Browsing by Author "Fiadjoe, Hope"
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Item Anti-proliferative effects of a copper(II) complex with a thiosemicarbazone ligand against selected human cancer cells(2023) Fiadjoe, Hope; Lambring, Christoffer B.; Sankpal, Umesh; Alajroush, Duaa; Smith, Chloe; Anderson, Brittney; Mann, Novia; Beebe, Stephen; Holder, Alvin; Basha, RiyazPurpose: The frequent relapse and drug resistance associated with the current cancer chemotherapy treatments necessitate the development of alternative strategies. Thiosemicarbazones are a class of metal chelators that have been explored to treat diverse human diseases, including cancer. Copper, a crucial structural component for many significant enzymes and a key catalytic co-factor in redox processes, is being explored for several medical applications. Additionally, the anti-cancer activity of certain chemotherapeutic agents can be enhanced by the use of copper-containing complexes. This study aimed to evaluate the antiproliferative effects of a copper(II) complex with a thiosemicarbazone ligand (Cu-acetylethTSC or [Cu(acetylethTSC)Cl]Cl·0.25C2H5OH (where acetylethTSC = (E)-N-ethyl-2-[1-(thiazol-2-yl)ethylidene]hydrazinecarbothioamide)) against human cancer cell lines, viz., medulloblastoma (DAOY, D283), glioblastoma (LN-229), Ewing sarcoma (TC205, CHLA10), and acute lymphoblastic leukemia (CCRF-CEM, SUP-B15). Methods: These selected cell lines were cultured using standard protocols. Cell viability was measured using a Cell Titer-Glo kit at 48 h after treatment with various concentrations of Cu-acetylethTSC. Each treatment group and the controls were read in triplicates and the data were plotted as percentage cell viability versus concentration of the complex. Dose-response curves were generated based on the cell viability data obtained, and IC50 values were calculated. Cardiomyocytes (H9C2) were also cultured and used to test cytotoxicity in non-malignant cells. Results: Cell viability was inhibited in a dose-dependent manner in all the selected cancer cell lines whiles that of H9C2 was not significantly affected. Conclusion: This indicates that Cu-acetylethTSC was selective for malignant cells. Further studies are underway to understand the efficacy, protein targets, and underlying mechanisms of the role of Cu- acetylethTSC.Item Targeting Sp1 in Ewing Sarcoma: A multi-approach method for the utilization of Mithramycin(2023) Lambring, Christoffer B.; Basha, Riyaz; Sankpal, Umesh; Fiadjoe, Hope; Ray, AnishPurpose: Ewing Sarcoma (ES) is a bone and soft tissue cancer affecting young adults and children. ES mostly occurs in the bones or soft tissue of the arms, legs, and pelvis. Localized ES presents with 5-year survival rate of 70%, but metastatic 5-year survival rate is between 15% and 30%. Our laboratory is interested in combination treatments using less toxic agents to induce sensitization to chemotherapy in ES. The anti-cancer activity of an antineoplastic antibiotic, Mithramycin, against ES cells has been shown. Mithramycin inhibits Specificity protein 1 (Sp1) a marker associated with aggressive cancer cell growth and resistance to chemo/radiation therapies. However, its mechanistic effects on other oncogenic proteins have yet to be elucidated in ES. The purpose of this study is to evaluate the effectiveness of Mithramycin and various combinations with other chemotherapeutic agents, Etoposide and Vincristine, to inhibit ES cell growth and assess the effect on key cancer related proteins regulated by Sp1. Future studies will include expanding upon Mithramycin’s mechanism of action in Ewing Sarcoma utilizing RNA sequencing and various computational methods. Methods: Cell lines were obtained from Children’s Oncology Group (COG). Anti-proliferative activity of Mithramycin and/or Vincristine and Etoposide against ES cell lines, TC205 and CHLA10, was evaluated using CellTiterGlo kit. Dose curves were plotted and IC50 values were determined by Sigma-Plot software. The expression of Sp1 and survivin was determined by Western blot analysis. The specific type of effect (additive/antagonistic/ synergistic) of the combination treatments were determined by analyzing the combination index obtained via Calcusyn software. Nude mice were injected with TC205 cells and treated over two weeks with either Mithramycin (1mg/kg per week) and/or Etoposide (5mg/kg per week) and tumor volume was compared. Protein models were obtained from RCSB PDB and homology tests were performed using the Swiss-model workspace. Results: Mithramycin, etoposide, and vincristine decreased ES cell line viability in TC205 and CHLA10 cells as monotherapies, but more effectively in combination. Tumor volume was greatly attenuated upon Mithramycin and/or etoposide introduction, but more significantly when used in combination. Mithramycin showed the ability to reduce the expression of Sp1 and offer differing effects on survivin expression, indicative of anti-apoptotic mechanisms being implemented in the ES cell lines. Decreases in viability upon chemotherapeutic and Mithramycin introduction were drastically increased when used in combination and this effect was mirrored in further decreases in Sp1 expression. Synergistic drug responses were shown in the combination of Mithramycin with both Vincristine and Etoposide (CI <1). Sp1 and survivin protein models were established and homology verification using Ramachandran plots and QMEAN Z-scores indicated quality protein models for further computational studies. Conclusions: Mithramycin may effectively sensitize ES cells and improve the response of chemotherapy while lowering necessary effective dosages. Studies to understand the mechanism of action of Mithramycin on Sp1, survivin, and other proteins involved in Ewing Sarcoma are underway.Item Understanding the role of Annexin A2 expression in the incidence of Hepatocellular Carcinoma.(2024-03-21) Fiadjoe, Hope; Chaudhary, PankajPurpose: Hepatocellular carcinoma (HCC) is a rapidly growing cancer with high mortality rates worldwide, necessitating improved diagnostic and therapeutic strategies. Annexin A2 (AnxA2), a calcium-dependent phospholipid-binding protein and a member of the annexin protein family, holds promise as a diagnostic, prognostic, and therapeutic target in several cancers. This study evaluates the clinical significance of AnxA2 in HCC progression. Methods: The Cancer Genome Atlas (TCGA) data was mined to assess AnxA2 mRNA expression in HCC and its correlation with tumor stage, grade, overall survival, and progression-free survival. Additionally, immunoblot analysis was conducted on tumor tissue samples to determine the AnxA2 expression in HCC patients. Results: Analysis of TCGA data revealed a significant upregulation of AnxA2 mRNA expression in HCC compared to normal liver tissues, correlating with higher pathological grades and stages and poor overall and progression-free survival. The immunoblot analysis further confirmed that the expression of AnxA2 was high in tumor tissues of HCC patients compared to matched adjacent non-tumorigenic liver tissues. Conclusion: These findings underscore the potential of AnxA2 as a biomarker for cancer aggressiveness and prognosis, highlighting its role as a promising therapeutic target.