K+/H+ ionophore; NLRP3

In a dose-dependent way, nigericin (0.1 μM) impeded the growth and colony formation of H460 lung cancer cells. Nigericin prevents H460 lung cancer cells from migrating and from thinning[1]. There appears to be a dual effect of nigericin (0.1–10 nM) on cell volume: a shrinking effect at lower concentrations and a swelling effect at higher ones. At concentrations of 0.1–1 nM, nigerin dramatically lowers cytosolic pH (pHi) and marginally raises PHi at 5 and 10 nM [2]. Nigerin is toxic to S18 and S26 cells, with IC50 values of 2.03±, 0.55 μM, and 4.77±2.35 μM, respectively. In vitro, niridmycin specifically eradicates stem tumors in NPCs. Nirimycin dramatically inhibits S18 and HONE-1 cell migration [3]. HT29 and SW116 cell lines demonstrated fetal toxicity to nigericin, with IC50 values of 12.92±0.25 μMol and 15.86±0.18 μMol, respectively. In typical soft agar assays, nigericin also shows a decreased capacity to form colonies under anchorage-independent circumstances [4].

Volumetric data showed that ngericin (4 mg/kg, ip) exhibited a significant reduction in tumor growth and exhibited good interaction with the chemotherapeutic agent DDP. In vivo, nigericin dramatically lowers Bmi-1. Under nigericin treatment, the CSC content and metastatic potential of NPC cells were partially impacted by overexpression of Bmi-1. The inhibition of nigericin on nasopharyngeal cancer stem cells may be connected to the decline in Bmi-1 [3].

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Nigericin exhibits selective toxicity to CSCs in vivo [3]
To evaluate the in vivo effects of nigericin on NPC cells, nude mice subcutaneously inoculated with S18 and S26 cells, respectively, were randomly divided into four subgroups with treatments of vehicle, DDP, nigericin or the combination of DPP and nigericin, respectively. In the S18 group, nigericin significantly reduced tumor growth and acted synergistically with the chemotherapeutic agent DDP, as shown by the tumor volumes (P < 0.05 or <0.01, Fig. 6A). However, in the S26 group, nigericin only slightly suppressed the growth of S26 xenografts, whereas DDP either alone or in combination with nigericin significantly inhibited the tumor growth (P < 0.05 or <0.01, Fig. 6B). Importantly, each treatment of drugs had effects on the loss of body weights of mice as compared to the control group, with increasing severity ranging from nigericin, DDP to the combination of the two drugs (Fig. 6C).
Immunohistochemistry analysis in S18 xenografts showed the expression of Bmi-1 was lower in the nigericin treated group, suggesting that nigericin could downregulate Bmi-1 in vivo.
Moreover, we assessed the change of PTEN and Snail, two molecules involved in Bmi-1 pathway, after nigericin treatment. As expected, PTEN protein level increased and Snail expression decreased after using nigericin in vivo, as compared to the control groups. These results suggest that downregulation of Bmi-1 might contribute to the inhibited effect of nigericin on NPC CSCs.

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Next, we evaluated the synergistic anti-tumor effect of Nigericin with anti-PD-1 antibody in the 4T1 xenograft model, which included relatively cold tumors and was resistant to immune checkpoint inhibitor treatment due to a lack of T cell infiltration and activation [43,44]. The 4T1 cells were orthotopically transplanted into the mammary fat pad of BALB/c mice. Mice were randomly divided into four groups and treated with the control, nigericin (subcutaneous) or anti-PD-1 antibody (intraperitoneal) alone and together. As expected, PD-1 antibody alone did not show significant anti-tumor effect, whereas nigericin showed moderate anti-tumor effect. The combination of nigericin and anti-PD-1 antibody almost completely suppressed tumor growth (Figure 6B–D). Consistently, the tumor infiltrated CD4+ or CD8+ T cells were increased in the nigericin-treated and combination therapy groups (Figure 6E), suggesting that nigericin-mediated pyroptosis modulated the tumor microenvironment to facilitate the T cell infiltration, thus turning cold tumors into hot tumors. The levels of TNF-α and IFN-γ secreted by CD4+ or CD8+ cells were higher in the nigericin and anti-PD-1 combination therapy groups (Figure 6F and Figure S4C). In accordance with above results, cleaved Caspase-1 and cleaved Caspase-3 also increased in the nigericin-treated group (Figure 6F). In addition, we did not observe that nigericin impacted the expressions of PD-1 or PD-L1 in immune cells and cancer cells (Figure S4D). These data confirmed the synergistic anti-tumor effect of nigericin with anti-PD-1 antibody.
Meanwhile, the systematic side effects of these treatments were assessed in vivo. No noticeable histological toxicity was observed in the tissues from heart, liver, spleen, lung and kidney (Figure S5A). Hematological parameters, including white blood cells, hemoglobin, aspartate aminotransferase, alanine aminotransferase, albumin and creatinine, were in the normal range when treatment was completed (Figure S5B). In conclusion, these results suggested that applying nigericin was an effective strategy for sensitizing TNBCs to immune checkpoint blockage therapy with acceptable systematic side effects. [5]

