Abstract
Cabergoline (CAB) is the first choice for treatment of prolactinoma and the most common subtype of pituitary adenoma. However, drug resistance and lack of effectiveness in other pituitary tumor types remain clinical challenges to this treatment. Brusatol (BT) is known to inhibit cell growth and promote apoptosis in a variety of cancer cells. In our present studies, we investigate the effects of BT on pituitary tumor cell proliferation in vitro and in vivo. BT treatment resulted in an increase in Annexin V-expressing cells and promoted the expression of apoptosis-related proteins in rat and human pituitary tumor cells. Investigation of the mechanism underlying this effect revealed that BT increased the production of reactive oxygen species (ROS) and inhibited the phosphorylation of 4EBP1 and S6K1. Furthermore, treatment with a combination of BT and CAB resulted in greater antitumor effects than either treatment alone in nude mice and pituitary tumor cells. Collectively, our results suggest that the BT-induced ROS accumulation and inhibition of mTORC1 signaling pathway leads to inhibition of tumor growth. Combined use of CAB and BT may increase the clinical effectiveness of treatment for human pituitary adenomas.
Highlights
Brusatol (BT) is a natural product obtained from Brucea javanica, a common evergreen shrub used in traditional Chinese medicine [1]
BT increases the efficacy of chemotherapy by inhibiting NRF2 expression in lung cancer cells [6] and suppresses glioma tumor growth by interrupting glutathione metabolism [7]
This study is aimed at determining whether BT exerts antitumor effects on pituitary adenoma and whether it acts synergistically with cabergoline to solve the problem of drug resistance
Summary
Brusatol (BT) is a natural product obtained from Brucea javanica, a common evergreen shrub used in traditional Chinese medicine [1]. BT exerts an array of biological effects, including triggering anticancer and anti-inflammatory activity [2, 3]. The mechanism underlying the anticancer activity of BT involves its effects on protein synthesis and ROS [4]. Mata-Greenwood et al observed that BT exhibits cytotoxic effects on leukemic cells via inhibition of c-Myc expression [5]. BT increases the efficacy of chemotherapy by inhibiting NRF2 expression in lung cancer cells [6] and suppresses glioma tumor growth by interrupting glutathione metabolism [7]. BT is reported to induce autophagy and apoptosis in hepatocellular carcinoma via inhibition of the PI3K/AKT/mTOR pathway [8]. Whether BT has antitumor effects on pituitary tumors is unknown
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