Mudhish Ethar A, Ebrahim Hassan Y, Helal Iman E, Alhowiriny Abdullah T, El Sayed Khalid A
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, Louisiana 71201, United States.
Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
ACS Pharmacol Transl Sci. 2024 Oct 17;7(12):3902-3913. doi: 10.1021/acsptsci.4c00448. eCollection 2024 Dec 13.
Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive phenotype of prostate cancer (PC). Tryptophan oxidative catabolism by indoleamine 2,3-dioxygenase-1 (IDO1) cleaves the indole ring to kynurenine (Kyn), an endogenous ligand for the aryl hydrocarbon receptor (AhR), which activates multiple tumorigenesis pathways. The IDO1-Kyn-AhR axis is aberrantly dysregulated in mCRPC. (-)-Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid. CBD showed antitumor activities against human malignancies, including PC. CBD showed potent in vitro dose-dependent reduction of viability and clonogenicity of diverse human PC cell lines. CBD reduced the expression of IDO1 and AhR in PC cells. A daily 15 mg/kg oral dose of CBD for 30 days effectively suppressed the progression of the mCRPC CWR-R1ca-Luc cells xenografted in male nude mice. Continued CBD oral dosing for an additional 45 days suppressed the CWR-R1ca-Luc tumor locoregional and distant recurrences after the primary tumors' surgical excision. Collected CBD-treated tumors showed a reduced level of IDO1 expression. CBD-treated mice displayed a significant systemic reduction of Kyn. CBD is a novel, nonpsychoactive phytocannabinoid lead useful for the control of mCRPC via targeting the tryptophan catabolism.
转移性去势抵抗性前列腺癌（mCRPC）是前列腺癌（PC）的一种侵袭性表型。吲哚胺2,3-双加氧酶-1（IDO1）介导的色氨酸氧化分解代谢将吲哚环裂解为犬尿氨酸（Kyn），Kyn是芳烃受体（AhR）的内源性配体，可激活多种肿瘤发生途径。在mCRPC中，IDO1-Kyn-AhR轴存在异常失调。（-）-大麻二酚（CBD）是一种无精神活性的植物大麻素。CBD对包括PC在内的人类恶性肿瘤具有抗肿瘤活性。CBD在体外对多种人类PC细胞系的活力和克隆形成能力有显著的剂量依赖性降低作用。CBD降低了PC细胞中IDO1和AhR的表达。每天口服15 mg/kg CBD，持续30天，可有效抑制雄性裸鼠体内移植的mCRPC CWR-R1ca-Luc细胞的进展。继续口服CBD 45天可抑制CWR-R1ca-Luc肿瘤在原发肿瘤手术切除后的局部和远处复发。收集的经CBD处理的肿瘤显示IDO1表达水平降低。经CBD处理的小鼠体内Kyn水平显著降低。CBD是一种新型的、无精神活性的植物大麻素，可通过靶向色氨酸分解代谢来控制mCRPC。
