New Treatments in Renal Cancer: The AhR Ligands

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.

Cigarette Smoking and Estrogen-Related Cancer

“…The fact that smoking appears to exert an anti-estrogenic effect through AhR signaling suggests that this pathway would be a productive avenue for research regarding prevention or treatment for estrogen-related malignancies. Indeed, use of selective AhR ligands for treatment of breast cancer, and perhaps other malignancies, is an active line of research (122) and the AhR-active drug aminoflavone (186,187) has been in clinical trials for treatment of breast and other cancers.…”

Targeting Dietary and Microbial Tryptophan-Indole Metabolism as Therapeutic Approaches to Colon Cancer

“…Despite these complexities, the role of AhR in therapeutics for tumor suppression is under intense investigation. Several AhR ligands were recently in clinical trials for renal and breast cancer, autoimmune diseases, and multiple sclerosis [ 179 , 180 , 181 , 182 ]. Recently, however, a trial using an AhR inhibitory drug (BAY2416964) was initiated for treatment of advanced colon cancer (NCT04069026).…”

Repurposing screen highlights broad-spectrum coronavirus antivirals and their host targets

“…Further to this, Phortress, an AHR ligand, emerged as broad-spectrum antiviral with activity in primary differentiated human lung cells. Ligands of the AHR are in clinical development for treatment of kidney cancer (Itkin et al, 2020) (ClinicalTrials.gov Identifier: NCT04069026).…”

“…Upon ligand binding, AHR disassociates from Hsp90, traffics to the nucleus and transactivates genes downstream of the xenobiotic response element. AHR-dependent genes include metabolic enzymes such as cytochrome (CYP) P450 1A1, CYP1A2 and CYP1B1 (Itkin et al, 2020). AHR also participates in immune regulatory processes: for instance constitutive activation of AHR downregulates type I IFN-dependent innate immune responses (Yamada et al, 2016).…”