Curcumin induces mitophagy by promoting mitochondrial succinate dehydrogenase activity and sensitizes human papillary thyroid carcinoma BCPAP cells to radioiodine treatment.

Thyroid cancer is one of the most common endocrine malignancies. Differentiated thyroid cancer (DTC) treatment is based on the ability of thyroid follicular cells to accumulate radioactive iodide (RAI). DTC generally has a good prognosis. However, tumor dedifferentiation or defect in certain cell death mechanism occurs in a subset of DTC patients, leading to RAI resistance. Therefore, developing novel therapeutic approaches that enhance RAI sensitivity are still warranted. We found that curcumin, an active ingredient in turmeric with anti-cancer properties, rapidly accumulated in the mitochondria of thyroid cancer cells but not normal epithelial cells. Curcumin treatment triggered mitochondrial membrane depolarization, engulfment of mitochondria within autophagosomes and a robust decrease in mitochondrial mass and proteins, indicating that curcumin selectively induced mitophagy in thyroid cancer cells. In addition, curcumin-induced mitophagic cell death and its synergistic cytotoxic effect with radioiodine could be attenuated by autophagy inhibitor, 3-methyladenine (3-MA). Interestingly, the mechanism of mitophagy-inducing potential of curcumin was its unique mitochondria-targeting property, which induced a burst of SDH activity and excessive ROS production. Our data suggest that curcumin induces mitochondrial dysfunction and triggers lethal mitophagy, which synergizes with radioiodine to kill thyroid cancer cells.

Capsaicin inhibits the stemness of anaplastic thyroid carcinoma cells by triggering autophagy-lysosome mediated OCT4A degradation.

Capsaicin (CAP) is a well-known anti-cancer agent. Recently, we reported capsaicin-induced apoptosis in anaplastic thyroid cancer (ATC) cells. It is well accepted that the generation of cancer stem cells (CSCs) is responsible for the dedifferentiation of ATC, the most lethal subtype of thyroid cancer with highly dedifferentiation status. Whether CAP inhibited the ATC growth through targeting CSCs needed further investigation. In the present study, CAP was found to induce autophagy in ATC cells through TRPV1 activation and subsequent calcium influx. Meanwhile, CAP dose-dependently decreased the sphere formation capacity of ATC cells. The stemness-inhibitory effect of CAP was further by extreme limiting dilution analysis (ELDA). CAP significantly decreased the protein level of OCT4A in both 8505C and FRO cells. Furthermore, CAP-induced OCT4A degradation was reversed by autophagy inhibitors 3-MA and chloroquine, BAPTA-AM and capsazepine, but not proteasome inhibitor MG132. Collectively, our study firstly showed CAP suppressed the stemness of ATC cells partially via calcium-dependent autophagic degradation of OCT4A. Our study lent credence to the feasible application of capsaicin in limiting ATC stemness.

Diallyl trisulphide, a H2 S donor, compromises the stem cell phenotype and restores thyroid-specific gene expression in anaplastic thyroid carcinoma cells by targeting AKT-SOX2 axis.

It is widely accepted that anaplastic thyroid carcinoma (ATC), a rare, extremely aggressive malignant, is enriched by cancer stem cells (CSCs), which are closely related to the pathogenesis of ATC. In the present study, we demonstrated that diallyl trisulphide (DATS), a well-known hydrogen sulphide (H2 S) donor, suppressed sphere formation and restored the expression of iodide-metabolizing genes in human ATC cells, which were associated with H2 S generation. Two other H2 S donors, NaHS and GYY4137, could also suppress the self-renewal properties of ATC cells in vitro. Compared with normal thyroid tissues and papillary thyroid carcinomas (PTCs), the elevated expressions of SOX2 and MYC, two cancer stem cell markers, in ATCs were validated in the combined Gene Expression Omnibus (GEO) cohort. DATS decreased the expression of SOX2, which was mediated by H2 S generation. Furthermore, knockdown of AKT or inhibition of AKT by DATS led to a decrease of SOX2 expression in ATC cells. AKT knockdown phenocopied restoration of thyroid-specific gene expression in ATC cells. Our data suggest that H2 S donors treatment can compromise the stem cell phenotype and restore thyroid-specific gene expression of ATC cells by targeting AKT-SOX2 pathway, which may serve as a therapeutic strategy to intervene the CSC progression of ATC.

