LaSOM335, active against bladder cancer cells, interferes withLet‐60(hRas) and reducesCD73 expression/activity

Abstract

AbstractBladder cancer is the fourth most common malignancy in men. It can present along the entire continuum of severity, from mild to well‐differentiated disease to extremely malignant tumors with low survival rates. HumanRASgenes are the most frequently mutated oncogenes in human cancers, and the critical role of aberrant Ras protein function in carcinogenesis is well established. Therefore, considerable efforts have been devoted to the development of anti‐Ras inhibitors for cancer treatment. This study presents the biphenyl dihydropyrimidinone LaSOM 335 with high activity against T24 bladder cancer cells (IC50 = 10.73 ± 0.53 μM) and selectivity of cytotoxicity for this cancer cell line compared to two non‐cancer cell lines investigated. Furthermore, we also show that this compound reduced vulvar development in the mutantlet‐60 gene ofCaenorhabditis elegans.Let‐60 is a homolog of the mammalian Ras gene. In addition, we observed that LaSOM 335 inhibits the enzymatic activity of CD73 and decreases CD73 expression. Possibly, this expression decrease is due to downstream EGFR signaling via the Ras–Raf–ERK pathway, that directly regulates CD73 expression via ERK1/2. Evidence suggests that non‐immunomodulating functions of CD73 play an equally important role for cancer cell survival, progression, and migration. Regarding we also notice that LaSOM 335 was safe in the in vivo model ofC. elegans. The set of these findings makes this biphenyl dihydropyrimidinone a promising candidate for further investigations in the bladder cancer field.