Senescent cells and SASP in cancer microenvironment: New approaches in cancer therapy.

Cellular senescence was first described as a state characterized by telomere shortening, resulting in limiting cell proliferation in aging. Apart from this type of senescence, which is called replicative senescence, other senescence types occur after exposure to different stress factors. One of these types of senescence induced after adjuvant therapy (chemotherapy and radiotherapy) is called therapy-induced senescence. The treatment with chemotherapeutics induces cellular senescence in normal and cancer cells in the tumor microenvironment. Thus therapy-induced senescence in the cancer microenvironment is accepted one of the drivers of tumor progression. Recent studies have revealed that senescence-associated secretory phenotype induction has roles in pathological processes such as inducing epithelial-mesenchymal transition and promoting tumor vascularization. Thus senolytic drugs that specifically kill senescent cells and senomorphic drugs that inhibit the secretory activity of senescent cells are seen as a new approach in cancer treatment. Developing and discovering new senotherapeutic agents targeting senescent cells is also gaining importance. In this review, we attempt to summarize the signaling pathways regarding the metabolism, cell morphology, and organelles of the senescent cell. Furthermore, we also reviewed the effects of SASP in the cancer microenvironment and the senotherapeutics that have the potential to be used as adjuvant therapy in cancer treatment.

Validation of Fenoterol to Study ß2-Adrenoceptor Function in the Rat Urinary Bladder.

Fenoterol is a ß2-adrenoceptor (AR)-selective agonist that is commonly used to investigate relaxation responses mediated by ß2-AR in smooth muscle preparations. Some data have questioned this because fenoterol had low potency in the rat urinary bladder when a muscarinic agonist was used as a pre-contraction agent and because some investigators proposed that fenoterol may act in part via ß3-AR. We designed the present study to investigate whether fenoterol is a proper pharmacological tool to study ß2-AR-mediated relaxation responses in the rat urinary bladder. Firstly, we have compared the effect of pre-contraction agents on fenoterol potency and found that fenoterol potency was about 1.5 log units greater against KCl than carbachol (pEC50 7.19 ± 0.66 and 5.62 ± 1.09 of KCl and of carbachol, respectively). To test the selectivity of fenoterol, we have determined the effects of the ß2-AR antagonist ICI 118,551 and the ß3-AR antagonist L 748,337 on relaxation responses to fenoterol. While 300 nM L 748,337 had little effect on the potency of fenoterol (pEC50 6.56 ± 0.25 and 6.33 ± 0.61 in the absence and presence of L 748,337, respectively), the relaxation curve for fenoterol was right-shifted in the presence 300 nM ICI 118,551 (pEC50 5.03 ± 0.18). Thus, we conclude that fenoterol is a proper pharmacological tool to assess ß2-AR-mediated responses in the rat urinary bladder and most likely in other smooth-muscle preparations containing multiple subtypes of the ß-AR.

Effects of sitagliptin on ß-adrenoceptor mediated relaxation in streptozotocin-diabetic rat aorta

Background/aim: Dipeptidyl peptidase-4 (DPP4) inhibitors, a class of oral antidiabetic drugs, have been shown to be protective on the vascular system because of their antiinflammatory, antiatherosclerotic, and vasodilatory effects. ß2-adrenoceptors (ß2-ARs) mediate the vasorelaxation in the aorta. However, ß3-adrenoceptor-mediated relaxation has not been studied in diabetic aorta yet. Thus, we aimed to study the effect of sitagliptin treatment on ß2- and ß3-adrenoceptor-mediated relaxations in the diabetic rat aorta. Materials and methods: Eight-week old Sprague Dawley rats were divided into three groups: control, diabetic, sitagliptin treated diabetic. Diabetes was induced by injection of streptozotocin (35 or 40 mg/kg, intraperitoneally). After 10 weeks of diabetes, some of the diabetic rats were treated with sitagliptin (orally, 10mg/kg/day). ß2- and ß3-AR-mediated relaxation responses were evaluated by using isoprenaline and CL 316,243, respectively. ß3-AR-mediated relaxation experiments were repeated in presence of L-NAME. Western blotting and immunohistochemistry were performed to determine the abundance of ß3-adrenoceptor and endothelial nitric oxide synthase (eNOS). Results: The isoprenaline-mediated relaxation response was impaired in the diabetic group and sitagliptin treatment did not improve it. There was no significant change in CL316,243 mediated-relaxation or protein expression of ß3-ARs among the groups. However, the ratio of phosphorylated eNOS/NOS protein was increased markedly in the sitagliptin treated group, which points the stimulating effect of this drug towards the eNOS pathway. Conclusion: Our results indicate that sitagliptin treatment does not alter ß-AR-mediated relaxation in streptozotocin-diabetic rat aorta; however, it significantly stimulates the eNOS pathway. Future studies are needed to clarify the relationship between the eNOS pathway and DPP-4 inhibition.

Urinary Bladder Weight and Function in a Rat Model of Mild Hyperglycemia and Its Treatment With Dapagliflozin.

Hypertrophy and dysfunction of the urinary bladder are consistently observed in animal models of type 1 and less consistently in those of type 2 diabetes. We have tested the effects of mild hyperglycemia (n = 10 per group) in a randomized, blinded study and, in a blinded pilot study, of type 2 diabetes (n = 6 per group) and its treatment with dapagliflozin (1 mg/kg per day) on weight, contraction, and relaxation of the rat bladder. Based on a combination of high-fat diet and a low dose of streptozotocin, animals in the main study reached a mean peak blood glucose level of about 300 mg/dl, which declined to 205 mg/dl at study end. This was associated with a small, if any, increase in bladder weight. In a pooled analysis of all animals of the main and the pilot study, we detected a correlation of moderate strength between blood glucose and bladder weight (r 2 = 0.2013; P = 0.0003 for Pearson correlation coefficient). Neither the main nor the pilot study found evidence for an altered contractility (responses to carbachol or KCl) or relaxation (responses to isoprenaline, fenoterol, CL 316,243, or forskolin). Treatment with dapagliflozin in the absence of hyperglycemia increased diuresis in the main study by 43% relative to control and increased bladder weight by 15% in the pooled groups of both studies (post hoc analysis). We conclude that mild hyperglycemia has no major effects on bladder hypertrophy or function.