Selenium promotes immunogenic radiotherapy against cervical cancer metastasis through evoking P53 activation.

Radiotherapy is still the recommended treatment for cervical cancer. However, radioresistance and radiation-induced side effects remain one of the biggest clinical problems. Selenium (Se) has been confirmed to exhibit radiation-enhancing effects for cancer treatment. However, Se species dominate the biological activities and which form of Se possesses better radiosensitizing properties and radiation safety remains elusive. Here, different Se species (the valence state of Se ranged from - 2, 0, +4 to + 6) synergy screen was carried out to identify the potential radiosensitizing effects and radiation safety of Se against cervical cancer. We found that the therapeutic effects varied with the changes in the Se valence state. Sodium selenite (+4) displayed strong cancer-killing effects but also possessed severe cytotoxicity. Sodium selenate (+6) neither enhanced the killing effects of X-ray nor possessed anticancer activity by its alone treatment. Although nano-selenium (0), especially Let-SeNPs, has better radiosensitizing activity, the - 2 organic Se, such as selenadiazole derivative SeD (-2) exhibited more potent anticancer effects and possessed a higher safe index. Overall, the selected Se drugs were able to synergize with X-ray to inhibit cell growth, clone formation, and cell migration by triggering G2/M phase arrest and apoptosis, and SeD (-2) was found to exhibit more potent enhancing capacity. Further mechanism studies showed that SeD mediated p53 pathway activation by inducing DNA damage through promoting ROS production. Additionally, SeD combined with X-ray therapy can induce an anti-tumor immune response in vivo. More importantly, SeD combined with X-ray significantly inhibited the liver metastasis of tumor cells and alleviated the side effects caused by radiation therapy in tumor-bearing mice. Taken together, this study demonstrates the radiosensitization and radiation safety effects of different Se species, which may shed light on the application of such Se-containing drugs serving as side effects-reducing agents for cervical cancer radiation treatment.

Protective effect of spore oil-functionalized nano-selenium system on cisplatin-induced nephrotoxicity by regulating oxidative stress-mediated pathways and activating immune response.

In clinical practice, cisplatin is the most commonly used chemotherapy drug to treat a range of malignancies. Severe ROS-regulated nephrotoxicity, however, restricts its applicability. Currently, the main mechanisms leading to cisplatin-induced nephrotoxicity in clinical settings involve hydration or diuresis. However, not all patients can be treated with massive hydration or diuretics. Therefore, it is crucial to develop a treatment modality that can effectively reduce nephrotoxicity through a foodborne route. Selenium has been reported to have strong antioxidant as well as anticancer effects when administered as spore oil. Herein, we established cellular and animal models of cisplatin-induced nephrotoxicity and synthesized spore oil-functionalized nano-selenium (GLSO@SeNPs). We found that GLSO@SeNPs inhibit the mitochondrial apoptotic pathway by maintaining oxidative homeostasis and regulating related signaling pathways (the MAPK, caspase, and AKT signaling pathways). In vivo, GLSO@SeNPs could effectively improve cisplatin-induced renal impairment, effectively maintaining oxidative homeostasis in renal tissues and thus inhibiting the process of renal injury. In addition, GLSO@SeNPs were converted into selenocysteine (SeCys2), which may exert protective effects. Furthermore, GLSO@SeNPs could effectively modulate the ratio of immune cells in kidneys and spleen, reducing the proportions of CD3+CD4+ T cells, CD3+CD8+ T cells, and M1 phenotype macrophages and increasing the proportion of anti-inflammatory regulatory T cells. In summary, in this study, we synthesized food-derived spore oil-functionalized nanomaterials, and we explored the mechanisms by which GLSO@SeNPs inhibit cisplatin-induced nephrotoxicity. Our study provides a basis and rationale for the inhibition of cisplatin-induced nephrotoxicity by food-derived nutrients.

Selenium-containing ruthenium complex synergizes with natural killer cells to enhance immunotherapy against prostate cancer via activating TRAIL/FasL signaling.

