The incidence of prostate cancer (PCa) is rising in the U.S., with nearly 290,000 diagnoses projected for 2023 [1]. This escalation calls for innovative PCa therapies. One prospective therapy is Selenium (Se), the essential trace element, which has been studied as both a chemopreventative and chemotoxic agent against PCa [2], [3], [4], [5], [6]. Se appears in myriad chemical compounds, each with markedly different effects on PCa cell genome and proteome expression [7], [8], [9], [10]. Details on the distinct efficacies of Se compounds are given in this review and perspective [11], [12].

Recognizing the recent success of combination therapies in oncology, our study focuses on the synergistic potential of three different Se compounds against the PC-3 PCa cell line: methylseleninic acid (MSA), selenite, and nano-Se. These compounds directly activate cell death in the PC-3 cell line [4], [8], [13], [14]. Both MSA and Selenite act as potent apoptosis inducers in PCa cells, MSA via sensitization of tumor cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and selenite via AKT inhibition and upregulation of proapoptotic factors [15], [16]. Meanwhile, nano-Se activates tumor necrosis factor (TNF) in PCa cells to induce necroptosis, a form of non-apoptotic cell death [17].

While the literature is replete with Se effects on PCa cells, our research adopts the novel approach of Mixture Design Response Surface Methodology (MDRSM) to optimize Se compound combinations against PCa. Although MDRSM has seen limited application in cancer research, our results definitively underscore its practicality [18], [19].

Subsequent sections detail our application of MDRSM to identify the ideal combinatorial ratio of MSA, selenite, and nano-Se against the PC-3 cell line. Our results emphasize the differential effects of Se compounds on PCa and the potential of these chemicals in treating prostate malignancy. We hope this research will guide the design of novel therapeutics against PCa, decreasing the incidence of PCa and prolonging patient health.