Abstract
Prostate cancer is the leading cause of cancer death among men globally, with castration development resistant contributing significantly to treatment failure and death. By analyzing the differentially expressed genes between castration-induced regression nadir and castration-resistant regrowth of the prostate, we identified soluble guanylate cyclase 1 subunit alpha as biologically significant to driving castration-resistant prostate cancer. A virtual screening of the modeled protein against 242 experimentally-validated anti-prostate cancer phytochemicals revealed potential drug inhibitors. Although, the identified four non-synonymous somatic point mutations of the human soluble guanylate cyclase 1 gene could alter its form and ligand binding ability, our analysis identified compounds that could effectively inhibit the mutants together with wild-type. Of the identified phytochemicals, (8′R)-neochrome and (8′S)-neochrome derived from the Spinach (Spinacia oleracea) showed the highest binding energies against the wild and mutant proteins. Our results identified the neochromes and other phytochemicals as leads in pharmacotherapy and as nutraceuticals in management and prevention of castration-resistance prostate cancers.
Highlights
Malignancy of the prostate is the most commonly diagnosed cancer in men worldwide and ranked second as the cause of death, in cancer-related diseases [1]
This state is referred to as castrationresistant prostate cancer (CRPC), and it is characterized by loss of ability to respond to androgen deprivation therapy and the recurrence of prostate cancer and subsequent metastasis [7]
The normalized Affymetrix data were used to determine the biological significance of each gene in driving castration-induced regression of prostate cancer into castration-resistant regrowth
Summary
Malignancy of the prostate is the most commonly diagnosed cancer in men worldwide and ranked second as the cause of death, in cancer-related diseases [1]. In order to understand the factors that underlie the development of CRPC, previous studies have employed differential gene expression analysis to characterize the genetic and molecular factors that drive a prostate cell into being resistant to castration [18]. This study analyzed the differentially expressed genes that drive CRPC and identified novel drug targets, as well as putative phytochemicals that can serve as inhibitors for the identified targets and its somatic variants.
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