Comparative safety of tyrosine kinase inhibitors in the treatment of metastatic renal cell carcinoma: a systematic review and network meta-analysis.

Objective: This study aimed to compare the safety profile of tyrosine kinase inhibitors (TKIs) approved for use as monotherapy or combination therapy for the first-line treatment of adult patients with metastatic clear cell renal cell carcinoma (RCC). Methods: A systematic review with frequentist network meta-analysis (NMA) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included randomized controlled trials (RCTs) investigating the use of: cabozantinib, pazopanib, sorafenib, sunitinib, tivozanib, cabozantinib + nivolumab, lenvatinib + pembrolizumab, axitinib + avelumab, and axitinib + pembrolizumab in previously untreated adult patients with metastatic clear cell RCC. Eligible studies were identified by two reviewers in MEDLINE (via PubMed), EMBASE, and Cochrane Library. The risk of bias for RCTs was assessed using the Cochrane Collaboration tool. The P score was used to determine the treatment ranking. The mean probability of an event along with the relative measures of the NMA was considered with the treatment rankings. Results: A total of 13 RCTs were included in the systematic review and NMA. Sorafenib and tivozanib used as monotherapy were the best treatment options. Sorafenib achieved the highest P score for treatment discontinuation due to adverse events (AEs), fatigue, nausea, vomiting of any grade, and hypertension of any grade or grade ≥3. Tivozanib achieved the highest P score for AEs, grade ≥3 AEs, dose modifications due to AEs, and grade ≥3 diarrhea. Sunitinib was the best treatment option in terms of diarrhea and dysphonia of any grade, while cabozantinib, pazopanib, and axitinib + pembrolizumab-in terms of grade ≥3 fatigue, nausea, and vomiting. TKIs used in combination were shown to have a poorer safety profile than those used as monotherapy. Lenvatinib + pembrolizumab was considered the worst option in terms of any AEs, grade ≥3 AEs, treatment discontinuation due to AEs, dose modifications due to AEs, fatigue of any grade, nausea, vomiting, and grade ≥3 nausea. Axitinib + avelumab was the worst treatment option in terms of dysphonia, grade ≥3 diarrhea, and hypertension, while cabozantinib + nivolumab was the worst option in terms of grade ≥3 vomiting. Interestingly, among the other safety endpoints, cabozantinib monotherapy had the lowest P score for diarrhea and hypertension of any grade. Conclusion: The general safety profile, including common AEs, is better when TKIs are used as monotherapy vs. in combination with immunological agents. To confirm these findings, further research is needed, including large RCTs.

Visfatin increases the invasive potential of ovarian granulosa tumor spheroids by reprogramming glucose metabolism.

In brief: The role of visfatin in ovarian granulosa cell tumor (GCT) invasion and glucose metabolism reprogramming is largely unexplored. These studies imply that visfatin or its inhibitor is involved in regulating ovarian granuloma invasion by reprogramming glucose metabolism and may be a potential candidate for the diagnosis and treatment of ovarian GCT. Abstract: Visfatin is an adipokine with nicotinamide phosphoribosyltransferase (NAMPT) activity, the concentration of which is higher in ascitic fluid than in serum, and is associated with ovarian cancer peritoneal dissemination. Potentially important effects of visfatin on glucose metabolism have been previously reported. However, the mechanism underlying the effects of visfatin on ovarian cancer cell invasion, and whether this involves altered glucose metabolism, has not been elucidated. Here, we tested the hypothesis that visfatin, which can reprogram cancer metabolism, promotes invasion by ovarian cancer spheroids. Visfatin increased glucose transporter (GLUT)1 expression and glucose uptake in adult granulosa cell tumor-derived spheroid cells (KGN) and also increased the activities of hexokinase 2 and lactate dehydrogenase. We showed a visfatin-induced increase in glycolysis in KGN cells. Moreover, visfatin increased the potential invasiveness of KGN spheroid cells by upregulating MMP2 (matrix metalloproteinase 2) and downregulating CLDN3 and CLDN4 (claudin 3 and 4) gene expression. Interestingly, an inhibitor of GLUT1 and lactate dehydrogenase (LDHA) abolished the stimulatory effect of visfatin on the potential invasiveness of KGN cells. More importantly, silencing expression of the NAMPT gene in KGN cells demonstrated its important effect on glycolysis and invasiveness in adult granulosa cell tumor cells (AGCTs). In summary, visfatin appears to increase AGCT invasiveness through effects on glucose metabolism and to be an important regulator of glucose metabolism in these cells.

Visfatin induces ovarian cancer resistance to anoikis by regulating mitochondrial activity.

PURPOSE: Ovarian cancer is characterized by recurrent peritoneal and distant metastasis. To survive in a non-adherent state, floating ovarian cancer spheroids develop mechanisms to resist anoikis. Moreover, ascitic fluid from ovarian cancer patients contains high levels of visfatin with anti-apoptotic properties. However, the mechanism by which visfatin induces anoikis resistance in ovarian cancer spheroids remains unknown. Here, we aimed to assess wheather visfatin which possess anti-apoptotic properties can induce resistance of anoikis in ovarian cancer spheroids. METHODS: Visfatin synthesis were examined using a commercial human visfatin ELISA Kit. Spheroid were exposed to visfatin and cell viability and caspase 3/7 activity were measured using CellTiter-Glo 3D cell viability assay and Caspase-Glo® 3/7 Assay System. mRNA and protein expression were analyzed by Real-time PCR and Western Blot analysis, respectively. Analysis of mitochondrial activity was estimated by JC-1 staining. RESULTS: First, our results suggested higher expression and secretion of visfatin by epithelial than by granulosa ovarian cells, and in non-cancer tissues versus cancer tissues. Interestingly, visfatin increased the proliferation/apoptosis ratio in ovarian cancer spheroids. Specifically, both the intrinsic and extrinsic pathways of anoikis were regulated by visfatin. Moreover, the effect of the visfatin inhibitor (FK866) was opposite to that of visfatin. Furthermore, both NAMPT and FK866 affected mitochondrial activity in ovarian cancer cells. CONCLUSION: In conclusion, visfatin acts as an anti-apoptotic factor by regulating mitochondrial activity, leading to anoikis resistance in ovarian cancer spheroids. The finding suggest visfatin as a potential novel therapeutic target for the treatment of ovarian carcinoma with peritoneal dissemination.

