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Androgen receptor (AR) expression and activity is highly linked to the development and progression of prostate cancer and is a target of therapeutic strategies for this disease. We investigated whether the antimalarial drug artemisinin, which is a sesquiterpene lactone isolated from the sweet wormwood plant Artemisia annua, could alter AR expression and responsiveness in cultured human prostate cancer cell lines. Artemisinin treatment induced the 26S proteasome-mediated degradation of the receptor protein, without altering AR transcript levels, in androgen-responsive LNCaP prostate cancer cells or PC-3 prostate cancer cells expressing exogenous wild-type AR. Furthermore, artemisinin stimulated AR ubiquitination and AR receptor interactions with the E3 ubiquitin ligase MDM2 in LNCaP cells. The artemisinin-induced loss of AR protein prevented androgen-responsive cell proliferation and ablated total AR transcriptional activity. The serine/threonine protein kinase AKT-1 was shown to be highly associated with artemisinin-induced proteasome-mediated degradation of AR protein. Artemisinin treatment activated AKT-1 enzymatic activity, enhanced receptor association with AKT-1, and induced AR serine phosphorylation. Treatment of LNCaP cells with the PI3-kinase inhibitor LY294002, which inhibits the PI3-kinase-dependent activation of AKT-1, prevented the artemisinin-induced AR degradation. Furthermore, in transfected receptor-negative PC-3 cells, artemisinin failed to stimulate the degradation of an altered receptor protein (S215A/S792A) with mutations in its two consensus AKT-1 serine phosphorylation sites. Taken together, our results indicate that artemisinin induces the degradation of AR protein and disrupts androgen responsiveness of human prostate cancer cells, suggesting that this natural compound represents a new potential therapeutic molecule that selectively targets AR levels.

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Background The aim of this study is to assess for regional variation in the incidence of post-operative myocardial infarction (POMI) following nonemergent vascular surgery across the United States to identify potential areas for quality improvement initiatives. Methods We evaluated POMI rates across 17 regional Vascular Quality Initiative (VQI) groups that comprised 243 centers with 1,343 surgeons who performed 75,057 vascular operations from 2010 to 2014. Four procedures were included in the analysis: carotid endarterectomy (CEA, n = 39,118), endovascular abdominal aortic aneurysm (AAA) repair (EVAR, n = 15,106), infrainguinal bypass (INFRA, n = 17,176), and open infrarenal AAA repair (OAAA, n = 3,657). POMI was categorized by the method of diagnosis as troponin-only or clinical/ECG and rates were investigated in regions with ≥100 consecutive cases. Regions with significantly different POMI rates were defined as those >1.5 interquartile lengths beyond the 75th percentile of the distribution. Risk-adjusted rates of POMI were assessed using the VQI Cardiac Risk Index all-procedures prediction model to compare the observed versus expected rates for each region. Results Overall rates of POMI varied by procedure type: CEA 0.8%, EVAR 1.1%, INFRA 2.7%, and OAAA 4.2% (P < 0.001). Significant variation in POMI rates was observed between regions, resulting in differing ranges of POMI rates for each procedure: CEA 0.5–2.0% (P = 0.001), EVAR 0.3–3.1% (P < 0.001), INFRA 1.1–4.8% (P < 0.001), and OAAA 2.2–10.0% (P < 0.001). A single region in 3 of the 4 procedure-specific datasets was identified as a statistical outlier with a significantly higher POMI rate after CEA, EVAR, and OAAA; this region was identical for the EVAR and OAAA datasets but was a different region for the CEA dataset. No significant variation in POMI was noted between regions after INFRA. Procedure-specific clinical POMI rates (mean; range) were significantly different between regions for EVAR (0.4%; 0–1.1%, P = 0.01) and INFRA (1.4%; 0.5–2.9%, P = 0.01), but not for CEA (0.4%; 0–0.8%, P = 0.53) or OAAA (1.6%; 0–3.8%, P = 0.23). Procedure-specific troponin-only POMI rates (mean; range) were significantly different between regions for all procedures: CEA (0.4%; 0.1–1.2%, P < 0.001), EVAR (0.7%; 0–2.1%, P < 0.001), INFRA (1.3%; 0.4–2.5%, P = 0.001), and OAAA (2.5%; 0–8.5%, P < 0.001). After risk adjustment, regional variation was again noted with 3 regions having higher and 4 regions having lower than expected rates of POMI. Conclusions Significant variation in POMI rates following major vascular surgery exists across VQI regions even after risk adjustment. These findings may present an opportunity for focused regional quality improvement efforts.