Antineoplastic Activity of an Old Natural Antidiabetic Biguanide on the Human Thyroid Carcinoma Cell Line.

BACKGROUND: In the last decades, metformin (Met), an herbal anti-diabetic medicine, has been proposed as an anti-cancer agent. OBJECTIVE: Thyroid cancers are the most common malignancy of the endocrine system. Therefore, the current study was performed to assess the effects of Met on cell proliferation and activation of the Phosphoinositide 3- Kinase (PI3K)/Protein kinase B (AKT)/Forkhead Box O1 (FOXO1) signaling pathway in the Medullary Thyroid Carcinoma (MTC) cells. The effects of Met on the expression of REarranged during Transfection (RET) proto-oncogene were also investigated. METHODS: MTC cell line (TT) was treated with 0, 2.5, 5, 10, 20, 30, 40, 50, and 60 mM concentrations of Met for 24, 48, and 72h. The viability and apoptosis of the treated cells were measured by the 3-(4,5-Dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Annexin V- Propidium Iodide (PI) assays. The expression level of PI3K, AKT, FOXO1, and RET genes was investigated by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR), and phosphorylation of their proteins was determined by the Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: Results showed that Met significantly decreased the viability of the MTC cells. Met also reduced the expression level of PI3K, AKT, and FOXO1 genes (P<0.05), whereas it elevated the expression level of RET proto-oncogene (P<0.05). CONCLUSION: It seems that the Met has a cytostatic effect on the TT cells. Our results showed that anti-tumoral effects of Met may be cell type-specific, and according to the induction of RET (as a proto-oncogene) and inhibition of FOXO1 (as a tumor suppressor gene), Met could not be an appropriate agent in the treatment of MTC. The antineoplastic activity of Met has been confirmed against several malignancies in "in vitro" and "in vivo" studies. However, its molecular mechanisms in the treatment of different carcinomas particularly in thyroid cancers are not clearly understood and more studies are required to confirm its exact effect on the MTC.

Effects of bariatric surgery in different obesity phenotypes: Tehran Obesity Treatment Study (TOTS).

BACKGROUND: Not all morbid obese patients suffer from metabolic co-morbidities; thus, a sub-group of metabolically healthy morbid obese (MHMO) individuals are identified. However, the role of bariatric surgery is not well understood in this subgroup. METHODS: A total of 2244 morbid obese individuals aged 18-65 years undergoing bariatric surgery were selected. Patients were considered MHMO according to the joint interim statement (JIS) definition, as having two or less abnormalities in these five parameters: waist circumference (WC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), systolic or diastolic blood pressure (SBP or DBP), and fasting plasma glucose (FPG). Otherwise, they were considered metabolically unhealthy morbid obese (MUMO). Follow-up data were collected at 6, 12, and 24 months post-surgery. RESULTS: Prior to surgery, 36.2% of participants were MHMO and had significantly lower BMI, WC, TG, FPG, SBP, and DBP and higher HDL-C compared to MUMO. Both MHMO and MUMO participants showed a significant decrease in BMI, WC, TG, SBP, DBP, and FPG and increase in HDL-C and the percentage of excess weight loss (%EWL). Two-year post-operative changes (from baseline) of BMI, WC, and %EWL were greater in MHMO subjects and changes of TG, HDL-C, DBP, SBP, and FPG were greater in MUMO subjects. Further multivariate regression analysis for delta (∆) change in these characteristics revealed that only the delta (∆) changes of WC and %EWL were statistically different between the two phenotypes and were greater in MHMO subjects, 2 years after the surgery (- 3.077 cm decrease in WC and + 3.612% higher %EWL compared to MUMO subjects). CONCLUSION: Bariatric surgery is an effective method for reduction of metabolic abnormalities and weight loss in both MUMO and MHMO phenotypes. Benefits of this intervention are comparable between patients with these two obesity phenotypes.

Effects of metformin on the PI3K/AKT/FOXO1 pathway in anaplastic thyroid Cancer cell lines.

BACKGROUND: The PI3K/AKT/FOXO signaling pathway plays an important role in the survival, proliferation and apoptosis of tumor cells. The aim of the present study was to explore whether metformin could affect insulin-promoting cell growth by regulation of this pathway. MATERIAL AND METHODS: Anaplastic thyroid cancer cells were treated with 0-60 mM metformin for 24, 48 and 72 h. Cell viability, morphology, apoptosis and migration were investigated by MTT assay, microscopy observation, AnexinV-PI and the wound healing assay, respectively. Expression levels of PI3K, AKT and FOXO1 were detected by RT-qPCR, and proteins phosphorylated levels were determined by ELISA. RESULTS: Metformin decreased cell viability and migration in a significant time-and dose-dependent manner, and induced apoptosis and morphological changes in the cells. RT-qPCR results showed that expression levels of PI3K, AKT and FOXO1 was inhibited by metformin (P < 0.05). However, there was no significant change in the expression level of AKT following metformin treatment for C643 cell line (P > 0.05). ELISA results showed that metformin treatment had no significant effects on the phosphorylated levels of PI3K, AKT and FOXO1 (P > 0.05). CONCLUSUION: The downregulation of FOXO1 was intensified by metformin, but no increase in cell viability was observed following FOXO1 downregulation by metformin. However, the exact molecular mechanism of metformin on inhibition of the PI3K/AKT pathway and subsequent decrease in cell viability remains unclear and further studies are required for its clarification.