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nigericin is efficacious in mouse models of USA300 infection [6]
Since the outstanding antibacterial properties of NIG and its efficacy has not been evaluated in animal models of infection, we further tested the in vivo efficacy of NIG using mouse models of S. aureus USA300 infection. We first used deep-seated mouse biofilm infection model with the S. aureus USA300 strain to mimic human deep-seated chronic infections. 5 × 107 CFU of S. aureus USA300 was injected to the thigh of each mouse. Twenty-four hours after bacterial infection, mice were administrated intraperitoneally with 50 mg/kg VAN or 1 mg/kg NIG every 12 hours for 3 days. VAN treatment did not significantly reduce S. aureus USA300 abundance, which suggests the presence of a VAN-tolerant bacterial population in this model ( Figure 3A ). Remarkably, treatment with NIG led to an approximately 103-fold reduction of USA300 load in the infected thigh ( Figure 3A ). The potency of NIG reducing the stationary cells and biofilm populations in vivo was encouraging.

Then, we used a trauma infection model with the S. aureus USA300 strain. Wounds were punched on the back skin of mice, followed by infection with S. aureus USA300. One day after infection, NIG ointment was applied once daily for 9 days. The results showed that NIG reduced USA300 loads approximately 104-fold in the wound ( Figure 3B ). Meanwhile, NIG treatment reduced the wound size by 80% after 10 days, as did mupirocin, an established anti-staphylococcal agent ( Figures 3C, D ), indicating that NIG, as well as mupirocin, may promote wound healing by drastically reducing bacterial load at the site of infection. Through hematoxylin and eosin (H&E) staining of the infected skin, disruption of the skin epidermis layer and infiltration of numerous lymphocytes in the interstitium were observed in the USA300-infected mice, while the mice treated with mupirocin or NIG showed more healed skin structures and decreased lymphocyte levels in the interstitium ( Figure 3E ). Notably, the efficacy of NIG was comparable to that of mupirocin but at an 8,000-fold lower concentration.

A murine model of bloodstream infection was further used. One hour after injection with a lethal dose of USA300 through the tail vein, mice were treated with drugs (via ip) every 12 h for 3 days. Treatment with 1 mg/kg NIG significantly prolonged the survival of USA300-infected mice, which was comparable to that of mice treated with 5 mg/kg VAN ( Figure 3F ). The bacterial loads of USA300 in the heart, liver, spleen, lung and kidney were also detected at 72 h post-infection. NIG treatment led to a 1,000- to 10,000-fold reduction in the bacterial burden in the major organs. The effect of 1 mg/kg NIG was slightly better than that of 2.5 mg/kg VAN ( Figures 3G–K ). These results demonstrate the in vivo efficacy of NIG in the treatment of S. aureus infection.

The K(+),H(+) ionophore and antibiotic nigericin has been shown to trigger apoptosis and is thus considered for the treatment of malignancy. Cellular mechanisms involved include induction of oxidative stress, which is known to activate erythrocytic Ca(2+)-permeable unselective cation channels leading to Ca(2+) entry, increase in cytosolic Ca(2+) activity ([Ca(2+)]i) and subsequent stimulation of eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. This study explored whether and how nigericin induces eryptosis. Phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, [Ca(2+)]i from Fluo3 fluorescence, pHi from BCECF fluorescence, ceramide abundance utilizing antibodies and reactive oxygen species (ROS) formation from DCFDA-dependent fluorescence. A 48-hr exposure of human erythrocytes to nigericin significantly increased the percentage of annexin-V-binding cells (0.1-10 nM), significantly decreased forward scatter (0.1-1 nM), significantly decreased cytosolic pH (0.1-1 nM) and significantly increased Fluo3 fluorescence (0.1-10 nM). Nigericin (1 nM) slightly, but significantly, increased ROS, but did not significantly modify ceramide abundance. The effect of nigericin on annexin V binding was significantly blunted, but not abolished by removal of extracellular Ca(2+). The nigericin-induced increase in [Ca(2+)]i and annexin V binding was again significantly blunted but not abolished by the Na(+)/H(+) exchanger inhibitor cariporide (10 μM). Nigericin triggers eryptosis, an effect paralleled by ROS formation, in part dependent on stimulation of Ca(2+) entry, and involving the cariporide-sensitive Na(+)/H(+) exchanger[2].

