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INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options. This study explores the potential of novel 5-nitro-thiophene-thiosemicarbazone derivatives as therapeutic agents for PDAC. METHODS: We evaluated the cytotoxicity of seven derivatives in peripheral blood mononuclear cells (PBMCs) and PDAC cell lines. Promising candidates (PR12 and PR17) were further analyzed for their effects on colony formation, cell cycle progression, and reactive oxygen species (ROS) production. PR17, the most promising derivative, was subjected to additional investigation, including analysis of autophagy-related genes and protein kinase inhibition. RESULTS: Three derivatives (PR16, PR19, and PR20) displayed cytotoxicity towards PBMCs. PR12 reduced colony formation and G0/G1 cell cycle arrest in PDAC cells. Notably, PR17 exhibited potent activity in MIA PaCa-2 cells, inducing S-phase cell cycle arrest, downregulating autophagy genes, and inhibiting key protein kinases. CONCLUSION: PR17, a 5-nitro-thiophene-thiosemicarbazone derivative, demonstrates promising antineoplastic activity against PDAC cells by potentially modulating cell cycle progression, autophagy, and protein kinase signaling. Further studies are warranted to elucidate the detailed mechanism of action and explore its efficacy in vivo.
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INTRODUCTION: Cancer is the major cause of morbidity and mortality worldwide. Current treatments for both solid and hematological tumors are associated with severe adverse effects and drug resistance, necessitating the development of novel selective antineoplastic drugs. METHODS: The present study describes the antitumor activity of the imidazacridine derivative 5-acridin-9-ylmethylidene-2-thioxoimidazolidin-4-one (LPSF/AC05) in breast cancer, leuke-mia, and lymphoma cells. Cytotoxicity assays were performed in PBMC and in breast cancer, leukemia, and lymphoma cell lines using the MTT method. Changes in cell cycle progression and apoptosis were assessed using flow cytometry. Moreover, topoisomerase II inhibition as-says were performed. LPSF/AC05 exhibited cytotoxicity in six of the nine cell lines tested. RESULTS: The best results for leukemia and lymphoma were observed in the Toledo, Jurkat, and Raji cell lines (IC50 = 27.18, 31.04, and 33.36 ïM, respectively). For breast cancer, the best re-sults were observed in the triple-negative cell line MDA-MB-231 (IC50 = 27.54 µM). The compound showed excellent selectivity, with no toxicity to normal human cells (IC50 > 100ïM; selectivity index > 3). Cell death was primarily induced by apoptosis in all cell lines. Furthermore, LPSF/AC05 treatmentinduced cell cycle arrest at the G0/G1 phase in leuke-mia/lymphoma and at the G2/M phase in breast cancer. CONCLUSION: Finally, topoisomerase II was inhibited. These results indicate the potential ap-plication of LPSF/AC05 in cancer therapy.
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BACKGROUND: Oxazolidinones display several biological effects, including anticancer activity. The purpose of this present work was to investigate a series of novel oxazolidinone derivatives with potential antineoplastic activity. Their mechanisms of death induction and effects in the cell cycle were also evaluated. A molecular docking study was accomplished through proteins of the Cyclin-Dependent Kinases family (CDK). The new compound LPSF/NBM-2 was appeared to promote cell cycle arrest at the G2/M phase and increase the percentage of apoptotic cells. METHODS: Oxazolidinone derivatives were obtained through Knoevenagel condensation. The cytotoxic assay was evaluated through the MTT method. Moreover, flow cytometry was performed in order to investigate the effects of the new compounds on the cell cycle, induction of cell death, and apoptosis. A blind docking was performed through the SwissDock online server and the analysis of the results was performed using the UCSF Chimera and Biovia discovery studio software. RESULTS: LPSF/NBM-1 and LPSF/NBM-2 displayed the most cytotoxic activity against HL-60 (IC50 = 54.83 µM) and MOLT-4 (IC50 = 51.61 µM) cell lines. LPSF/NBM-2 showed an increased percentage of cell population at the G2/M phase. Molecular-docking results of LPSF/NBM-1 and LPSF/NBM-2 suggested a binding affinity with the evaluated CDK proteins. CONCLUSION: LPSF/NBM-1 and LPSF/NBM-2 displayed cytotoxic profiles against Hl-60 and MOLT-4. LPSF/NBM-2 increased cell population percentage at the G2/M phase and promoted cell death compared to non-treated cells in the MOLT-4 cell line. Based on these findings, oxazolidinone derivatives could be highlighted as possible cytostatic agents against lymphoma cells. Molecular docking results suggested the action of LPSF/NBM-1 and LPSF/NBM-2 compounds on enzymes of cyclin-dependent kinases family, however, more studies are needed to establish this correlation.