Diallyl trisulfide, a H2 S donor, inhibits cell growth of human papillary thyroid carcinoma KTC-1 cells through a positive feedback loop between H2 S and cystathionine-gamma-lyase.

Diallyl trisulfide (DATS), derived from garlic, is a well-known hydrogen sulfide (H2 S) donor. H2 S has recently emerged as a novel gasotransmitter involved in the regulation of cancer progression. The present study demonstrated that DATS along with other two H2 S donors, NaHS and GYY4137, significantly inhibited papillary thyroid carcinoma KTC-1 cells growth. DATS treatment triggered a rapid H2 S generation within 5 min in KTC-1 cells. Iodoacetamide, a potent thiol blocker reagent, partially rescued the cell membrane damage and ultimate cell death induced by DATS, indicating H2 S contributed to the apoptosis-inducing efficacy of DATS on thyroid cancer cells. Specifically, DATS treatment significantly upregulated the expression and enzymatic activity of cystathionine gamma-lyase (CTH), one of H2 S-producing enzymes, which was responsible for endogenous H2 S generation. After DATS treatment, H2 S quickly permeated cell membranes and activated NF-κΒ/p65 signaling pathway in KTC-1 cells. Nuclear translocated NF-κB bound to the promoter of CTH to enhance its transcription. These evidences proved that exogenous H2 S elevated CTH expression. CTH, in turn, catalytically generated a much higher level of endogenous H2 S. This positive feedback sustained excess H2 S production, which resulted in PTC cells growth inhibition. These findings may shed light on the development of novel H2 S-based antitumor agents.

Induction of Apoptosis in Human Papillary-Thyroid-Carcinoma BCPAP Cells by Diallyl Trisulfide through Activation of the MAPK Signaling Pathway.

This study aimed to elucidate the potential effects of diallyl trisulfide (DATS) on human papillary-thyroid-carcinoma BCPAP cells and its underlying mechanisms. DATS is an organosulfur compound derived from garlic. In this study, we demonstrated that compared with the solvent control, DATS treatment at concentrations of 5, 10, and 20 µΜ decreased cell survival rates of BCPAP cells to 84.51 ± 2.67, 57.16 ± 1.18, and 41.22 ± 1.19% respectively. DATS also caused cell-cycle arrest at G0/G1 phase, and the proportion of cells arrested in G0/G1 phase rose from 68.8 ± 8.38 to 80.4 ± 8.38%, which eventually resulted in cell apoptosis through a mitochondrial apoptotic pathway in BCPAP cells. Further evidence showed that DATS activated ERK, JNK, and p38, members of the MAPK family. Moreover, ERK and JNK inhibitors partially reversed apoptosis in BCPAP cells induced by DATS treatment. Taken together, our results demonstrated that DATS exerted an apoptosis-inducing effect on papillary-thyroid-cancer cells via activation of the MAPK signaling pathway, which shed light on a prospective therapeutic target for thyroid-cancer treatment.

Traditional Chinese lipid-lowering agent red yeast rice results in significant LDL reduction but safety is uncertain - a systematic review and meta-analysis.

