. Recent studies, including our own, have revealed that CAB and CQ are involved in induction of autophagy and activation of autophagic cell death.
To test whether CAB and CQ can function cooperatively to suppress growth of pituitary adenomas as well as other cancers.
In vitro studies using the rat pituitary tumor cell lines MMQ and GH3, human pituitary tumor cell primary cultures, and several human cancer cell lines showed that CQ enhanced suppression of cell proliferation by CAB. These results were confirmed in in vivo xenograft models in nude mice and estrogen-induced rat prolactinomas. To understand the mechanism of combined CAB and CQ action, we established a low-CAB-dose condition in which CAB was able to induce autophagy but failed to suppress cell growth. Addition of CQ to low-dose CAB blocked normal autophagic cycles and induced apoptosis, evidenced by the further accumulation of p62/caspase-8/LC3-II.
The data suggest that combined use of CAB and CQ may increase clinical effectiveness in treatment of human pituitary adenomas, as well as other cancers, making it an attractive option in tumor and cancer therapies.
多巴胺激动剂卡麦角林（CAB）已广泛用于治疗催乳素瘤和其他类型的垂体腺瘤，但由于一些催乳素瘤患者不耐受和其他垂体肿瘤类型无效，其临床应用受到阻碍。氯喹（CQ）是一种广泛用于治疗疟疾的老药。最近的研究，包括我们自己的研究，揭示了 CAB 和 CQ 参与诱导自噬和激活自噬性细胞死亡。
测试 CAB 和 CQ 是否可以协同作用抑制垂体腺瘤以及其他癌症的生长。
使用大鼠垂体肿瘤细胞系 MMQ 和 GH3、人垂体肿瘤细胞原代培养物和几种人癌细胞系进行的体外研究表明，CQ 增强了 CAB 对细胞增殖的抑制作用。这些结果在裸鼠和雌激素诱导的大鼠催乳素瘤的体内异种移植模型中得到了证实。为了了解 CAB 和 CQ 联合作用的机制，我们建立了一个低 CAB 剂量条件，其中 CAB 能够诱导自噬，但不能抑制细胞生长。将 CQ 添加到低剂量 CAB 中会阻断正常的自噬循环并诱导细胞凋亡，这可以通过 p62/caspase-8/LC3-II 的进一步积累来证明。
数据表明，CAB 和 CQ 的联合使用可能会增加人类垂体腺瘤以及其他癌症的临床疗效，使其成为肿瘤和癌症治疗的一个有吸引力的选择。
