Drug Development Research最新文献

This study assessed the neuroprotective potential of empagliflozin (EMPA) as antidiabetic drug on glucose metabolism, comparing it to rivastigmine (RIVA) as standard treatment for Alzheimer's disease (AD), and their combination. Male rats were sorted into five groups. Group I served as the control, while groups II, III, IV, and V received the scopolamine plus heavy metal mixture for AD induction. Groups III and IV were administered RIVA and EMPA, respectively, and group V received both treatments. Cognitive function was evaluated behaviorally. Subsequently, glucose levels, acetylcholinesterase, oxidative stress, and inflammatory markers were assessed. Alongside the brain histopathological changes, the expression of phosphorylated tau protein was assessed. Moreover, glycolytic enzymes and glucose transporters were assessed using PCR analysis. The findings were attributed to a notable suppressive impact of EMPA on lipid peroxidation, acetylcholinesterase, glucose levels, phosphorylated tau protein, pro-inflammatory cytokines, and neuropathological changes, while enhancing antioxidant and interleukin-10 levels. It also improves glucose metabolism. The findings suggest that EMPA may be a viable candidate for future therapeutic exploration in AD, which has a multifaceted mechanism of action encompassing anti-neuroinflammation, antioxidant stress, and enhanced glucose metabolism, as well as decreased acetylcholinesterase activity and phosphorylated tau protein levels. Interestingly, combined treatment showed a superior effect than EMPA alone.

Glioblastoma (GBM) is the most common and lethal primary intracranial tumor, and glycolysis has been reported to play a critical role in its progression. Formin-binding protein 1 (FNBP1) has been implicated in GBM progression; however, the precise molecular mechanisms remain unclear. In this study, we demonstrated that FNBP1 expression was significantly higher in GBM tissues compared with adjacent tissues. Elevated FNBP1 expression was correlated with higher tumor grade and reduced 5-year survival in GBM patients. In vitro, knockdown of FNBP1 inhibited proliferation, invasion, and glycolysis, while promoting apoptosis in GBM cells. Mechanistically, RNA-binding motif protein 15B (RBM15B) increased the m6A modification level of FNBP1 mRNA, and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) recognized this m6A mark and enhanced the stability of FNBP1 mRNA. Furthermore, FNBP1 interacted with LIM and SH3 Domain Protein 1 (LASP1), upregulating LASP1 protein expression and subsequently activating the Smad3 signaling pathway to promote glycolysis. In vivo, subcutaneous xenograft models were established using U251/U87 cells, and a lung metastasis model was generated via tail vein injection of U87 cells. FNBP1 knockdown significantly suppressed tumor growth in the subcutaneous model and reduced the number of lung nodules in the metastasis model. In conclusion, FNBP1, regulated by the RBM15B-m6A-IGF2BP2 axis, promotes GBM progression by interacting with LASP1 to activate Smad3-mediated glycolysis.

Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options and poor prognosis. This study investigated the therapeutic potential of β-Elemene, a sesquiterpene from traditional Chinese medicine, against TNBC. We first confirmed that SIX-1 was significantly upregulated in TNBC tissues and cell lines. Our findings demonstrated that β-Elemene inhibited TNBC cell proliferation in a dose- and time-dependent manner. It also attenuated cell migration and invasion by reducing the expression and activity of MMP-2 and MMP-9. Furthermore, β-Elemene reversed epithelial-to-mesenchymal transition (EMT), as shown by the downregulation of N-cadherin, Snail, and TGF-β1, upregulation of E-cadherin, and a morphological shift towards an epithelial phenotype. The compound also diminished cancer stemness, evidenced by reduced spheroid formation and decreased expression of OCT4 and SOX2. Mechanistically, β-Elemene suppressed the β-Catenin/ID2 signaling pathway, an effect that was reversed by SIX-1 overexpression. In conclusion, β-Elemene suppresses TNBC proliferation, migration, invasion, and stemness in vitro by modulating the SIX-1/β-Catenin/ID2 axis, suggesting its promise as a candidate for further therapeutic development.

The literature represented that the 2-quinolone moiety is present in diverse potent EGFR, VEGFR-2, and telomerase cellular downregulators. Accordingly, it was incorporated in new scaffolds (2, 3, 5, and 8-12), keeping in mind its attachment to the requested pharmacophores of more than one target receptor to produce novel multi-target ligands. First, the growth inhibition % (GI%) of all candidates was recorded in seven diverse human cancer cell lines. Second, the IC₅₀ values of compounds (5, 6, and 12) were determined against six cancer cell lines. Interestingly, analogue (6) displayed the highest cytotoxicity, particularly against CaCo2, with an IC₅₀ value of 21.99 µM. Then, the EGFR, VEGFR-2, and telomerase inhibitory potentials of compounds (5, 6, and 12) were recorded. Notably, compound 6 showed the highest EGFR, VEGFR-2, and telomerase inhibitory potentials with 0.34, 0.31, and 0.54-fold changes, respectively. Additionally, the apoptotic potency of analogue (6) was evaluated by measuring the expression of caspases 3, 8, and 9 (proapoptotic markers), besides CDK 2, 4, and 6 (antiapoptotic markers) proteins. To sum up, compound 6 showed remarkable upregulation of the caspases 3, 8, and 9, while it showed detrimental results against the CDK 2, 4, and 6 proteins. This further emphasizes the potent apoptotic potential of compound 6 in CaCo2 cancer cells. Moreover, compound 6′s impact on cell cycle progression in CaCo2 showed a notable increase in cell cycle arrest in the G0 and G1 phases, equivalent to 28.72% and 68.20%, respectively, relative to control cells with 25.77% and 60.49%, respectively. Furthermore, the superior antitumor analogue (6) was tested by in silico molecular docking and dynamic simulations (for 200 ns) against EGFR, VEGFR-2, and telomerase targets to investigate its affinity and interactions. A structure–activity relationship (SAR) was performed to determine the anticancer potential of the tested candidates through modifications to the 2-oxoquinoline-3-carbaldehyde scaffold.

Cancer remains a significant global health challenge, with increasing incidence and mortality rates worldwide. The mechanistic target of rapamycin (mTOR) pathway, a central regulator of cell growth, proliferation, metabolism, and survival, has emerged as a promising therapeutic target in cancer. Dysregulation of mTOR signaling is implicated in various cancers, including breast, colon, lung, renal cell carcinoma, and multiple myeloma, making it an attractive target for inhibition. This review provides a comprehensive analysis of mTOR-targeted therapies, focusing on the clinical outcomes, efficacy, safety, and adverse effects of mTOR inhibitors. We explore the mechanisms of mTOR regulation, the impact of mTOR mutations on drug sensitivity, and the development of resistance to mTOR inhibitors. The review also highlights the potential of combination therapies and next-generation inhibitors to overcome resistance and improve therapeutic outcomes. Key mTOR inhibitors, including rapalogs (e.g., sirolimus, everolimus) and ATP-competitive inhibitors (e.g., MLN0128, PP242), are discussed in detail, along with their clinical applications and limitations. Additionally, we summarize the findings from major clinical trials, including FDA-approved mTOR inhibitors like everolimus and temsirolimus, and non-FDA-approved inhibitors such as sapanisertib and ridaforolimus. The review underscores the importance of understanding mTOR signaling and its role in cancer progression, offering insights into the future of mTOR-targeted therapies in oncology.