The androgen receptor (AR) belongs to the steroid hormone group of nuclear receptors with the estrogen receptor (ER), glucocorticoid receptor (GR), progesterone receptor (PR), and mineralocorticoid receptor (MR). Activation of androgen receptor (AR) is crucial for prostate cancer growth[3]. ODM-201 is a potent androgen receptor inhibitor with IC50 value of 26nM. In vitro, ODM-201 inhibited the androgen-induced nuclear translocation of overexpressed AR in HS-HEK293 cells. ODM-201 inhibited VCap cell proliferation with IC50 value of 230nM. However, ODM-201 had no effect on the viability of AR-negative tested, DU-145 prostate cancer cells and H1581 lung cancer cells[1].In vivo, oral administration of ODM-201 at 50mg/kg once or twice daily for 37 days significantly inhibited tumor growth in castrated (ORX) nude mice with subcutaneous VCap tumor [1]. After 7 days of oral administration with ODM-201 at 25~100mg/kg twice daily, blood: plasma levels for ODM-201 were 1.9–3.9% in mice, suggesting that the penetrance of ODM-201 through the blood brain barrier was negligible. Phase I/II clinical trial in men with mCRPC show that ODM-201 has promising anti-tumor activity in chemotherapy-pretreated patients[4].
作用机制
ODM-201 inhibits potently androgen binding to AR and androgen-induced nuclear translocation of AR[1].
Darolutamide/达洛鲁胺 细胞实验
Cell Line
Concentration
Treated Time
Description
References
LNCaP cells
10 µM
24 hours
Darolutamide significantly induces ferroptosis in AR+ PCa cells by downregulating SREBP1, which inhibits FASN transcription, thereby modulating phospholipid remodeling and inducing ferroptosis.
Int J Biol Sci. 2024 Sep 3;20(12):4635-4653.
C4-2 cells
50 µM
24 hours
Darolutamide significantly induces ferroptosis in AR+ PCa cells by downregulating SREBP1, which inhibits FASN transcription, thereby modulating phospholipid remodeling and inducing ferroptosis.
Int J Biol Sci. 2024 Sep 3;20(12):4635-4653.
LNCaP cells
36.6 nM –37.5 µM
4 days
Evaluate the synergistic antiproliferative activity of PSMA-TTC with darolutamide, showing synergistic effects (combination index of 0.47)
Clin Cancer Res. 2021 Aug 1;27(15):4367-4378.
VCaP cells
36.6 nM –37.5 µM
4 days
Evaluate the synergistic antiproliferative activity of PSMA-TTC with darolutamide, showing synergistic effects (combination index of 0.36)
Clin Cancer Res. 2021 Aug 1;27(15):4367-4378.
C4-2
10-100 µM
48 hours
To evaluate the effect of Darolutamide on prostate cancer cell sensitivity, results showed that downregulation of circRBM33 increased prostate cancer cell sensitivity to Darolutamide
Int J Biol Sci. 2023 Mar 5;19(5):1543-1563.
22Rv1
10-100 µM
48 hours
To evaluate the effect of Darolutamide on prostate cancer cell sensitivity, results showed that downregulation of circRBM33 increased prostate cancer cell sensitivity to Darolutamide
Int J Biol Sci. 2023 Mar 5;19(5):1543-1563.
LNCaP cells
7.72 µM
6 days
To evaluate the suppressive effect of darolutamide and radium-223 on LNCaP cell proliferation, showing moderate synergism.
Int J Mol Sci. 2024 Dec 21;25(24):13672.
LNCaP
5,260 ± 2,510 nM (IC50)
6 days
To evaluate the effect of Darolutamide on prostate cancer cell viability. Results showed that Darolutamide significantly inhibited LNCaP cell viability.
Int J Cancer. 2019 Sep 1;145(5):1382-1394.
LAPC-4
500 ± 220 nM (IC50)
6 days
To evaluate the effect of Darolutamide on prostate cancer cell viability. Results showed that Darolutamide significantly inhibited LAPC-4 cell viability.
Int J Cancer. 2019 Sep 1;145(5):1382-1394.
VCaP
410 ± 150 nM (IC50)
6 days
To evaluate the effect of Darolutamide on prostate cancer cell viability. Results showed that Darolutamide significantly inhibited VCaP cell viability.
Int J Cancer. 2019 Sep 1;145(5):1382-1394.
DU145
11.0 µM (IC 50)
72 hours
To evaluate the in vitro efficacy of darolutamide against castration-resistant prostate cancer, showing DU145 cells were sensitive to darolutamide with an IC50 of 11.0 µM.
Am J Cancer Res. 2024 Dec 25;14(12):6012-6036.
PC3
32.3 µM (IC 50)
72 hours
To evaluate the in vitro efficacy of darolutamide against castration-resistant prostate cancer, showing PC3 cells were sensitive to darolutamide with an IC50 of 32.3 µM.
Am J Cancer Res. 2024 Dec 25;14(12):6012-6036.
LNCaP
33.8 µM (IC 50)
72 hours
To evaluate the in vitro efficacy of darolutamide against castration-resistant prostate cancer, showing LNCaP cells were sensitive to darolutamide with an IC50 of 33.8 µM.
Am J Cancer Res. 2024 Dec 25;14(12):6012-6036.
22RV1
46.6 µM (IC 50)
72 hours
To evaluate the in vitro efficacy of darolutamide against castration-resistant prostate cancer, showing 22RV1 cells were sensitive to darolutamide with an IC50 of 46.6 µM.
