BACKGROUND: The rising incidence of prostate cancer in the U.S. necessitates innovative therapeutic approaches to this disease. Though extensive research has studied Selenium as an anticarcinogen against prostate cancer, results have varied due to overlooked experimental confounds. Recent studies have identified differential effects of various selenium compounds on prostate cancer cells. This study leverages Mixture Design Response Surface Methodology to characterize the ideal combination of select Se forms against the PC-3 prostate cancer cell line.
METHODS: The PC-3 cell line was chosen as a model for its representation of advanced-stage malignancy. Three Se compounds-sodium selenite, methylseleninic acid, and nano-selenium-were selected for their promising antineoplastic potential. Nano-Se particles were synthesized and subsequently characterized by transmission electron microscopy. Cells were cultured, treated with Se compounds, and assessed for viability using an Alamar Blue Assay. IC50 values of individual Se compounds were determined, and treatment combinations evaluated. In collaboration with statical modeling experts, MDRSM was utilized to optimize Se compound combinations.
RESULTS: Absolute IC50 values were identified for methylseleninic acid (5.01 μmol/L), sodium selenite (13.8 μmol/L), and nano-selenium (14.6 μmol/L). Combining methylseleninic acid and sodium selenite resulted in only 5% PC-3 cell viability, whereas individual treatments reduced viability by approximately 45%. Among the tested mixtures, the 50:50 combination of MSA and sodium selenite most effectively decreased PC-3 cell viability. Regression analysis indicated the special cubic model had a strong fit (multiple r² = 0.9853), predicting maximum cell viability reduction from the methylseleninic acid and selenite mixture.
CONCLUSIONS: The specific form of Selenium plays a pivotal role in determining its physiological effects and therapeutic potential against prostate cancer. All three selenium compounds showed variable antineoplastic effects, with a 50:50 mixture of methylseleninic acid and selenite exhibiting optimal results. Nano-selenium, when combined with selenite, showed no additive effect, implying a shared mechanism of action. Our research underscores the critical need to consider Se compound forms as distinct entities in prostate cancer treatment and encourages further exploration of Se compounds against prostate cancer.

Selenium-containing agents showed novel anticancer activity by triggering pro-oxidative mechanism. Studies confirmed that methylseleninic acid (MeSe) displayed broad-spectrum anti-tumor activity against kinds of human cancers. However, the anticancer effects and mechanism of MeSe against human glioma growth have not been explored yet. Herein, the present study showed that MeSeA dose-dependently inhibited U251 and U87 human glioma cells growth in vitro. Flow cytometry analysis indicated that MeSe induced significant U251 cells apoptosis with a dose-dependent manner, followed by the activation of caspase-7, caspase-9 and caspase-3. Immunofluorescence staining revealed that MeSe time-dependently caused reactive oxide species (ROS) accumulation and subsequently resulted in oxidative damage, as convinced by the increased phosphorylation level of Ser428-ATR, Ser1981-ATM, Ser15-p53 and Ser139-histone. ROS inhibition by glutathione (GSH) effectively attenuated MeSe-induced ROS generation, oxidative damage, caspase-3 activation and cytotoxicity, indicating that ROS was an upstream factor involved in MeSe-mediated anticancer mechanism in glioma. Importantly, MeSe administration in nude mice significantly inhibited glioma growth in vivo by inducing apoptosis through triggering oxidative damage. Taken together, our findings validated the possibility that MeSe as a selenium-containing can act as potential tumor chemotherapy agent for therapy of human glioma.

COVID-19 patients suffer from the detrimental effects of cytokine storm and not much success has been achieved to overcome this issue. We sought to test the ability of selenium to reduce the impact of two important cytokine storm players: IL-6 and TNF-α. The effects of four selenium compounds on the secretion of these cytokines from THP-1 macrophages were evaluated in vitro following an LPS challenge. Also, the potential impact of methylseleninic acid (MSeA) on Nrf2 and IκBα was determined after a short treatment of THP-1 macrophages. MSeA was found to be the most potent selenium form among the four selenium compounds tested that reduced the levels of IL-6 and TNF-α secreted by THP-1 macrophages. In addition, an increase in Nrf2 and decrease in pIκBα in human macrophages was observed following MSeA treatment. Our data indicate that COVID-19 patients might benefit from the addition of MSeA to the standard therapy due to its ability to suppress the key players in the cytokine storm.