The human colorectal cancer (CRC) cell lines HT29 and SW480 were treated with nigericin or oxaliplatin under the conditions specified. Cell viability assay and invasion and metastasis assay were performed to evaluate the effect of nigericin on CRC cells. Sphere-forming assay and soft agar colony-forming assay were implemented to assess the action of nigericin on the cancer stem cell properties of CRC cells undergone epithelial-mesenchymal transition (EMT).
Results: Compared with oxaliplatin, nigericin showed more toxicity for the HT29 cell line (IC50, 12.92 ± 0.25 μmol vs 37.68 ± 0.34 μmol). A similar result was also obtained with the SW116 cell line (IC50, 15.86 ± 0.18 μmol vs 41.02 ± 0.23 μmol). A Boyden chamber assay indicated that a significant decrease in the number of HT29 cells migrating through polyvinylidene fluoride membrane was observed in the nigericin-treated group, relative to the vehicle-treated group [11 ± 2 cells per high-power field (HPF) vs 19.33 ± 1.52 cells per HPF, P < 0.05]. Compared to the control group, the numbers of HT29 cells invading through the Matrigel-coated membrane also decreased in the nigericin-treated group (6.66 ± 1.52 cells per HPF vs 14.66 ± 1.52 cells per HPF, P < 0.05). Nigericin also reduced the proportion of CD133+ cells from 83.57% to 63.93%, relative to the control group (P < 0.05). Nigericin decreased the number of spheres relative to the control group (0.14 ± 0.01 vs 0.35 ± 0.01, P < 0.05), while oxaliplatin increased the number of spheres relative to the control group (0.75 ± 0.02 vs 0.35 ± 0.01; P < 0.05). Nigericin also showed a decreased ability to form colonies under anchorage-independent conditions in a standard soft agar assay after 14 d in culture, relative to the control group (1.66 ± 0.57 vs 7 ± 1.15, P < 0.05), whereas the colony numbers were higher in the oxaliplatin group relative to the vehicle-treated controls (14.33 ± 0.57 vs 7 ± 1.15, P < 0.05). We further detected the expression of E-cadherin and vimentin in cells treated with nigericin and oxaliplatin. The results showed that HT29 cells treated with nigericin induced an increase in E-cadherin expression and a decrease in the vimentin expression relative to vehicle controls. In contrast, oxaliplatin downregulated the expression of E-cadherin and upregulated the expression of vimentin in HT29 cells relative to vehicle controls.
Conclusion: This study demonstrated that nigericin could partly reverse the EMT process during cell invasion and metastasis[4].

Animal/Disease Models: balb/c (Bagg ALBino) mouse orthotopically injected with 4T1 cells [5]
Doses: 0.025 mg/kg
Route of Administration: subcutaneous injection
Experimental Results: Shown almost complete inhibition of tumor growth with anti-PD-1 antibody.

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Animal/Disease Models: Staphylococcus aureus-infected mice USA300[6]
Doses: 1 mg/kg
Route of Administration: intraperitoneal (ip) injection
Experimental Results: Major The bacterial load in the organs is diminished to 1,000-10,000 times.

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Deep-seated mouse biofilm infection model [6]
A previously reported deep-seated mouse biofilm infection model (Conlon et al., 2013) was used with modifications. 100 μL of stationary-phase S. aureus USA300 (5 × 107 CFU) was injected to the thigh of each mouse. Starting at 24 h post-infection, mice were administrated with 200 µL of nigericin (1 mg/kg, dissolved in 20% (w/v) Kolliphor® HS 15), vancomycin (50 mg/kg), or vehicle intraperitoneally every 12 h for 3 days. Mice were sacrificed 4 days post-infection, and their infected thighs were homogenized, diluted, and plated on MH agar for determination of CFU.

