You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) II1 Apr 2017PD37-08 ENHANCING THE EFFICACY OF VALPROIC ACID IN PROSTATE CANCER CELLS WITH NUTRITIONAL SUPPLEMENTS Wasim H. Chowdhury, Anna-Barbara O'James, Abhinav Sidana, Jatindar Goyal, Daniel Oh, Grace I. Todd, Mizanur Rahman, and Ronald Rodriguez Wasim H. ChowdhuryWasim H. Chowdhury More articles by this author , Anna-Barbara O'JamesAnna-Barbara O'James More articles by this author , Abhinav SidanaAbhinav Sidana More articles by this author , Jatindar GoyalJatindar Goyal More articles by this author , Daniel OhDaniel Oh More articles by this author , Grace I. ToddGrace I. Todd More articles by this author , Mizanur RahmanMizanur Rahman More articles by this author , and Ronald RodriguezRonald Rodriguez More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1570AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The use of histone deacetylase inhibitors (HDACIs) in treating Castrate Resistant Prostate Cancer is well studied. We have previously published the beneficial effects of treating Bladder as well as Prostate cancer (CaP) in animal models with Valproic acid (VPA), a type I HDACI. Docosahexaenoic acid (DHA), an ω-3 fatty acid, is a primary structural component of the human brain, skin, sperm, testicles and retina. Fish oil, a popular nutritional supplement, is a major source of DHA. Over two decades of research show favorable effects of DHA on bone health, as well as a chemo-sensitizing agent in treating cancer. Here we report an interim analysis of a randomized, controlled phase II study of VPA in patients with non-metastatic biochemical progression of (BCR) CaP, and the utility of combining DHA with VPA in potentially reducing side effects. METHODS Patients with non-metastatic BCR CaP were screened for eligibility and randomized into either observation or VPA (oral, twice daily) arms. Serum VPA and PSA levels were monitored bi-weekly and monthly. We also investigated methods of minimizing the side effects of VPA while maintaining efficacy. RESULTS Treatment with VPA resulted in an increased PSA doubling time (PSADT) in patients from 4.02 to 40.67 months, while the PSADT in the control group stayed relatively unchanged at 6.34 to 6.95 months. However, the treatment group suffered from debilitating fatigue and lethargy at the dose required for effective treatment. As such we investigated options of reducing the VPA dose while maintaining efficacy. Both in vitro and in a mouse model we demonstrate that combining VPA with DHA has a greater efficacy. In the in vitro model we show that in the combination we can reduce the dose of VPA by half and still maintain similar efficacy. Also chronic treatment with the combination had a much greater effect on cell kill as opposed to acute treatment. Moreover, folic acid, another common supplement, enhances cell kill by the combination. CONCLUSIONS Based on our studies VPA could be used in combination with DHA, a supplement, to delay or even prevent the use of hormone therapy in prostate cancer patients with BCR. In addition, both clinicians and patients should be made aware of the effects of dietary supplements, as they can positively or potentially negatively affect the efficacy of certain drugs. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e676-e677 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Wasim H. Chowdhury More articles by this author Anna-Barbara O'James More articles by this author Abhinav Sidana More articles by this author Jatindar Goyal More articles by this author Daniel Oh More articles by this author Grace I. Todd More articles by this author Mizanur Rahman More articles by this author Ronald Rodriguez More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Abstract Circulating tumor cells (CTCs) offer a new strategy to access cancer tissue through a simple blood sample. CTCs levels can be predictive of overall survival in patients with metastatic cancers and changes in CTC levels following therapy can be indicative of therapeutic response. Moreover, CTCs may provide a means to select patients for specific therapeutic approaches by identifying active or susceptible pathways. However, most of the current methods for detecting CTCs have limitations including the need for specialized equipment, the reliance on cell capture through cell surface markers such as EpCAM, limited sensitivity, the inability to distinguish cancer from normal, tissue type, active pathways, or cell viability. Here we present a novel CTC detection approach which applies tissue-selective replicating adenoviruses and highly sensitive secreted reporters. These Circulating Tumor Cell Reporter Viruses (CTC-RVs) were generated by replacing the early viral E1A gene promoter with the prostate specific probasin promoter and prostate specific antigen enhancer (PSE-PBN). The secreted reporter gene, humanized metridia luciferase (hMLuc), was incorporated into the viral major late transcriptional unit, at the fiber gene locus, to limit reporter expression to only those cells in which the virus has replicated. Cells from total blood, including mononuclear cells and CTCs, are placed in tissue culture media and infected with the CTC-RV. After three days, viral replication dramatically amplifies reporter levels within infected prostate cancer cells with active Androgen Receptor pathways leading to the secretion of the bioluminescent reporter. Non-prostatic cells will not amplify the virus or express the reporter gene. LNCaP cellular dilution study results show that as few as five CTCs per million lymphocytes cells could be readily detected without any cell isolation. LNCaP cells diluted in healthy volunteer blood samples identified the optimal time and dosing conditions. Initial studies in clinical samples support the detection of viable CTCs with this assay. This new approach offers a means to quantify live CTC levels in a tissue-specific manner, without the need for cell capture, through the use of a secreted signal which can be detected separate from the large blood cell population. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2392. doi:1538-7445.AM2012-2392