Past chemopreventive human trials on dietary selenium supplements produced controversial outcomes. They largely employed selenomethionine (SeM)-based diets. SeM was less toxic than selenite or methylseleninic acid (MSeA) to lung cancer cells. We thus investigated the toxic action of these Se agents in two non-small cell lung cancer (NSCLC) cell lines and ex vivo organotypic cultures (OTC) of NSCLC patient lung tissues. Stable isotope-resolved metabolomics (SIRM) using 13C6-glucose and 13C5,15N2-glutamine tracers with gene knockdowns were employed to examine metabolic dysregulations associated with cell type- and treatment-dependent phenotypic changes. Inhibition of key anaplerotic processes, pyruvate carboxylation (PyC) and glutaminolysis were elicited by exposure to MSeA and selenite but not by SeM. They were accompanied by distinct anabolic dysregulation and reflected cell type-dependent changes in proliferation/death/cell cycle arrest. NSCLC OTC showed similar responses of PyC and/or glutaminolysis to the three agents, which correlated with tissue damages. Altogether, we found differential perturbations in anaplerosis-fueled anabolic pathways to underlie the distinct anti-cancer actions of the three Se agents, which could also explain the failure of SeM-based chemoprevention trials.

Acquired resistance compromises the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-based therapy for non-small cell lung cancer (NSCLC), and activation of hepatocyte growth factor receptor (MET) is one of the pivotal strategies for cancer cells to acquire refractory phenotype. However, the mechanisms involved in regulating MET activity remain to be further elucidated. Using gefitinib-resistant HCC827GR cell line as a model, we unraveled that the dysregulated amino acid metabolisms reflected by elevated expression of cysteine-preferring transporter 2 (ASCT2), cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) and asparagine synthetase (ASNS) might contribute to survival advantage of HCC827GR cells, and rendered the cells more sensitive to asparagine (ASN) deprivation compared to parental HCC827 cells. We further identified that the increased ASNS expression is a contributing factor for the activation of MET in HCC827GR cells. More importantly, we found that methylseleninic acid (MSeA), a precursor of methylselenol, effectively suppressed tumor growth in HCC827GR xenograft model, which is associated with decrease of intracellular ASN content along with inactivation of MET- T-lymphokine-activated killer cell-originated protein kinase (TOPK) signaling axis. Finally, we demonstrated that combination of MSeA and gefitinib induced a synergistic growth inhibition in HCC827GR cells. The findings of our work reveal that ASN-MET-TOPK signaling axis as a novel mechanism contributed to gefitinib-resistance and combined utilization of gefitinib and MSeA holds potential to improve the efficacy for gefitinib-resistant NSCLC.

As the most common selenium derivative, methylseleninic acid (MSA) has attracted wide attention. Its apoptotic induction ability and the possible molecular mechanism in human bladder cancer (BC) J82 and T24 cells were investigated in the present study. We found that the survival of J82 and T24 cells were inhibited in a dose-dependent manner after MSA treatment. Propidium iodide (PI) staining and Annexin V-fluorescein isothiocyanate/PI double staining clarified that MSA stocked cells at G2 /M phase and caused apoptosis in J82 and T24 cells. Further, typical morphological features of apoptotic cells were also observed. Accumulation of reactive oxygen species (ROS) and loss of mitochondrial membrane potential were also detected by dichlorodihydrofluorescein diacetate and Rhodamin123 staining. Meanwhile, pretreatment with N-acetylcysteine, an ROS scavenging agent, found that the apoptosis of BC cells induced by MSA was related to the production of ROS. Western blot analysis results showed that MSA interrupted Bax/Bcl-2 balance, stimulated cytochrome c release into the cytoplasm, activated caspase-9 and caspase-3, and finally induced the apoptosis of the BC cells. These findings demonstrated that MSA was able to induce apoptosis in J82 and T24 cells through ROS-mediated mitochondrial apoptosis.

