Oseni, Saheed Oluwasina

The oncogenic role of many of inflammatory genes in prostate cancer (PCa) remains unexplored despite the increasing association of chronic inflammation with PCa initiation, progression, and therapy resistance. The overarching goal of this project was to identify dysregulated inflammatory genes that correlate with PCa progression and seek to understand their molecular mechanisms and the therapeutic potential of targeting them. To achieve this, we utilized cutting-edge integrative (epi) genomic and transcriptomic techniques to identify and characterize inflammatory genes whose deregulation or (epi) genetic alterations correlate with PCa progression.
Weighted Gene Co-expression Network Analysis and other multivariate analysis techniques identified IRAK1 as one of the inflammatory signatures found to be overexpressed in over 80% of prostate adenocarcinoma (PRAD) samples.
We also explored the diagnostic and prognostic potential of IRAK1 as a biomarker using Kaplan Meier Survival Analysis and AUROC Analysis. DNA methylation analysis showed that IRAK1 is hypomethylated and found to negatively correlate with its overexpression in PRAD patients. We also found some missense and truncated mutations in some patients and reported a high level of IRAK1 gene amplification in castration-resistant and neuroendocrine PCa patients.

In 2015, an estimated 220, 800 new cases and 27, 540 deaths are expected to occur due to prostate
cancer in US men, thus adding to the economic burden of the over 2.6 million men currently battling the
disease. Plethora of studies have demonstrated the phytotherapeutic potentials of beta-lapachone, a
phytochemical compound derived from the bark of the lapacho tree, native to South America. Betalapachone
(β-lap) has been shown to exhibit its anti-cancer effects majorly by the futile cycling between
the oxidized and the two electron reduction of β-lap mediated by NAD(P)H:quinone oxidoreductase
(NQO1) resulting in the generation of reactive oxygen species (ROS) using NADH or NAD(P) as
electron sources. β-lap is known to selectively kill human cancer cells, since NQO1 is expressed more
abundantly in numerous human solid tumors than in the adjacent normal tissues; NQO1 has been
shown to be exceptionally under expressed in hormone dependent prostate cancer cells (LNCaP)
compared to the hormone independent prostate cancer cells (PC3). This study was aimed to
investigate the enhancing effects of very low dose radiation (VLDR (20mGy)) derived from a
pyroelectric crystal generator on the phytotherapeutic activity of beta-lapachone in LNCaP cell line in
vitro accessed by MTT and Trypan blue assay. Treatment-induced intracellular levels of ROS were also
assessed using Nitro blue tetrazolium assay. NQO1 activities in LNCaP cells were also investigated
following treatment with VLDR and/or β-lap using Dicoumarol (NQO1 inhibitor). Results indicate that
LNCaP cells respond significantly to combined treatments compared to single treatments.

Prostate cancer after many years is still the second most common cancer in American
men with about 233,000 new cases and 29,480 deaths estimated to be occurring in 2014.
Despite the wide spectra of reports demonstrating the anti-cancer phytotherapeutic potentials of
beta-lapachone and soybean-derived genistein in various tumors, little emphasis had been placed
on their synergistic effects in androgen-independent PC3 and androgen-dependent LNCaP
prostate cancer cell lines. In this study, we aim to characterize the combined effects of genistein
and b-lapachone on the phyto/chemosensitivity of LNCaP and PC3 human prostate cancer cells
in-vitro, using MTT assay and LDH assay to study treatment-induced growth inhibition and
cytotoxicity. Annexin-V-FITC and PI-TUNEL assays were also used to determine the potential
treatment-induced apoptosis and/or necrosis.
Our results revealed that both PC3 and LNCaP are phytosensitive to both single and combined
treatments, though time-and dose-dependent. We observed that our treatments induced dual
death pathways-apoptosis and necrosis-in both cell types and also observed that growth
inhibition in both correlated positively with cell death in which, b-lapachone and genistein
induced cell cycle arrest at the G1 and/or S phase and G2–M checkpoints respectively.
Invariably, our results indicate that combination treatments with b-lapachone and genistein are
more potent in killing both PC3 and LNCaP cancer cells than treatment with either genistein or
b-lapachone alone. Our current results are therefore in agreement with the hypothesis that drugcombinations
that target cell cycles at different critical checkpoints are more effective in causing
cell death.

An estimated 220,800 new prostate cancer cases and 27,540 deaths are expected to occur in US men by the end of 2015. Despite the increased treatment modes for prostate cancer, there is still no definite cure, and prognosis remains, at best, cautiously optimistic. The explicit amalgamation of two or more cancer therapeutic modalities such as surgery, radiation, and chemotherapy, has been one of the main interests of clinical investigation for several decades. Genistein (GN) and Beta-lapachone (BL) are two of the most promising anticancer phytochemical compounds. However, the anticancer activities of BL have been correlated with the enzyme activity of NQO1. The aim of this study was to investigate the enhancing effects of VLDR derived from a portable pyroelectric crystal generator on the chemopreventive and/or chemotherapeutic effects of GN and BL in NQO1+ PC3 and NQO1± (deficient) LNCaP prostate cancer cells (PCa) in vitro. The combination treat ment-induced cytotoxicity was investigated via MTT and Trypan blue exclusion assays. Dicoumarol (an NQO1 inhibitor) was co-administered to assess the effect of VLDR on NQO1 modulation. Nitro-blue tetrazolium assay was used to assess the intracellular ROS levels. Fluorescence microscopy was also used to assess the mode of cell death. In this study, a novel quantitative modeling approach was employed to comparably assess the cytotoxic effects of specific drugs used alone or in combinations with VLDR and to predict the potential synergistic therapeutic combinations. The data suggests that VLDR induced a rise in ROS levels, followed by upregulation in NQO1 levels. Pharmacodynamic indices were developed to quantify and characterize the combination treatment as synergistic, additive or antagonistic per dose or time-interval. Synergism was found to be dose and time-interval dependent. The major mode of cell death by this combination therapeutic regimen was found to be via apoptosis . In conclusion, our results confirm that VLDR enhanced cytotoxicity effects of both drugs dose- and time-dependently.