Bisphenols S and F drive ovarian granulosa cell tumor invasion via a metabolic switch.

Alterations in the metabolism of cancer cells are crucial for tumor growth and progression. However, the mechanism whereby environmental pollutants such as bisphenols F (BPF) and S (BPS) affect glucose metabolism through the glycolytic pathway, and therefore influence tumor progression, are unclear. Both bisphenols are endocrine-disrupting molecules that are used in plastics. As a consequence of their widespread use, these compounds have been detected in various human body fluids. Thus, hormone-sensitive cancers, such as ovarian cancers, are exposed to these compounds. In the present study, we aimed to determine the effects of the concentrations of BPS and BPF found in body fluids on the cell viability, glucose uptake, glycolysis, oxygen consumption, and invasion by the adult ovarian granulosa cell tumor (AGCT) cell line. We found that BPS and BPF increased the glucose uptake, hexokinase activity, proliferation, and invasion of the cells at environmentally relevant concentrations. Furthermore, we identified an inhibition of glycolysis in parallel with an increase in oxygen consumption, suggesting a BPS/BPF-induced switch from aerobic glycolysis to mitochondrial respiration. In summary, these findings demonstrate a new mechanism through which BPS and BPF promote ovarian granulosa cell tumor progression by increasing energy production through mitochondrial respiration. Thus, both bisphenols induced a metabolic switch that appears to be a stimulus for AGCT progression.

Persistent organic pollutants affect steroidogenic and apoptotic activities in granulosa cells and reactive oxygen species concentrations in oocytes in the mouse.

CONTEXT: The destruction of granulosa cells (GCs), the main functional cell type in the ovary, prevents steroid hormone production, which in turn may damage oocytes, resulting in ovarian failure. The accumulation of a number of persistent organic pollutants (POPs) in the ovarian follicular fluid (FF) has been documented, which raises serious questions regarding their impact on female fertility. AIMS: We aimed to determine whether a mixture of POPs reflecting the profile found in FF influences mouse GCs or oocyte function and viability. METHODS: A mixture of POPs, comprising perfluorooctanoate, perfluorooctane sulfonate, 2,2-dichlorodiphenyldichloroethylene, polychlorinated biphenyl 153, and hexachlorobenzene, was used. In addition to using the exact concentration of POPs previously measured in human FF, we tested two other mixtures, one with10-fold lower and another with 10-fold higher concentrations of each POP. KEY RESULTS: Steroidogenesis was disrupted in GCs by the POP mixture, as demonstrated by lower oestradiol and progesterone secretion and greater lipid droplet accumulation. Furthermore, the POP mixture reduced GC viability and increased apoptosis, assessed using caspase-3 activity. The POP mixture significantly increased the number of oocytes that successfully progressed to the second meiotic metaphase and the oocyte reactive oxygen species (ROS) concentration. CONCLUSIONS: Thus, a mixture of POPs that are typically present in human FF has detrimental effects on ovarian function: it reduces the viability of GCs, and increases the oocyte concentrations of ROS. IMPLICATIONS: These results indicate that chronic exposure to POPs adversely affects female reproductive health.

A mixture of persistent organic pollutants detected in human follicular fluid increases progesterone secretion and mitochondrial activity in human granulosa HGrC1 cells.

Disruption of granulosa cells (GCs), the main functional cells in the ovary, is associated with impaired female fertility. Epidemiological studies demonstrated that women have detectable levels of organic pollutants (e.g., perfluorooctanoate, perfluorooctane sulfonate, 2,2-dichlorodiphenyldichloroethylene, polychlorinated biphenyl 153, and hexachlorobenzene) in their follicular fluid (FF), and thus these compounds may directly affect the function of GCs in the ovary. Considering that humans are exposed to multiple pollutants simultaneously, we elucidated the effects of a mixture of endocrine-disrupting chemicals (EDCs) on human granulosa HGrC1 cells. The EDC mixture directly increased progesterone secretion by upregulating 3ß-hydroxysteroid dehydrogenase (3ßHSD) expression. Furthermore, the EDC mixture increased activity of mitochondria, which are the central sites for steroid hormone biosynthesis, and the ATP content. Unexpectedly, the EDC mixture reduced glucose transporter 4 (GLUT4) expression and perturbed glucose uptake; however, this did not affect the glycolytic rate. Moreover, inhibition of GLUT1 by STF-31 did not alter the effects of the EDC mixture on steroid secretion but decreased basal estradiol secretion. Taken together, our results demonstrate that the mixture of EDCs present in FF can alter the functions of human GCs by disrupting steroidogenesis and may thus adversely affect female reproductive health. This study highlights that the EDC mixture elicits its effects by targeting mitochondria and increases mitochondrial network formation, mitochondrial activity, and expression of 3ßHSD, which is associated with the inner mitochondrial membrane.