No abstract

We investigated activity and mechanism of action of two AhR ligand antitumor agents, AFP 464 and 5F 203 on human renal cancer cells, specifically examining their effects on cell cycle progression, apoptosis and migration. TK-10, SN12C, Caki-1 and ACHN human renal cancer cell lines were treated with AFP 464 and 5F 203. We evaluated cytotoxicity by MTS assays, cell cycle arrest and apoptosis by flow cytometry and corroborated a mechanism of action involving AhR signal transduction activation. Changes in migration properties by wound healing assays were investigated: 5F 203-sensitive cells show decreased migration after treatment, therefore we measured c-Met phosphorylation by Western blot in these cells. Both compounds caused cell cycle arrest and apoptosis in sensitive cell lines TK-10, SN12C and Caki-1 cell lines. 5F 203 induced a decrease in cell viability which was more remarkable marked than AFP 464. This cytotoxicity was reduced after treatment with the AhR inhibitor α-NF for both compounds indicating Ahr AhR signaling activation plays a role in the mechanism of action. 5F 203 is sequestered by TK-10 cells and induces CYP1A1 expression; 5F 203 only potently inhibited migration of TK-10, Caki-1 and SN12C cells, and inhibited c-Met receptor phosphorylation in TK-10 cells. AhR ligand antitumor agents AFP 464 and 5F 203 represent potential new candidates for the treatment of renal cancer. 5F 203 only inhibited migration of sensitive cells and c-Met receptor phosphorylation in TK-10 cells. c-Met receptor signal transduction is important in migration and metastasis. Therefore we consider that 5F 203 offers potential for the treatment of metastatic renal carcinoma.

Breast cancer is the first cause of cancer death in women. Many patients are resistant to current therapies, and even those were sensitive at first may eventually become resistant later. Thiosemicarbazones (TSCs) are synthetic compounds that exhibit several pharmacological activities. In this study, we investigated the potential anti-tumor activity of a set of N -arylsubstituted TSCs (N -TSCs) on human breast cancer cell lines. Studies on the effect of N -TSCs (T1, T2, and T3) were carried on MCF-7, MDA-MB 231, and BT 474 cell lines which differ in their expression of ER, PR, and Her2/neu. Non-transformed MCF-10A breast cell line were used as normal cells. Action of N -TSCs were evaluated by proliferation assay, quantification of apoptosis and cell cycle analysis. Modulation of clonogenic efficiency and migratory capacity by N -TSCs were also evaluated. We further investigated the effects of N -TSCs on ROS level and Ribonucleotide Reductase (RR) activity. We analyzed the action of these compounds on cellular mammosphere-forming capacity. We found that T1 and T2 had specific anti-tumor effect on all breast cancer cell lines based on their pro-apoptotic action and inhibitory effect on clonogenic efficiency and cell migration capacity. We also showed that both compounds increased ROS level and inhibited RR activity. Finally, we found that all N -TSCs diminished mammospehere-forming capacity of MCF-7 and BT 474 cells. N -TSCs showed specific anti-tumor action on human breast cancer cells independently their biomarkers expression pattern. Our results place these compounds as promising novel anti-tumor drugs with potential therapeutic application against different types of breast cancer.