Am J Cancer Res. 2024 Dec 25;14(12):6012-6036.
LAPC4 cells
500 nM (low) or 2 µM (high)
8 or 22 hours
To characterize the effects of darolutamide on the PCa transcriptome, it was observed that darolutamide strongly antagonized genome-wide AR binding and inhibited androgen-dependent gene regulation.
Mol Oncol. 2020 Sep;14(9):2022-2039.
VCaP cells
500 nM (low) or 2 µM (high)
8 or 22 hours
To characterize the effects of darolutamide on the PCa transcriptome, it was observed that darolutamide strongly antagonized genome-wide AR binding and inhibited androgen-dependent gene regulation.
Mol Oncol. 2020 Sep;14(9):2022-2039.
LAPC4 cells
500 nM or 2 µM
8 or 22 hours
To study the impact of Darolutamide on the PCa transcriptome, it was found that Darolutamide significantly inhibited R1881-induced AR signaling and blocked AR-driven transcriptional signaling.
Mol Oncol. 2020 Sep;14(9):2022-2039.
VCaP cells
500 nM or 2 µM
8 or 22 hours
To study the impact of Darolutamide on the PCa transcriptome, it was found that Darolutamide significantly inhibited R1881-induced AR signaling and blocked AR-driven transcriptional signaling.
Mol Oncol. 2020 Sep;14(9):2022-2039.
Darolutamide/达洛鲁胺 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NOD.scid mice
LNCaP prostate cancer bone metastasis model
Oral (Darolutamide), Intravenous (Radium-223)
100 mg/kg
Darolutamide twice daily for 41 days; Radium-223 every four weeks for two doses
To evaluate the antitumor efficacy of darolutamide in combination with radium-223, showing significant reduction in serum PSA levels and tumor-induced abnormal bone formation.
Int J Mol Sci. 2024 Dec 21;25(24):13672.
CB17-Scid mice
VCaP prostate cancer xenograft model
Orally
100 mg/kg
Twice daily for 23 days
Evaluate the in vivo synergistic antitumor efficacy of PSMA-TTC with darolutamide, showing significant tumor growth inhibition (T/C values of 0.56 and 0.55) and increased PSMA expression
Clin Cancer Res. 2021 Aug 1;27(15):4367-4378.
CB17-SCID male mice
LAPC-4 cell line-derived xenograft model
Oral
100 mg/kg (bi-daily) or 200 mg/kg (once daily)
Once or twice daily for 56 days
Evaluate the inhibitory effect of Darolutamide on tumor growth in the LAPC-4 xenograft model
Int J Cancer. 2019 Sep 1;145(5):1382-1394.
CB17-SCID male mice
LAPC-4 cell line-derived xenograft model
Oral
100 mg/kg (bi-daily) or 200 mg/kg (once daily)
Once or twice daily for 56 days
To evaluate the effect of Darolutamide on tumor growth in the LAPC-4 xenograft model. Results showed that oral Darolutamide significantly inhibited tumor growth.
Int J Cancer. 2019 Sep 1;145(5):1382-1394.
NOD.scid mice
LNCaP prostate cancer bone metastasis model
Oral (Darolutamide), Intravenous (Radium-223)
100 mg/kg (Darolutamide), 330 kBq/kg (Radium-223)
Twice daily (Darolutamide), Every four weeks (Radium-223), for 41 days
To evaluate the antitumor efficacy of darolutamide in combination with radium-223, showing significant reduction in serum PSA levels and tumor-induced abnormal bone formation.
Int J Mol Sci. 2024 Dec 21;25(24):13672.
NOD.scid mice
LNCaP prostate cancer bone metastasis model
Oral (Darolutamide), Intravenous (Radium-223)
100 mg/kg (Darolutamide), 330 kBq/kg (Radium-223)
Darolutamide twice daily for 41 days; Radium-223 every four weeks for two doses
To evaluate the antitumor efficacy of darolutamide in combination with radium-223, showing significant reduction in serum PSA levels and tumor-induced abnormal bone formation.
Int J Mol Sci. 2024 Dec 21;25(24):13672.
BALB/c nude mice
Prostate cancer xenograft model
Intraperitoneal injection
20 mg/kg
Once daily for 14 days
Combination therapy of darolutamide with ferroptosis inducers (RSL-3) significantly inhibited prostate cancer tumor growth by inducing ferroptosis through the SREBP1-FASN axis.
Int J Biol Sci. 2024 Sep 3;20(12):4635-4653.
BALB/c nude mice
Prostate cancer xenograft model
Oral
50 mg/kg
Once daily for 28 days
To evaluate the effect of Darolutamide on prostate cancer xenograft model, results showed that downregulation of circRBM33 enhanced the antitumor activity of Darolutamide
Int J Biol Sci. 2023 Mar 5;19(5):1543-1563.
Male athymic mice
22RV1-LUC xenograft model
Oral gavage
50 mg/kg or 100 mg/kg
Twice weekly for 6 weeks
To evaluate the anti-tumor efficacy of ONC201 in combination with darolutamide in the 22RV1 CRPC xenograft model, demonstrating therapeutic effects.
Am J Cancer Res. 2024 Dec 25;14(12):6012-6036.
Nude mice
VCaP xenograft model
Oral
50 mg/kg
Twice daily for 37 days
Evaluate the antitumor activity of Darolutamide in a CRPC model, showing Darolutamide significantly inhibits tumor growth
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