Abstract
Kidney cancer rapidly acquires resistance to antiangiogenic agents, such as sunitinib, developing an aggressive migratory phenotype (facilitated by c-Metsignal transduction). The Aryl hydrocarbon receptor (AhR) has recently been postulated as a molecular target for cancer treatment. Currently, there are two antitumor agent AhR ligands, with activity against renal cancer, that have been tested clinically: aminoflavone (AFP 464, NSC710464) and the benzothiazole (5F 203) prodrug Phortress. Our studies investigated the action of AFP 464, the aminoflavone pro-drug currently used in clinical trials, and 5F 203 on renal cancer cells, specifically examining their effects on cell cycle progression, apoptosis and cell migration. Both compounds caused cell cycle arrest and apoptosis but only 5F 203 potently inhibited the migration of TK-10, Caki-1 and SN12C cells as well as the migration signal transduction cascade, involving c-Met signaling, in TK-10 cells. Current investigations are focused on the development of nano-delivery vehicles, apoferritin-encapsulated benzothiazoles 5F 203 and GW610, for the treatment of renal cancer. These compounds have shown improved antitumor effects against TK-10 cells in vitro at lower concentrations compared with a naked agent.
Highlights
aryl hydrocarbon receptor (AhR) activation by AF has to be confirmed in future studies using other papillary and clear cell carcinoma tumors
In contrast to the other cell lines, ACHN cells showed resistance to AF treatment, which was associated with the lack of induction of CYP1A1 and CYP1B1 transcription
We demonstrated that AhR activation does not occur in these cells in response to AF
Summary
Renal cell carcinoma (RCC) is the sixth most common malignancy in men and tenth in women worldwide with a significant variation in incidence and mortality between different geographic regions. It has recently been described that aryl hydrocarbon receptor (AhR) activation mediates kidney disease and renal cell carcinoma [5]. The targeted therapies include vascular endothelial growth factor receptor tyrosine-kinase inhibitors (VEGFR TKIs) and rapalogues, which inhibit the mammalian target of the rapamycin (mTOR) pathway signaling. This therapy aims to override the effects of hypoxia-inducible growth factor activation. Monoclonal antibodies directed against programmed death receptor-1 (PD-1), e.g., nivolumab and pembrolizumab, and its ligand (PD-L1) Avelumab, inhibit the immunosuppressive co-signals mediated by PD-1/PD-L1 interaction, enhancing the anti-tumor activity of the T-cells [12]. We discuss the role of the AhR ligands aminoflavone and benzothiazoles as potential new agents for the treatment of advanced mRCC
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