6-bromoindirubin-3--oxime and Ovarian-Neoplasms

Cisplatin is an anticancer agent marred by nephrotoxicity. Limiting this adverse effect may allow the use of higher doses to improve its efficacy. The Wnt/β-catenin signaling pathway plays a critical role in nephrogenesis and repair of renal diseases. BIO, a small molecule agonist of this pathway, exerted a protective effect in adriamycin nephropathy and promoted nephrogenesis. The aim of this study, therefore, was to investigate whether Wnt/β-catenin agonist BIO could protect against cisplatin-induced nephrotoxicity in vivo and in vitro, as well as its possible mechanism.. Male mice and human renal proximal tubular cells (HK-2) were subjected to cisplatin to study reno-protective effect of BIO. Renal function, cell viability, tubular apoptosis, production of reactive oxygen species (ROS) and proliferative level were analyzed respectively. Additionally, xenograft model was induced to investigate if BIO would impair the antitumor effect of cisplatin.. Cisplatin increased serum creatinine levels and promoted histological renal injury as well as oxidative stress levels. Besides, renal apoptotic level and the expression of pro-apoptotic proteins, Bax/bcl-2 and cleaved-caspase3 included, in the kidney were increased. All these features were decreased by BIO, which also activated Wnt/β-catenin pathway in cisplatin-induced nephrotoxicity. Similarly, accompanied by the motivation of Wnt/β-catenin pathway, BIO exerted a positively protective effect on HK-2 challenged cisplatin. Last, the chemotherapeutic effects of cisplatin in xenograft mice of ovary tumor models and in lung cancer cells weren't compromised by BIO.. Wnt/β-catenin agonist BIO has the potential to prevent cisplatin nephrotoxicity without compromising its anti-proliferation efficacy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line; Cell Line, Tumor; Cell Proliferation; Cisplatin; Female; Humans; Indoles; Kidney Diseases; Kidney Tubules, Proximal; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Ovarian Neoplasms; Oxidative Stress; Oximes; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

Ovarian cancer (OC) is a deadly disease, and despite improvements in treatment, overall 5-year survival is low. Glycogen synthase kinase (GSK)-3β is a multifunctional serine/threonine kinase. We wished to ascertain if the GSK-3β inhibitor (2Z,3E)-6-bromoindirubin-3'-oxime, known as "BIO," can suppress OC development. The OC cell lines A2780 and OVCAR3 were exposed to BIO. At different time points, cell proliferation, apoptosis, cell cycle, and cell invasion/cell migration assays were carried out. Phalloidin staining was undertaken to observe lamellipodia formation. Real-time reverse transcription-polymerase chain reaction and western blotting were used to assess expression of messenger RNA (mRNA) and protein of GSK-3β, cyclin D1, matrix metalloproteinase (MMP)-9, and p21. BIO suppressed the proliferation, invasion, and migration of OC cells; reduced lamellipodia formation; and induced G1 arrest of the cell cycle. BIO exposure led to a significant downregulation of mRNA and protein expression of cyclin D1 and MMP9 in comparison with untreated control cells. In contrast, BIO exposure upregulated mRNA and protein expression of p21 in comparison with untreated control cells. Besides, GSK-3β small interfering RNA (siRNA) transfection in ovarian cancer cells also downregulated GSK-3β, cyclin D1, and MMP9 protein expression while upregulated p21 expression. These data suggest that BIO, as an inhibitor of GSK-3β, can suppress OC development. Therefore, BIO could be a candidate drug for the treatment of OC.

Topics: Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclin D1; Enzyme Inhibitors; Female; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3 beta; Humans; Indoles; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Ovarian Neoplasms; Oximes; Phosphorylation; Signal Transduction