Serefoglu EC, et al. World J Mens Health. 2024 Sep;42:e79. https://doi.org/10.5534/wjmh.240059

Introduction: There are various methods used in cases of metastatic endometrial cancer. However, the prognosis is generally poor. Therefore, new anticancer agents are expected to exhibit the potential to prevent metastasis, as well as their effects on the viability of cancer cells. In in vitro conditions, the Ishikawa cell line represents endometrial adenocarcinoma and the Huvec cell line represents human umbilical vein endothelial cells. Oxadiazole derivatives may be promising new agents for endometrial cancer treatments by exhibiting anticancer and antiangiogenic properties. Objective: The aim of this study was to examine the anticancer, antimigration and antiangiogenic effects of 5-[(4-Phenylpiperazine-1-yl)methyl]-1,3,4-oxadiazol-2-thiol (FP-Oxa) on co-cultured Ishikawa and Huvec cells. Materials and Methods: In silico molecular docking, ADME and toxicity analyzes were performed for FP-Oxa. The effect on the viability of two- and three-dimensional mono- and co-culture models created with HUVEC and Ishikawa cells was evaluated by MTT analysis and IC50 values were calculated. The effect on the migration of two-dimensional cultured cells was determined by wound healing assay. Changes in VEGF expression in three-dimensional co-culture models were evaluated by immunofluorescence staining. Results: As a result of in silico analyses, it was determined that FP-Oxa was within the oral bioavailability limits, exhibited class 4 toxicity, and had inhibition potential by binding to VEGR2. While FP-Oxa clearly inhibited migration in two-dimensionally cultured Ishikawa cells, it did not show the same level of success in Huvec and co-cultured cells. It was effective in reducing VEGF expression in three-dimensional co-cultures. Conclusion: FP-Oxa may have various therapeutic effects on endometrial adenocarcinoma cells. It will be important to conduct biological activity studies in three-dimensional models that mimic the tumor structure created with different types of cancer cells.

Background: Endometrial cancer remains a significant health concern, with type 1 endometrial cancer characterized by aberrant expression of estrogen-dependent and mTOR pathway proteins. In this study, we evaluated the effects of two novel hydrazone derivatives against the Ishikawa cell line, a model for endometrial cancer. Methods: Two novel hydrazone derivatives, MVB1 and MVB2, were synthesized and characterized. The anticancer activity of the compounds in both two- and three-dimensional cultured Ishikawa cells was evaluated by MTT assay. The interaction of the compounds with proteins in the PI3K/AKT/mTOR pathway was evaluated by molecular docking studies and in vitro western blot analyses were performed. Additionally, ADME/T calculations were performed to evaluate the drug-like properties of the compounds. Results: MVB1 and MVB2 showed promising anticancer activity with IC₅₀ values of 8.3 ± 0.5 µM and 9.0 ± 1.2 µM in 2D cultures, respectively, and 49.9 ± 2 µM and 20.6 ± 1.9 µM in 3D cultures, respectively. Molecular docking studies revealed significant interactions between these compounds and key proteins in the PI3K/AKT/mTOR pathway, with MVB1 exhibiting the highest mean binding score (−10.5 kcal/mol) among PI3K, AKT1, and mTOR proteins. In vitro studies confirmed that MVB1 effectively suppressed PI3K protein expression in both 2D and 3D cultures (p ≤ 0.0001). Conclusions: The findings suggest that MVB1 and MVB2, especially MVB1, are promising candidates for further development as potential therapeutics for endometrial cancer by targeting the PI3K/AKT/mTOR pathway.

Background Since cartilage, unlike skin, does not contain vessels, it obtains nutrition by diffusion. This reduces graft viability, resulting in problems such as reductions in size, changes in shape, and resorption of the cartilage graft in the late post-graft period. This study aimed to investigate the effects of adipose-derived mesenchymal cells and conditioned medium (CM) on cartilage graft viability.Methods Dissections were performed 4 months after the injection of 0.5 mL of CM or 2×106 mesenchymal stem cells (MSCs) in 0.5 mL after grafting into a control group and two experimental groups (n=21 rabbits in total). Chondrocyte viability and type II collagen expression in the grafted areas were analyzed by hematoxylin-eosin staining and immunohistochemical methods, respectively.Results In the MSC and CM groups, chondrocyte proliferation at the graft tissue incision margin (MSC: P<0.01, CM: P<0.0001), chondrocyte proliferation at the auricular cartilage incision margin (MSC: P<0.05, CM: P<0.0001), integration of the graft with the surrounding cartilage (MSC: P<0.001, CM: P<0.0001) and type II collagen expression levels (MSC: P=0.001, CM: P=0.0002) significantly increased.Conclusions Xenogenic injection of MSCs and CM contributed to new cartilage production without any tumoral effects or immune reactions. In particular, the cell-free nature of CM strengthened its potential for safe use. Since injections of MSC and CM can preserve cartilage graft viability, interest in this technique is expected to increase as long-term results from clinical studies on the subject become available.

Colon cancer remains a leading cause of cancer-related deaths, and drug repurposing offers a promising strategy to identify new therapies. Hydroquinidine (HQ), a class I antiarrhythmic agent, has recently been suggested to possess anticancer properties; however, its preclinical safety and efficacy in colorectal cancer are not well defined. The safety of HQ was evaluated in Wistar rats following OECD guidelines. Rats received daily intraperitoneal doses (2.5–25 mg/kg) for 90 days, with hematological, biochemical, and histopathological assessments performed. HQ was well tolerated up to 12.5 mg/kg, whereas 25 mg/kg caused signs of hepatotoxicity without lethality. A 1,2-dimethylhydrazine-induced colorectal cancer model was then used to assess HQ at safe doses (6.25 and 12.5 mg/kg) compared with cisplatin. Tissue histopathology and selected molecular markers associated with inflammation, apoptosis, epithelial–mesenchymal transition, and PI3K/AKT/mTOR pathway activity were analyzed. In the DMH-induced colon cancer model, HQ improved colonic tissue architecture and was associated with lower histopathological scores compared with untreated tumor controls. HQ also modulated tumor-associated markers by reducing IL-6 immunoreactivity, increasing caspase-3 expression, enhancing E-cadherin immunoreactivity, and decreasing vimentin expression. Moreover, HQ was associated with reduced immunoreactivity of mTOR pathway-related markers, suggesting attenuation of pathway activation in this experimental context. Overall, HQ showed an acceptable safety profile at the selected doses and exerted favorable histopathological and molecular modulatory effects, supporting further investigation as a potential repurposing candidate.