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Murine wound infection [6]
Murine wounds were generated as round lesions having a diameter of 1 cm on the back of each mouse. Each wound was then infected with 10 μL of 3 × 107 CFU/mL S. aureus USA300. Staring at 24 h post-infection, nigericin (0.025 μg per wound) or mupirocin (200 μg per wound), diluted in 0.1% EtOH, was applied to the wounds once daily for 9 days. The wounds were monitored at 1, 5- and 10-days post-infection. The wound tissues were excised and grounded, and aliquots of the grounded tissue were diluted in normal saline and plated on drug-free agar to determine CFU. A portion of the wound tissue was also subjected to hematoxylin and eosin (H&E) staining for histopathological analysis.

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Murine bloodstream infection model [6]
Mice were infected by intravenous injection of 100 μL 1 × 108 CFU/mL S. aureus USA300. Starting at 4 h post-infection, nigericin (0.5, 1 mg/kg, dissolved in 20% (w/v) Kolliphor® HS 15), vancomycin (5 mg/kg), or vehicle (20% (w/v) Kolliphor® HS 15) in a volume of 200 µL was administrated via the intraperitoneal route every 12 h for 3 d. Survival curves were recorded during 3 days of treatment. For determining the bacterial loads of USA300, the mice were sacrificed 3 days post-infection, and their hearts, livers, spleens, lungs, and kidneys were homogenized, diluted, and plated on MH agar for determination of CFU.

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Six-to-eight-week old female immunocompetent BALB/c mice were used. Next, 5 × 105 4T1 cells were injected orthotopically into the left inguinal mammary fat pad of BALB/c mice. Mice were randomly divided into four groups and treated at the same time with indicated drugs. Nigericin (2 mg/kg) was injected subcutaneously every two days, and anti-PD-1 (250 μg/mouse) was injected intraperitoneally every week. Tumor volumes were monitored every three-to-four days. At the end of the experiment (after about 4 weeks), the mice were sacrificed via carbon dioxide euthanasia, and tumors were harvested for further analysis.[5]

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The S18 cells were injected near the scapula of the nude mice. Nine days after injection, the mice were randomly divided into four groups with six animals each (control, DDP, nigericin and DDP combined with nigericin). DDP (2.5 mg/kg) was injected intraperitoneally for five continuous days and nigericin (4 mg/kg) was administrated intraperitoneally every two days. Tumor length and width were measured with a vernier caliper every other day. Tumor volume was calculated using the formula V = 0.5 × (length × width2). The body weights of the mice were recorded every two days. Mice were humanely euthanized when the tumor volume reached 2000 mm3.[3]

mouse LD50 oral 190 mg/kg CRC Handbook of Antibiotic Compounds, Vols.1- , Berdy, J., Boca Raton, FL, CRC Press, 1980, 5(477), 1981
mouse LD50 intraperitoneal 2500 ug/kg Antibiotics and Chemotherapy, 1(594), 1951

[1]. Nigericin decreases the viability of multidrug-resistant cancer cells and lung tumorspheres and potentiates the effects of cardiac glycosides. Tumour Biol. 2017 Mar;39(3):1010428317694310.

[2]. Triggering of Suicidal Erythrocyte Death by the Antibiotic Ionophore Nigericin. Basic Clin Pharmacol Toxicol. 2016 May;118(5):381-9.

[3]. Nigericin selectively targets cancer stem cells in nasopharyngeal carcinoma. Int J Biochem Cell Biol. 2013 Sep;45(9):1997-2006.

[4]. Suppression of colorectal cancer metastasis by nigericin through inhibition of epithelial-mesenchymal transition. World J Gastroenterol. 2012 Jun 7;18(21):2640-8.

[5]. Nigericin Boosts Anti-Tumor Immune Response via Inducing Pyroptosis in Triple-Negative Breast Cancer. Cancers (Basel). 2023 Jun 16;15(12):3221.

[6]. Nigericin is effective against multidrug resistant gram-positive bacteria, persisters, and biofilms. Front Cell Infect Microbiol. 2022 Dec 20:12:1055929.

