Aldo–keto reductase (AKR) 1C3 catalyzes the synthesis of active androgens that promote the progression of prostate cancer. AKR1C3 also contributes to androgen-independent cell proliferation and survival through the metabolism of prostaglandins and reactive aldehydes. Because of its elevation in castration-resistant prostate cancer (CRPC) tissues, AKR1C3 is a promising therapeutic target for CRPC. In this study, we found a novel potent AKR1C3 inhibitor, N-(4-fluorophenyl)-8-hydroxy-2-imino-2H-chromene-3-carboxamide (2d), and synthesized its derivatives with IC50 values of 25–56 nM and >220-fold selectivity over other AKRs (1C1, 1C2, and 1C4). The structural factors for the inhibitory potency were elucidated by crystallographic study of AKR1C3 complexes with 2j and 2l. The inhibitors suppressed proliferation of prostate cancer 22Rv1 and PC3 cells through both androgen-dependent and androgen-independent mechanisms. Additionally, 2j and 2l prevented prostate tumor growth in a xenograft mouse model. Furthermore, the inhibitors significantly augmented apoptotic cell death induced by anti-CRPC drugs (abiraterone or enzalutamide).

Prostate cancer is known to have a relatively good prognosis, but long-term hormone therapy can lead to castration-resistant prostate cancer (CRPC). Cabazitaxel, a second-generation taxane, has been used for the CRPC treatment, but its tolerance is an urgent problem to be solved. In this study, to elucidate the acquisition mechanism of the cabazitaxel-resistance, we established cabazitaxel-resistant prostate cancer 22Rv1 (Cab-R) cells, which exhibited approximately 7-fold higher LD50 against cabazitaxel than the parental 22Rv1 cells. Cab-R cells showed marked increases in nuclear accumulation of NF-E2 related factor 2 (Nrf2) and expression of Nrf2-inducible antioxidant enzymes compared to 22Rv1 cells, suggesting that Nrf2 signaling is homeostatically activated in Cab-R cells. The cabazitaxel sensitivity of Cab-R cells was enhanced by silencing of Nrf2, and that of 22Rv1 cells was reduced by activation of Nrf2. Halofuginone (HF) has been recently identified as a potent Nrf2 synthetic inhibitor, and its treatment of Cab-R cells not only suppressed the Nrf2 signaling by decreasing both nuclear and cytosolic Nrf2 protein levels, but also significantly augmented the cabazitaxel sensitivity. Thus, inhibition of Nrf2 signaling may be effective in overcoming the cabazitaxel resistance in prostate cancer cells.

No abstract

Background/Aim: No practical predictive biomarkers exist to date for the response to androgen receptor-axis targeted (ARAT) therapies in metastatic castration-resistant prostate cancer (mCRPC). This study investigated whether prostate-specific antigen (PSA) kinetics in primary androgen-deprivation therapy for advanced hormone-sensitive prostate cancer may be associated with the response to ARAT agents in mCRPC. Patients and Methods: This study assessed 102 patients with mCRPC treated with enzalutamide or abiraterone to evaluate the associations between clinical outcomes and PSA kinetics, including the ratio of initial to nadir PSA (I/N PSA) level in primary combined androgen blockade. The PSA response was defined as a ≥50% decrease at 3 months from baseline in patients with mCRPC. Results: In patients treated with enzalutamide, the optimal cut-off I/N PSA value for PSA response was 531 ng/ml (sensitivity=66.7%, specificity=88.2%, area under the curve=0.73, using a receiver operating characteristic curve). The PSA response was 83.3% and 25.0% in the high and low I/N PSA groups, respectively. The median overall survival and radiographic progression-free survival from enzalutamide initiation were longer for the high compared to the low I/N PSA group. Multivariate analysis revealed I/N PSA (hazard ratio=0.275, p=0.026) as an independent risk factor for overall survival in the patients treated with enzalutamide. In contrast, I/N PSA showed no predictive ability for PSA response in patients treated with abiraterone. Conclusion: In patients with mCRPC, I/N PSA can be a practical predictive biomarker for response to the ARAT agent enzalutamide.Prostate cancer (PC) is the second most common malignancy among men (1). An estimated 1.41 million men were diagnosed with PC in 2020 globally, representing 14.1% of all cancers diagnosed in men, with 375,000 deaths caused by this disease (2).Androgen-deprivation therapy (ADT) has been the standard treatment for patients with metastatic hormonesensitive PC. Although PC is highly androgen-dependent and sensitive to primary ADT and although PC patients benefit from ADT at the beginning of their treatment plan, patients with metastatic hormone-sensitive PC eventually (within 2-3 years) develop metastatic castration-resistant PC (mCRPC), a disease associated with a high mortality rate (1, 3).The treatment landscape of advanced PC is changing rapidly. Multiple agents have been approved for advanced PC, including enzalutamide, abiraterone, apalutamide, darolutamide, docetaxel, cabazitaxel, immunotherapy, radium-223 and sipuleucel-T (4). Appropriate drug selection and sequencing remain crucial in this evolving landscape to derive maximum benefit for patients with mCRPC. However, the most effective use of these therapies -order of administration, duration of treatment, and efficacy of combinations -has not yet been defined because of the absence of direct comparative randomised data (4). Currently, there are no well-validated practical predictive markers of response to androgen receptor (A...

No abstract

Inflammation is observed in many tumors, which affects metastasis, infiltration, and immune escape and causes poor differentiation of the cancer cells. However, the molecular basis underlying the relationship between inflammation and poor differentiation in tumors has not been identified. In this study, we demonstrate that angiopoietin‐like protein‐8 (ANGPTL8), which is induced by stress stimuli such as inflammation, is involved in the maintenance of the undifferentiated state of clear cell renal cell carcinoma (ccRCC) cells. ANGPTL8 is also involved in the production of chemokines that attract immune suppressor cells to the tumor microenvironment. ANGPTL8 sustains the continuous production of chemokines by activating the NF‐κB signaling pathway and maintains the undifferentiated state of ccRCC cells. Finally, ANGPTL8 is induced by STAT3 signaling, which is activated by immune cells in the tumor microenvironment. These results support a role for ANGPTL8 in determining the properties of ccRCC by hampering tumor cell differentiation and establishing the tumor microenvironment.

No abstract