Natural killer (NK) cells-based therapy has been used widely for cancer treatment in clinic trails. However, the immunotherapeutic efficacy of this method has been greatly hindered by tumor evasion and diminished activities of NK cells. In the present study, a selenium (Se)-bearing ruthenium (Ru) complex (RuSe) was designed that could synergistically potentiate NK cell-mediated killing against prostate cancer cells. As expected, pretreatment of cancer cells with subtoxic doses of RuSe effectively augmented the lysis potency of NK cells, with up to 2.46-fold enhancement than NK cells alone, against PC3 cells. More importantly, low concentrations of RuSe could augment the tumor destroying potency of NK cells derived from 10 clinical patients, with the enhancement range from 0.78- to 11.9-fold against PC3 cells and 0.67- to 3.8-fold against LNCAP cells. Mechanistic studies revealed that the sensitizing effect of RuSe primarily depended on TRAIL/TRAIL-R and Fas/FasL-mediated signaling. Furthermore, the increased expression level of these ligands highly relied on ROS overproduction-triggered DNA damage and the downstream ATM and ATR pathways. Furthermore, RuSe potently activated and synergized with NK cells to restrain tumor growth in vivo without causing toxic side effects on major organs. Taken together, the current study not only provides a strategy for application of metal complexes in chemo-immunotherapy but also sheds light on the potential roles and mechanisms of action on such Se-containing drugs as efficient immune-sensitizing agents for NK cell-based immunotherapy.

Enhancement of Antiangiogenic Efficacy of Iron(II) Complex by Selenium Substitution.

Antiangiogenesis therapy is a proven strategy for the treatment of cancers. Herein, we demonstrate that iron(II) complexes containing 1,10-phenanthroline(phen) derivatives were capable of suppressing angiogenesis in vitro in a dose-dependent manner. Interestingly, the introduction of selenium into an iron(II) complex ((Fe(phenSe)3 (ClO4 )2 (phenSe=2-selenoimidazole[4,5-f]1,10-phenanthroline)) could enhance its antiangiogenic efficacy. Mechanistic studies demonstrated that the complex potently induced endothelial cell apoptosis as evidenced by activation of caspases and PARP cleavage. The iron(II) complex activated p53-mediated mitochondrial dysfunction as can be seen by the upregulation in the expression of p53 and proapoptotic Bcl-2 family proteins, and downregulation in the expression of Bcl-2 family proteins. Additionally, the complex inhibited VEGF expression and gave rise to dephosphorylated AKT, which suppressed the transmission of the mitogenic signaling pathway. Taken together, this study could provide a strategy for the rational design of high-efficacy antivascular agents.

RGD peptide-conjugated selenium nanoparticles: antiangiogenesis by suppressing VEGF-VEGFR2-ERK/AKT pathway.

Angiogenesis is essential for tumorigenesis, progression and metastasis. Herein we described the synthesis of RGD peptide-decorated and doxorubicin-loaded selenium nanoparticles (RGD-NPs) targeting tumor vasculature to enhance the cellular uptake and antiangiogenic activities in vitro and in vivo. After internalization by receptor-mediated endocytosis, this nanosystem disassembled under acidic condition with the presence of lysozymes and cell lysate, leading to bioresponsive triggered drug release. Mechanistic investigation revealed that RGD-NPs inhibited angiogenesis through induction of apoptosis and cell cycle arrest in human umbilical vein endothelial cells (HUVECs) via suppression of VEGF-VEGFR2-ERK/AKT signaling axis by triggering ROS-mediated DNA damage. Additionally, RGD-NPs can inhibit MCF-7 tumor growth and angiogenesis in nude mice via down-regulation of VEGF-VEGFR2, effectively reduce the toxicity and prolong the blood circulation in vivo. Our results suggest that the strategy to use RGD-peptide functionalized SeNPs as carriers of anticancer drugs is an efficient way to achieve cancer-targeted antiangiogenesis synergism.