Preclinical study using androgen receptor (AR) degradation enhancer to increase radiotherapy efficacy via targeting radiation-increased AR to better suppress prostate cancer progression

Abstract

BackgroundWhile androgen deprivation therapy (ADT) and radiotherapy (RT) are currently used together to treat locally advanced prostate cancer (PCa), RT might have the adverse effect of increasing the PCa androgen receptor (AR) protein expression, which might then increase the resistance to continued RT.MethodsWe used multiple assays for RT sensitivity, protein and RNA expression of AR and related DDR genes, ROS level, DNA damage/repair level, cell cycle and apoptosis. All statistical comparisons were analyzed with t-test or one-way ANOVA.FindingsWe demonstrated that RT induced AR expression in C4-2 and CWR22Rv-1 cells. We found that combining RT and ASC-J9®, but not the antiandrogen, Enzalutamide, could increase radiosensitivity via inducing DNA damage, altering the AR mediated and DNA repair pathways, and activating apoptosis. ASC-J9® had little effects on normal bladder cells.InterpretationTargeting ionizing radiation (IR)-increased AR with the AR degradation enhancer, ASC-J9®, could increase the radiosensitivity while sparing adjacent normal tissue. Mechanism dissection revealed that ASC-J9®, but not Enzalutamide, treatment could increase radiosensitivity via inducing DNA damage, altering DNA repair pathways, as well as activating the IR-induced apoptosis via suppressing the pATR-CHK1 signals. Importantly, results from preclinical studies using an in vivo mouse model also demonstrated that combining RT with ASC-J9® to target AR led to better therapeutic efficacy to suppress PCa progression.

Apalutamide Sensitizes Prostate Cancer to Ionizing Radiation via Inhibition of Non-Homologous End-Joining DNA Repair

“…However, the observed effects could also be explained by the additivity of both modalities. Previous reports came to opposing conclusions regarding the radiosensitizing effect of AR suppression in CRPC models, with studies showing a synergistic effect [7,15] or no effect [13,16]. Our in vitro CRPC cells and ex vivo androgen-dependent PCa tissue slices experiments provide new evidence that AR suppression can act as radiosensitizer in both AR-expressing hormone-sensitive PCa (which represents the majority of patients receiving EBRT) and AR-expressing CRPC.…”

“…Previous preclinical studies investigated the molecular mechanism of radiosensitization by ADT and discovered an interplay between AR signaling and the DNA repair machinery [7,8,10,11,16]. However, opposing conclusions were drawn from these studies about the DNA repair pathways that cause the radiosensitization.…”

Fatty Acid Inhibition Sensitizes Androgen-Dependent and -Independent Prostate Cancer to Radiotherapy via FASN/NF-κB Pathway

“…Radiotherapy (RT) is delivered to PCa patients with early or late stages for various purposes. Moreover, it has been shown that the androgen receptor (AR) signalling pathway affects the radiosensitivity in bladder cancer 27 and prostate cancer 28 . The clinical results also indicated that ADT could enhance the effects of RT on PCa.…”

Roles of Reactive Oxygen Species in Biological Behaviors of Prostate Cancer

“…Recent studies indicate that androgen effects might not be equal to the AR effects. Besides, androgen-independent (AI) cells have a higher level of oxidant species than androgen-sensitive (AS) cells, which suggest that ROS can cause deregulations of the AR axis pathway [ 113 ]. It is reported that AI PCa cells exhibited higher p66Shc protein levels that activate NOX complexes and stimulate mitochondrial superoxide production for intracellular ROS generation to a high degree [ 45 ].…”