Abstract 5080: Decursinol intercepts LNCaP human prostate cancer xenograft growth bypassing androgen receptor-prostate specific antigen axis

Abstract

Abstract The slow-growing nature of most prostate cancers (PCa) provides multiple windows of opportunity to block or delay disease progression to reduce patient suffering and mortality. This is especially true following the failure of radical prostatectomy (RP) and radiation therapy (RT) of localized PCa with biochemical recurrence detectable by a rise in plasma/serum prostate specific antigen (PSA) and prior to androgen deprivation therapy (ADT). Costly aside, ADT is not curative and causes many adverse effects which negatively affect the quality of life of the patients. Currently there is no standard of care regimen for post-RP/RT patients with rising PSA to stump the trajectory. Many patients seek food or supplement-based interventions with a hope to delay ADT. The root of Korean Angelica gigas Nakai (AGN) contains decursin (D) and its isomer decursinol angelate (DA) as the major pyranocoumarins. We have previously shown that daily gavage of AGN and D/DA suppressed the growth of androgen receptor (AR)+ and AR- xenograft tumors and TRAMP neuroendocrine carcinomas. We also showed that D/DA rapidly converted to decursinol (DOH) in rodents and humans, and DOH inhibited LNCaP-AR xenograft growth, therefore the likely in vivo active compound. To assess merit of DOH to intercept recurrent PCa, we tested in NSG SCID mice bearing s.c. inoculated human LNCaP PCa xenograft (a) its efficacy to inhibit tumor growth and b) serum PSA as an efficacy metric. A day prior to start of daily DOH gavage (120 mg/kg body weight) for the tumor bearing mice, blood was drawn through tail vein for baseline PSA. After 4 weeks, the mice were bled for post-PSA and their tumors/prostate were dissected and weighed. Gavage delivered DOH did not affect body weight, but significantly reduced the tumor volume and weight without decreasing the weight of the prostate, distinct from ADT drugs. The post-PSA showed a significant and tight linear correlation with the tumor weight for mice in the vehicle group (r2=0.94, n=6). Five of 7 DOH-treated mice showed post-PSA/tumor weight plot on the same regression line but two non-responders displayed exaggerated post-PSA/weight ratio. The much slower PSA rise in the DOH-responders (2.9 fold, n=5) than vehicle group (7.8 fold, n=6, p=0.031) directly reflected a reduction of tumor burden by DOH treatment. Histological (H&E) analysis showed that DOH responder tumors had greater necrosis and less hemorrhage than non-responders and control tumors. Immunohistochemistry staining for AR and PSA did not detect any reduction of either protein in the responder tumors which contained reduced mitotic marker phospho-histone 3. Our preclinical modeling therefore suggests serum PSA as a reliable efficacy metric for DOH-mediated PCa interception in post-PR/RT patients, involving mitosis inhibition and necrosis without affecting the cancer AR/PSA axis. Citation Format: Sangyub Kim, Chongtao Qin, Deepkamal N. Karelia, Arati Sharma, Cheng Jiang, Junxuan Lu. Decursinol intercepts LNCaP human prostate cancer xenograft growth bypassing androgen receptor-prostate specific antigen axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5080.