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3,3'-Diindolylmethane induces gastric cancer cells death via STIM1 mediated store-operated calcium entry.
Ye, Y, Li, X, Wang, Z, Ye, F, Xu, W, Lu, R, Shen, H, Miao, S
International journal of biological sciences. 2021;(5):1217-1233
Abstract
3,3'-Diindolylmethane (DIM), a natural phytochemicals isolated from cruciferous vegetables, has been reported to inhibit human gastric cancer cells proliferation and induce cells apoptosis as well as autophagy, but its mechanisms are still unclear. Store-operated calcium entry (SOCE) is a main Ca2+ influx pathway in various of cancers, which is activated by the depletion of endoplasmic reticulum (ER) Ca2+ store. Stromal interaction molecular 1 (STIM1) is the necessary component of SOCE. In this study, we focus on to examine the regulatory mechanism of SOCE on DIM-induced death in gastric cancer. After treating the human BGC-823 and SGC-7901 gastric cancer cells with DIM, cellular proliferation was determined by MTT, apoptosis and autophagy were detected by flow cytometry or Hoechst 33342 staining. The expression levels of related proteins were evaluated by Western blotting. Free cytosolilc Ca2+ level was assessed by fluorescence monitoring under a laser scanning confocal microscope. The data have shown that DIM could significantly inhibit proliferation and induce apoptosis as well as autophagy in two gastric cancer cell lines. After DIM treatment, the STIM1-mediated SOCE was activated by upregulating STIM1 and decreasing ER Ca2+ level. Knockdown STIM1 with siRNA or pharmacological inhibition of SOCE attenuated DIM induced apoptosis and autophagy by inhibiting p-AMPK mediated ER stress pathway. Our data highlighted that the potential of SOCE as a promising target for treating cancers. Developing effective and selective activators targeting STIM1-mediated SOCE pathway will facilitate better therapeutic sensitivity of phytochemicals acting on SOCE in gastric cancer. Moreover, more research should be performed to validate the efficacy of combination chemotherapy of anti-cancer drugs targeting SOCE for clinical application.
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3,3'-diindolylmethane exerts antiproliferation and apoptosis induction by TRAF2-p38 axis in gastric cancer.
Ye, Y, Ye, F, Li, X, Yang, Q, Zhou, J, Xu, W, Aschner, M, Lu, R, Miao, S
Anti-cancer drugs. 2021;(2):189-202
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Abstract
3,3'-diindolylmethane (DIM), an active phytochemical derivative extracted from cruciferous vegetables, possesses anticancer effects. However, the underlying anticancer mechanism of DIM in gastric cancer remains unknown. Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2), one of the signal transduction proteins, plays critical role in proliferation and apoptosis of human gastric cancer cells, but there are still lack of practical pharmacological modulators for potential clinical application. Here, we further explored the role of TRAF2 in inhibiting cell proliferation and inducing apoptosis by DIM in human gastric cancer BGC-823 and SGC-7901 cells. After treating BGC-823 and SGC-7901 cells with DIM for 24 h, cell proliferation, apoptosis and TRAF2-related protein were measured. Our findings showed that DIM inhibited the expressions of TRAF2, activated p-p38 and its downstream protein p-p53, which were paralleled with DIM-triggered cells proliferation, inhibition and apoptosis induction. These effects of DIM were reversed by TRAF2 overexpression or p38 mitogen-activated protein kinase (MAPK)-specific inhibitor (SB203580). Taken together, our data suggest that regulating TRAF2/p38 MAPK signaling pathway is essential for inhibiting gastric cancer proliferation and inducing apoptosis by DIM. These findings broaden the understanding of the pharmacological mechanism of DIM's action as a new modulator of TRAF2, and provide a new therapeutic target for human gastric cancer.
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Surufatinib in Chinese Patients with Locally Advanced or Metastatic Differentiated Thyroid Cancer and Medullary Thyroid Cancer: A Multicenter, Open-Label, Phase II Trial.