Nigericin is a polyether antibiotic which affects ion transport and ATPase activity in mitochondria. It is produced by Streptomyces hygroscopicus. It has a role as an antimicrobial agent, an antibacterial agent, a potassium ionophore and a bacterial metabolite.
A polyether antibiotic which affects ion transport and ATPase activity in mitochondria. It is produced by Streptomyces hygroscopicus. (From Merck Index, 11th ed)
Nigericin has been reported in Streptomyces, Streptomyces violaceusniger, and Streptomyces hygroscopicus with data available.
A polyether antibiotic which affects ion transport and ATPase activity in mitochondria. It is produced by Streptomyces hygroscopicus. (From Merck Index, 11th ed)

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Multiple factors including tumor heterogeneity and intrinsic or acquired resistance have been associated with drug resistance in lung cancer. Increased stemness and the plasticity of cancer cells have been identified as important mechanisms of resistance; therefore, treatments targeting cancer cells independent of stemness phenotype would be much more effective in treating lung cancer. In this article, we have characterized the anticancer effects of the antibiotic Nigericin in cells displaying varying degrees of stemness and resistance to anticancer drugs, arising from (1) routine culture conditions, (2) prolonged periods of serum starvation. These cells are highly resistant to conventional anticancer drugs such as Paclitaxel, Hydroxyurea, Colchicine, Obatoclax, Wortmannin, and LY294002, and the multidrug-resistant phenotype of cells growing under prolonged periods of serum starvation is likely the result of extensive rewiring of signaling pathways, and (3) lung tumorspheres that are enriched for cancer stem-like cells. We found that Nigericin potently inhibited the viability of cells growing under routine culture conditions, prolonged periods of serum starvation, and lung tumorspheres. In addition, we found that Nigericin downregulated the expression of key proteins in the Wnt canonical signaling pathway such as LRP6, Wnt5a/b, and β-catenin, but promotes β-catenin translocation into the nucleus. The antitumor effects of Nigericin were potentiated by the Wnt activator HLY78 and by therapeutic levels of the US Food and Drug Administration-approved drug Digitoxin and its novel synthetic analog MonoD. We believe that Nigericin may be used in a co-therapy model in combination with other novel chemotherapeutic agents in order to achieve potent inhibition of cancers that display varying degrees of stemness, potentially leading to sustained anticancer effects. [1]

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The K(+),H(+) ionophore and antibiotic nigericin has been shown to trigger apoptosis and is thus considered for the treatment of malignancy. Cellular mechanisms involved include induction of oxidative stress, which is known to activate erythrocytic Ca(2+)-permeable unselective cation channels leading to Ca(2+) entry, increase in cytosolic Ca(2+) activity ([Ca(2+)]i) and subsequent stimulation of eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. This study explored whether and how nigericin induces eryptosis. Phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, [Ca(2+)]i from Fluo3 fluorescence, pHi from BCECF fluorescence, ceramide abundance utilizing antibodies and reactive oxygen species (ROS) formation from DCFDA-dependent fluorescence. A 48-hr exposure of human erythrocytes to nigericin significantly increased the percentage of annexin-V-binding cells (0.1-10 nM), significantly decreased forward scatter (0.1-1 nM), significantly decreased cytosolic pH (0.1-1 nM) and significantly increased Fluo3 fluorescence (0.1-10 nM). Nigericin (1 nM) slightly, but significantly, increased ROS, but did not significantly modify ceramide abundance. The effect of nigericin on annexin V binding was significantly blunted, but not abolished by removal of extracellular Ca(2+). The nigericin-induced increase in [Ca(2+)]i and annexin V binding was again significantly blunted but not abolished by the Na(+)/H(+) exchanger inhibitor cariporide (10 μM). Nigericin triggers eryptosis, an effect paralleled by ROS formation, in part dependent on stimulation of Ca(2+) entry, and involving the cariporide-sensitive Na(+)/H(+) exchanger.[2]

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Nasopharyngeal carcinoma (NPC) is prevalent in southern China, northern Africa, and Alaska. The prognosis for NPC patients at early stage is good, while it is poor for patients at late stages. Cancer stem cells (CSCs) have been proposed to be associated with tumor initiation, relapse and metastasis, and the poor prognosis of NPC likely results from residual CSCs after therapy. Study on the therapy targeting CSCs in NPC remains poor, though it received intensive attentions in other cancers. Here, we used NPC cell lines with high and low proportion of CSCs as models to explore the effect of nigericin, an antibiotic, on CSCs. We found that nigericin could selectively target CSCs and sensitize CSCs in NPC to the widely used clinical drug cisplatin both in vitro and in vivo. Moreover, downregulation of the polycomb group protein Bmi-1 may contribute to the inhibitory effect of nigericin on CSCs. Furthermore, by using the in vitro NPC cell models, we found that nigericin could significantly decrease the migration and invasion abilities, which are known to be associated with CSCs. Taken together, our results suggest that nigericin can selectively target CSCs in NPC, which could be a candidate CSCs targeting drug for clinical evaluation.[3]

