MDV3100(enzalutamide) is a second-generation AR antagonist with an IC50 of 36nM in LNCaP prostate cells[1,2]. MDV3100 could reduce androgen binding to AR, inhibit AR transport to the nucleus and prevent the binding of AR to androgen response elements[2].
MDV3100 combined with TKIs exerted a synergistic effect on a variety of PCa cells. MDV3100 combined with afatinib could suppress the proliferation and migration of 22RV1 cells, as well as cause their cell cycle arrest and apoptosis[2]. MDV3100 probed the bone microenvironment that led to stronger cancer cell adaptive responses and osteomimicry than bicalutamide. MDV3100 presented with better treatment response, in line with MDV3100 delaying time to bone-related events and MDV3100 extending survival in mCRPC[3]. MDV3100 promoted macrophage migration to PCa cells that consequently led to enhanced PCa cell invasion in human (C4-2B/THP1) and mouse (TRAMP-C1/RAW264.7) PCa cells–macrophages co-culture systems[4]
MDV3100 combination with KIF15 inhibitors significantly suppressed MDV3100-resistant PCa cell growth and xenograft progression. KIF15 inhibitors may enhance the sensitivity of prostate tumors to MDV3100 treatment, and rationalize a combination therapy of KIF15 inhibitors with MDV3100 to treat CRPC patients [5]. The antitumor efficacy of MDV3100 can be substantially improved by methylselenol prodrug, which also downregulates AR-FL and AR-Vs in vivo[6]. MDV3100 prolonged overall survival of metastatic CRPC patients who progressed after chemotherapy in a Phase III trial[7]
参考文献:
[1]. Tran C, Ouk S, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324(5928):787-790.
[2]. Li J, Wu H, et al. Enhanced antitumor efficacy by combining afatinib with MDV3100 in castration-resistant prostate cancer. Pharmazie. 2022;77(2):59-66.
[3]. Bock N, Kryza T, et al. In vitro engineering of a bone metastases model allows for study of the effects of antiandrogen therapies in advanced prostate cancer. Sci Adv. 2021;7(27):eabg2564.
[4]. Lin TH, Izumi K, et al. Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 (Enzalutamide) or Casodex (Bicalutamide) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling. Cell Death Dis. 2013;4(8):e764.
[5]. Gao L, Zhang W, et al. KIF15-Mediated Stabilization of AR and AR-V7 Contributes to Enzalutamide Resistance in Prostate Cancer. Cancer Res. 2021;81(4):1026-1039.
[6]. Zhan Y, Cao B, et al. Methylselenol prodrug enhances MDV3100 efficacy for treatment of castration-resistant prostate cancer. Int J Cancer. 2013;133(9):2225-2233.
[7]. Scher HI, Fizazi K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187-1197.
MDV3100(enzalutamide) 是第二代 AR 拮抗剂，在 LNCaP 前列腺细胞中的 IC50 为 36nM[1,2]。 MDV3100可减少雄激素与AR的结合，抑制AR向细胞核的转运，阻止AR与雄激素反应元件的结合[2]。
MDV3100 联合 TKIs 对多种 PCa 细胞产生协同作用。 MDV3100联合阿法替尼可抑制22RV1细胞的增殖和迁移，并引起细胞周期停滞和凋亡[2]。 MDV3100 探测了导致比比卡鲁胺更强的癌细胞适应性反应和骨拟态的骨微环境。 MDV3100 表现出更好的治疗反应，与 MDV3100 延迟骨骼相关事件的时间和 MDV3100 延长 mCRPC 的生存期[3] 一致。 MDV3100 促进巨噬细胞向 PCa 细胞迁移，从而导致增强 PCa 细胞在人 (C4-2B/THP1) 和小鼠 (TRAMP-C1/RAW264.7) PCa 细胞-巨噬细胞共培养系统中的侵袭[4]< /sup>
MDV3100 与 KIF15 抑制剂的组合显着抑制了 MDV3100 抗性 PCa 细胞生长和异种移植进展。 KIF15 抑制剂可增强前列腺肿瘤对 MDV3100 治疗的敏感性，并合理化 KIF15 抑制剂与 MDV3100 联合治疗 CRPC 患者[5]。甲基硒醇前体药物可显着提高 MDV3100 的抗肿瘤功效，甲基硒醇前体药物还可在体内下调 AR-FL 和 AR-Vs[6]。在一项 III 期试验中，MDV3100 延长了化疗后进展的转移性 CRPC 患者的总生存期[7]
| Cell experiment [1]: | |
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Cell lines |
LNCap, C4-2, PC3, DU145 and 22RV1 cell lines |
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Preparation Method |
Different concentration gradients of various compounds (MDV3100， Afatinib, Erlotinib, Sorafenib, Gefitinib) were added to each group. The control group was treated with 0.1% DMSO. The cells were continuously treated for 72h, then supplemented with 10μL MTT solution for 4h. |
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Reaction Conditions |
0-100μM |
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Applications |
MDV3100 moderately inhibited the proliferation of PC3 and DU145 cells, both of which are androgen-independent PCa cell lines. Moreover, it also inhibited proliferation in the androgen-dependent LNCap, 22RV1 and C4-2 cell lines, with IC50 values of 1.74, 39.79 and 49.17μM, respectively. |
| Animal experiment [2]: | |
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Animal models |
Male nude mice, Four-week-old |
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Preparation Method |
6.0×106 C4-2B-ENZR cells, or 3.0×106 22Rv1 cells were injected subcutaneously into the mice. After the mice were surgically castrated, they were randomized into four groups (n=5/group) and treated as follows: (1) vehicle control (PBS, i.p.); (2) MDV3100 (10mg/kg, p.o.); (3) KIF15-IN-1 (10mg/kg, i.p.); (4) MDV3100 (10mg/kg, p.o.) + KIF15-IN-1 (10mg/kg, i.p.). Tumor tissues were harvested and weighed after 4 weeks of treatment. Tumor size was measured twice a week. |
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Dosage form |
(1) vehicle control (PBS, i.p.); (2) MDV3100 (10mg/kg, p.o.); (3) KIF15-IN-1 (10mg/kg, i.p.); (4) MDV3100 (10mg/kg, p.o.) + KIF15-IN-1 (10mg/kg, i.p.)/p> |
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Applications |
C4-2B-ENZR and 22Rv1 tumors treated with MDV3100 alone showed no difference to the control groups (MDV3100 vs. control; C4-2B-ENZR, 1145±119.3 vs. 1269±182mm3; 22Rv1, 1455±127.5 vs. 1547±97.93mm3). However, KIF15-IN-1 treatment reduced the tumor volume (C4-2B-ENZR, 633.5±85.3mm3; 22Rv1, 905.4±124.5mm3), and the combination of MDV3100 and KIF15-IN-1 induced further inhibition in tumor growth (C4-2B-ENZR,246.3±67.42mm3; 22Rv1, 481.5±87.82mm3). |
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参考文献: [1]. Li J, Wu H, et al. Enhanced antitumor efficacy by combining afatinib with MDV3100 in castration-resistant prostate cancer. Pharmazie. 2022;77(2):59-66. [2]. Gao L, Zhang W, et al. KIF15-Mediated Stabilization of AR and AR-V7 Contributes to Enzalutamide Resistance in Prostate Cancer. Cancer Res. 2021;81(4):1026-1039. |
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