OBJECTIVE: To verify the safety and effectiveness of traditional Chinese red yeast rice-extract (RYR) for reduction of LDL cholesterol. METHODS: Systematic literature review and meta-analysis. Medline and EMBASE were searched until November 2014. We selected randomized studies in which RYR with a known content of the active substance monacolin K was tested against placebo or an active control group. Outcome measures were the effect of RYR on LDL cholesterol and incidence of adverse reactions with emphasis on liver and kidney injury and muscle symptoms. RESULTS: Twenty studies were analyzed. Quality of safety assessment was low in the majority of studies. RYR lowered LDL cholesterol with 1.02 mmol/L [-1.20; -0.83] compared to placebo. Effect of RYR on LDL was not different from statin therapy (0.03 mmol/L [-0.36; 0.41]). The incidence of liver and kidney injury was 0-5% and the risk was not different between treatment and control groups (risk difference -0.01 [-0.01; 0.0] and 0.0 [-0.01; 0.02]). CONCLUSIONS: RYR exerts a clinically and statistically significant reduction of 1.02 mmol/L LDL cholesterol. Only when the mild profile of adverse reactions can be affirmed in studies with adequate methodology for safety assessment, RYR might be a safe and effective treatment option for dyslipidemia and cardiovascular risk reduction in statin intolerant patients.

The mechanism underlying proliferation-inhibitory and apoptosis-inducing effects of curcumin on papillary thyroid cancer cells.

Recently, many studies on health benefits associated with curcumin have been reported. In this study, the effects of curcumin on apoptosis of papillary thyroid cancer cell line K1 and its potential mechanisms were investigated. Curcumin was found to significantly inhibit cell viability and promoted cell apoptosis in a dose-dependent manner. Moreover, curcumin-induced cell apoptosis was characterized with a rapid stimulation of reactive oxygen species (ROS) production. Furthermore, curcumin-induced ROS generation led to the loss of mitochondrial membrane potential (MMP) and the disturbance of intracellular Ca(2+) concentration. A decrease in expression of Bcl-2 and the cleavage of poly ADP-ribose polymerase (PARP) were observed after exposure to curcumin. Results of this study may elucidate the curcumin-induced apoptosis effects on K1 cells. Thus, our results indicate a role of curcumin as health-promoting food ingredient, as well as a potential chemotherapeutic agent which is able to fight against papillary thyroid cancer.

Neuroprotective effects of salidroside against beta-amyloid-induced oxidative stress in SH-SY5Y human neuroblastoma cells.

Beta-amyloid (Abeta) peptide, the hallmark of Alzheimer's disease (AD), invokes a cascade of oxidative damages to neurons and eventually leads to neuronal death. In this study, salidroside (Sald), an active compound isolated from a traditional Chinese medicinal plant, Rhodiola rosea L., was investigated to assess its protective effects and the underlying mechanisms against Abeta-induced oxidative stress in SH-SY5Y human neuroblastoma cells. Abeta(25-35)-induced neuronal toxicity was characterized by the decrease of cell viability, the release of lactate dehydrogenase (LDH), morphological alterations, neuronal DNA condensation, and the cleavage of poly(ADP-ribose) polymerase (PARP) by activated caspase-3. Pretreatment with salidroside markedly attenuated Abeta(25-35)-induced loss of cell viability and apoptosis in a dose-dependent manner. The mechanisms of salidroside protected neurons from oxidative stress included the induction of antioxidant enzymes, thioredoxin (Trx), heme oxygenase-1 (HO-1), and peroxiredoxin-I (PrxI); the downregulation of pro-apoptotic protein Bax and the upregulation of anti-apoptotic protein Bcl-X(L). Furthermore, salidroside dose-dependently restored Abeta(25-35)-induced loss of mitochondrial membrane potential (MMP) as well as suppressed the elevation of intracellular reactive oxygen species (ROS) level. It was also observed that Abeta(25-35) stimulated the phosphorylation of mitogen-activated protein (MAP) kinases, including c-Jun NH(2)-terminal kinase (JNK) and p38 MAP kinase, but not extracellular signal-regulated kinase1/2 (ERK1/2). Salidroside inhibited Abeta(25-35)-induced phosphorylation of JNK and p38 MAP kinase, but not ERK1/2. These results suggest that salidroside has protective effects against Abeta(25-35)-induced oxidative stress, which might be a potential therapeutic agent for treating or preventing neurodegenerative diseases.