Luciferase Reporter Cell Line - 22RV1

Prostate cancer (PCa) is a common and aggressive disease worldwide. In the majority of cases, following 18 to 24 months of treatment, the disease typically progresses to incurable castration-resistant prostate cancer (CRPC). The androgen receptor (AR) is considered a pivotal factor in the pathogenesis of CRPC. Consequently, investigating the AR as a potential therapeutic target for CRPC holds promise for facilitating the control and comprehensive management of this disease throughout its entire course. Here, researchers identified HG122, a potent small-molecule compound that not only inhibits the proliferation and metastasis of CRPC cells but also effectively suppresses tumor growth in both subcutaneous and orthotopic tumor models. Furthermore, HG122 downregulates the mRNA expression levels of AR target genes-PSA and TMPRSS2-thereby inhibiting the growth and metastasis of CRPC cells, without affecting the mRNA expression level of the AR itself. Mechanistically, HG122 promotes the degradation of AR protein via the proteasomal pathway, thereby blocking the AR signaling pathway. Taken together, HG122 demonstrates the ability to overcome CRPC resistance to enzalutamide (ENZ) in both in vitro and in vivo settings, suggesting that HG122 holds promise as a potential drug candidate for the clinical prevention and treatment of CRPC.

Here, researchers employed an orthotopic xenograft model to evaluate the effects of HG122 on tumor growth and metastasis. Specifically, 5 × 10^5 22RV1-luc cells were surgically injected into the dorsolateral lobes of the prostates of the recipient animals. One week post-injection, the tumor-bearing mice were castrated and subsequently randomized into three groups. One week later, the animals were administered HG122 (10 mg/kg/d), ENZ (10 mg/kg/d), or DMSO (control group) via intraperitoneal injection. In the castrated mice, treatment with HG122 significantly inhibited the growth of the orthotopic 22RV1 xenograft tumors (Figure 1A). In contrast, these CRPC xenografts exhibited partial resistance to enzalutamide treatment. Although both enzalutamide and HG122 were able to substantially suppress prostate cancer metastasis, the inhibitory effect of HG122 on the growth of the orthotopic prostate tumors was evidently more pronounced. Treatment with HG122 (10 mg/kg/d) resulted in an 82% reduction in tumor volume, whereas enzalutamide treatment resulted in a reduction of only 60%. For the mice bearing 22RV1 xenografts, pathological changes in the tumor tissues were examined via light microscopy following H&E staining. Compared to the control group, the expression levels of the androgen receptor (AR) and Ki67 protein were markedly reduced in the xenograft tumor cells treated with HG122 (Figure 1B).

Figure 1. Therapeutic effects of HG122 on orthotopic castration-resistant xenograft model. (Cong, Xiaonan, et al., 2021)