Chen, J, Ji, Q, Bai, C, Zheng, X, Zhang, Y, Shi, F, Li, X, Tang, P, Xu, Z, Huang, R, et al
Thyroid : official journal of the American Thyroid Association. 2020;(9):1245-1253
Abstract
Background: Thyroid cancer is the most common endocrine tumor with an increasing incidence. Limited treatment options are available for patients with advanced or recurrent metastatic disease, resulting in a poor prognosis. Surufatinib targets multiple kinases (vascular endothelial growth factor receptors, fibroblast growth factor receptor-1, and colony-stimulating factor-1 receptor) involved in tumor angiogenesis and tumor immune evasion. Surufatinib has demonstrated promising antitumor activity in various advanced solid tumors. This study aimed to determine the objective response rate (ORR) of surufatinib in patients with locally advanced or distant metastatic differentiated thyroid cancer (DTC) or medullary thyroid cancer (MTC). Methods: This Phase II open-label study by Simon's two-stage design was conducted at 10 sites across China. Patients with radioiodine (RAI)-refractory DTC with locally advanced disease or distant metastasis (DTC1 group); patients who received limited initial surgery and then developed locally advanced unresectable recurrences and were not considered candidates for RAI therapy due to residual normal thyroid tissue (DTC2 group); or patients with MTC with locally advanced disease or distant metastasis (MTC group) were enrolled. A total of 59 patients were enrolled (26 in DTC1, 6 in DTC2, and 27 in MTC) and received 300 mg surufatinib daily in 28-day cycles. The primary endpoint was ORR as determined by the investigators. Results: Overall ORR was 23.2% [95% confidence interval, CI 12.98-36.42]: 21.7% in the DTC1 cohort, 33.3% in the DTC2 cohort, and 22.2% in the MTC cohort. Forty-nine patients achieved disease control (87.5% [CI 75.93-94.82]): 87.0% in the DTC1 cohort, 83.3% in the DTC2 cohort, and 88.9% in the MTC cohort. Median time to response was 59.0 days, and 59.0, 85.5, and 59.0 days in the DTC1, DTC2, and MTC cohorts. Overall median progression-free survival was 11.1 months [CI 5.98-16.69]; 11.1 months in DTC1 and MTC cohorts, while the DTC2 cohort had not reached the median at the data cutoff. The most common treatment-emergent adverse events grade ≥3 were hypertension (20.3%), proteinuria (11.9%), and then elevated blood pressure, hypertriglyceridemia, and pulmonary inflammation (5.1% each). Conclusions: Surufatinib demonstrated promising efficacy with a tolerable and manageable safety profile for patients with locally advanced or metastatic MTC, RAI-refractory DTC, or locally advanced unresectable recurrences unable to receive RAI.
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Effects of combination of statin and calcium channel blocker in patients with cardiac syndrome X.
Zhang, X, Li, Q, Zhao, J, Li, X, Sun, X, Yang, H, Wu, Z, Yang, J
Coronary artery disease. 2014;(1):40-4
Abstract
OBJECTIVES Statins and calcium channel blockers have been proven beneficial toward improvement of endothelial function. The aim of this study was to compare the effect of combination therapy of statin and calcium channel blocker with solo treatment in patients with cardiac syndrome X. METHODS AND RESULTS Sixty-eight patients with cardiac syndrome X were divided randomly into three groups: fluvastatin (40 mg/day, n=23), diltiazem (90 mg/day, n=22), and combination of fluvastatin (40 mg/day) and diltiazem (90 mg/day, n=23). At the end of 90 days, the coronary flow reserve was improved in the three groups (fluvastatin-treated group: 23.2%; diltiazem-treated group: 12.4%; fluvastatin+diltiazem-treated group: 29.1%, all P<0.05). The time to 1 mm ST segment depression increased significantly in the fluvastatin-treated group (from 241±97 to 410±140 s, P<0.05), the diltiazem-treated group (from 258±91 to 392±124 s, P<0.05), and the fluvastatin+diltiazem-treated group (from 250±104 to 446±164 s, P<0.05). The improvement in coronary flow reserve and prolonged time to 1 mm ST segment depression in the combination treatment group were more remarkable than in those who received monotherapy. Combination therapy also induced a significant increase (35.6%, P<0.05) in nitric oxide and an apparent reduction (48.7%, P<0.05) in endothelin-1. CONCLUSION Combination treatment with fluvastatin and diltiazem is more effective on endothelial function and exercise tolerance than solo treatment in patients with cardiac syndrome X. The benefits of these drugs may be related to the elevation of nitric oxide and reduction of endothelin-1.