BACKGROUND: Breast cancer (BC) accounts for the majority of cancers among the female population. Anomalous activation of various signaling pathways has become an issue of concern. The JAK-STAT signaling pathway is activated in numerous cancers, including BC. STAT3 is widely involved in BCs, as 40 % of BCs display phosphorylated STAT3. JAK-STAT signaling is crucial for proliferation, survival, metastasis and other cellular events associated with the tumor microenvironment. Hence, targeting this pathway has become an area of interest among researchers.
RESULTS: This review article focuses on the role of STAT3 in the initiation, proliferation, progression and metastasis of BC. The roles of various phytochemicals, synthetic molecules and biologicals against JAK-STAT and STAT3 in various cancers have been discussed, with special emphasis on BC.
CONCLUSIONS: JAK and STAT3 are involved in various phases from initiation to metastasis, and targeting this pathway is a promising approach to inhibit the various stages of BC development and to prevent metastasis. A number of phytochemicals and synthetic and biological molecules have demonstrated potential inhibitory effects on JAK and STAT3, thereby paving the way for the development of better therapeutics against BC.

It is known that seven mammalian selenoproteins are localized in the endoplasmic reticulum: SELENOM, SELENOT, SELENOF, SELENOK, SELENOS, SELENON, and DIO2. Among them, SELENOM and SELENOT are the least studied; therefore, the study of their function using the widespread method of suppressing the expression of genes encoding these proteins and the activity of the enzymes themselves by RNA interference is of great interest. We have shown that a decrease in the expression of SELENOM and SELENOT mRNA in the A-172 human glioblastoma cell line by more than 10 times and the quantitative content of enzymes by more than 3 times leads to ER stress, expressed as a decrease in the ER capacity for storing Ca2+ ions. At the level of regulation of apoptotic processes, SELENOM knockdown leads to an increase in the expression of pro-apoptotic CHOP, GADD34, PUMA, and BIM genes, but a compensatory increase in the levels of SELENOT and antioxidant genes from the group of glutathione peroxidases and thioredoxins did not induce cell death. Knockdown of SELENOT had the opposite effect, reducing the expression of pro-apoptotic proteins and regulating the level of a smaller number of genes encoding antioxidant enzymes, which also did not affect the baseline level of apoptosis in the studied cells. At the same time, ER stress induced by MSA or SeNPs induced a more pronounced pro-apoptotic effect in SELENOT knockdown cells through suppression of the expression of selenium-containing antioxidant proteins. Thus, in this work, for the first time, the mechanisms of fine regulation of the processes of apoptosis, cell proliferation, and ER stress by two ER resident proteins, SELENOM and SELENOT, are touched upon, which is not only fundamental but also applied to clinical importance due to the close relationship between the calcium signaling system of cells, folding proteins-regulators of apoptosis and cell survival pathways.

The review presents the latest data on the role of selenium-containing agents in the regulation of diseases of the immune system. We mainly considered the contributions of selenium-containing compounds such as sodium selenite, methylseleninic acid, selenomethionine, and methylselenocysteine, as well as selenoproteins and selenium nanoparticles in the regulation of defense mechanisms against various viral infections, including coronavirus infection (COVID-19). A complete description of the available data for each of the above selenium compounds and the mechanisms underlying the regulation of immune processes with the active participation of these selenium agents, as well as their therapeutic and pharmacological potential, is presented. The main purpose of this review is to systematize the available information, supplemented by data obtained in our laboratory, on the important role of selenium compounds in all of these processes. In addition, the presented information makes it possible to understand the key differences in the mechanisms of action of these compounds, depending on their chemical and physical properties, which is important for obtaining a holistic picture and prospects for creating drugs based on them.

S-Adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) are important metabolites in the one-carbon cycle that modulates cellular methylation required for proliferation and epigenetic regulation. Their concentrations, synthesis, and turnover are difficult to determine conveniently and reliably. We have developed such a method by coupling a simple and rapid purification scheme that efficiently captures both compounds, with high sensitivity, sample throughput direct infusion nanoelectrospray ultra-high-resolution Fourier transform mass spectrometry (DI-nESI-UHR-FTMS). This method is compatible with Stable Isotope-Resolved Metabolomic (SIRM) analysis of numerous other metabolites. The limits of detection for both SAM and SAH were <1 nM, and the linearity range was up to 1000 nM. The method was first illustrated for SAM/SAH analysis of mouse livers, and lung adenocarcinoma A549 cells. We then applied the method to track 13C1-CH3-Met incorporation into SAM and 13C6-glucose transformation into SAM and SAH via de novo synthesis. We further used the method to show the distinct effects on A549 and H1299 cells with treatment of anti-cancer methylseleninic acid (MSA), selenite, and selenomethionine, notably SAM depletion and increased SAM to SAH ratio by MSA, which implicates altered epigenetic regulation.