α-santalol, a major component of sandalwood oil inhibits growth of cultured prostate cancer cells in vitro by causing apoptosis. The present study was undertaken to determine the in vivo efficacy of α-santalol using TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice as a model. The i.p administration of α-santalol (50 mg/kg) did not cause any side effects or weight loss throughout the study. Administration of α-santalol (50 mg/kg) showed a trend in decrease in average wet weights of urogenital weights compared to control mice (∼34% decrease in α-santalol group compared to control). Furthermore, the dorsolateral sections of prostate from α-santalol-treated mice exhibited decreased cell proliferation in association with induction of apoptosis. Western blotting analysis of prostate tumor samples from α-santalol-treated group revealed an increase in the expression levels of cleaved PARP, phospho p53 (ser 15), cleaved caspase-3, cyclin B, p21 and a modest reduction in antiapoptotic protein Bcl-xL compared to control samples. In agreement with these results, α-santalol treatment resulted in G2/M cell cycle arrest in cultured prostate cancer cells. In conclusion, the present study indicates that α-santalol administration inhibits the development of prostate cancer in TRAMP mice by decreasing cell proliferation, causing cell cycle arrest, and inducing apoptosis. This study was supported by Wilkes University Type I grant, American Association of Colleges of Pharmacy and by Translational Cancer Research Center funded by South Dakota Governor's Office of Economic Development. Citation Format: Ajay Bommareddy, William Eggelston, Stacy Prelewicz, Andrea Antal, Adam L. VanWert, Hiral Patel, Aleona Chinikaylo, Linda S. Gutierrez, Santha Sreevidya, Chandradhar Dwivedi. Chemoprevention of prostate carcinogenesis in TRAMP mice by α-santalol by causing cell cycle arrest and induction of apoptosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3713. doi:10.1158/1538-7445.AM2013-3713

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α-santalol, a major component of sandalwood oil inhibits growth of cultured prostate cancer cells in vitro by causing apoptosis. The present study was undertaken to investigate the mechanistic details associated with the induction of apoptosis by α-santalol in cultured prostate cancer cells (LNCaP and PC-3). Expressions of major proteins studied in the present investigation were determined using standard Western blot protocol and analyzed by LICOR-Odyssey infra-red scanner. Activity of survivin was confirmed employing survivin ELISA kit. The cell viability was determined by trypan blue dye exclusion assay and caspase-3 activity was confirmed using caspase-3 (active) ELISA kit. Treatment of prostate cancer cells with α-santalol (20, 40 µM) resulted in the down regulation of survivin, XIAP and p-AKT (s-473) levels. Furthermore, α-santalol significantly reduced the activity of survivin as evidenced by survivin ELISA assay. Inhibition of PI3K/Akt by pharmacological inhibitor LY294002 synergized the apoptotic cell death induced by α-santalol as determined by cell viability, active caspase-3 activity and expression of cleaved PARP, caspase-3 levels. In conclusion, the present study reveals that α-santalol downregulates activity and expression of survivin and that inhibition of PI3K/Akt pathway synergize the apoptotic cell death by downregulating survivin. This study was supported by Mentoring Task Force, Type I grant by Wilkes University and by Translational Cancer Research Center funded by South Dakota Governor's Office of Economic Development. Citation Format: Ajay Bommareddy, Lauren Lockus, Jonathan Seward, William Eggelston, Stacy Prelewicz, Andrea Antal, Sarah Fillman, Christian Castro, Adam L. VanWert, Sreevidya Santha, Chandradhar Dwivedi. Akt/survivin pathway inhibition synergizes the apoptotic cell death induced by A-santalol in prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2152. doi:10.1158/1538-7445.AM2014-2152

Background Ibrutinib is a small-molecule inhibitor of Bruton tyrosine kinase (BTK) approved for various B-cell malignancies and cGVHD. Rates of serious infection—defined as requiring hospitalization or parenteral antimicrobials— and invasive fungal infection (IFI) in patients on ibrutinib are as high as 11.4% and 4.2% respectively (Varughese T, et al. Clin Infect Dis 2018;67(5):687-92), which may be related to off-target inhibition of interleukin-2-inducible T-cell kinase or macrophage function. Methods We retrospectively reviewed infection complications in patients receiving ibrutinib at our institution between 06/01/2014 and 08/31/2019, including patients who received single-agent or combination ibrutinib. In this study, serious infection was defined as above, or a diagnosis of pneumonia regardless of hospitalization or parenteral antimicrobial therapy. Logistic regression was used to identify risk factors. Results Baseline characteristics of 134 included patients are in Table 1. Infection and serious infection occurred in 96 (72%) and 48 (36%) patients, respectively. When pneumonia was not included as a criterion for serious infection, the serious infection rate was 22%. Prior allogeneic stem cell transplant (allo-HSCT) (OR 4.50; 95% CI 1.19 – 17.00) and corticosteroid use (OR 5.42; 95% CI 1.49 – 19.82) were significant risk factors for serious infection without pneumonia (Table 2). Of 37 patients (28%) who received primary HSV/VZV prophylaxis with acyclovir, there was one case of suspected herpes zoster infection (3%). IFI developed in 7 patients (5%): 5 with Pneumocystis jirovecii pneumonia (PJP), 1 with invasive aspergillosis, and 1 with a filamentous fungus, species unknown. Other identified organisms are detailed in Figure 1. Classical risk factors for IFI, including diabetes, allo-HSCT, and concurrent corticosteroid use, were not significant predictors in this group. Table 1. Baseline Characteristics Table 2. Risk Factor Analysis Figure 1. Identified Organisms in Serious Infection Conclusion Serious infections developed at a higher rate than previously reported in the literature, with IFI rates similar to those previously described. Prior allo-HSCT and steroid use were found to be risk factors for serious infection without pneumonia. Treating physicians should have a high index of suspicion for pneumonia, IFI, and PJP in this population. Disclosures All Authors: No reported disclosures