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Aim: To evaluate the effect of nigericin on colorectal cancer and to explore its possible mechanism. Methods: The human colorectal cancer (CRC) cell lines HT29 and SW480 were treated with nigericin or oxaliplatin under the conditions specified. Cell viability assay and invasion and metastasis assay were performed to evaluate the effect of nigericin on CRC cells. Sphere-forming assay and soft agar colony-forming assay were implemented to assess the action of nigericin on the cancer stem cell properties of CRC cells undergone epithelial-mesenchymal transition (EMT). Results: Compared with oxaliplatin, nigericin showed more toxicity for the HT29 cell line (IC50, 12.92 ± 0.25 μmol vs 37.68 ± 0.34 μmol). A similar result was also obtained with the SW116 cell line (IC50, 15.86 ± 0.18 μmol vs 41.02 ± 0.23 μmol). A Boyden chamber assay indicated that a significant decrease in the number of HT29 cells migrating through polyvinylidene fluoride membrane was observed in the nigericin-treated group, relative to the vehicle-treated group [11 ± 2 cells per high-power field (HPF) vs 19.33 ± 1.52 cells per HPF, P < 0.05]. Compared to the control group, the numbers of HT29 cells invading through the Matrigel-coated membrane also decreased in the nigericin-treated group (6.66 ± 1.52 cells per HPF vs 14.66 ± 1.52 cells per HPF, P < 0.05). Nigericin also reduced the proportion of CD133+ cells from 83.57% to 63.93%, relative to the control group (P < 0.05). Nigericin decreased the number of spheres relative to the control group (0.14 ± 0.01 vs 0.35 ± 0.01, P < 0.05), while oxaliplatin increased the number of spheres relative to the control group (0.75 ± 0.02 vs 0.35 ± 0.01; P < 0.05). Nigericin also showed a decreased ability to form colonies under anchorage-independent conditions in a standard soft agar assay after 14 d in culture, relative to the control group (1.66 ± 0.57 vs 7 ± 1.15, P < 0.05), whereas the colony numbers were higher in the oxaliplatin group relative to the vehicle-treated controls (14.33 ± 0.57 vs 7 ± 1.15, P < 0.05). We further detected the expression of E-cadherin and vimentin in cells treated with nigericin and oxaliplatin. The results showed that HT29 cells treated with nigericin induced an increase in E-cadherin expression and a decrease in the vimentin expression relative to vehicle controls. In contrast, oxaliplatin downregulated the expression of E-cadherin and upregulated the expression of vimentin in HT29 cells relative to vehicle controls. Conclusion: This study demonstrated that nigericin could partly reverse the EMT process during cell invasion and metastasis. [4]

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Although immune checkpoint inhibitors improved the clinical outcomes of advanced triple negative breast cancer (TBNC) patients, the response rate remains relatively low. Nigericin is an antibiotic derived from Streptomyces hydrophobicus. We found that nigericin caused cell death in TNBC cell lines MDA-MB-231 and 4T1 by inducing concurrent pyroptosis and apoptosis. As nigericin facilitated cellular potassium efflux, we discovered that it caused mitochondrial dysfunction, leading to mitochondrial ROS production, as well as activation of Caspase-1/GSDMD-mediated pyroptosis and Caspase-3-mediated apoptosis in TNBC cells. Notably, nigericin-induced pyroptosis could amplify the anti-tumor immune response by enhancing the infiltration and anti-tumor effect of CD4+ and CD8+ T cells. Moreover, nigericin showed a synergistic therapeutic effect when combined with anti-PD-1 antibody in TNBC treatment. Our study reveals that nigericin may be a promising anti-tumor agent, especially in combination with immune checkpoint inhibitors for advanced TNBC treatment. [5]

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Multidrug-resistant (MDR) bacteria pose a significant clinical threat to human health, but the development of antibiotics cannot meet the urgent need for effective agents, especially those that can kill persisters and biofilms. Here, we reported that nigericin showed potent bactericidal activity against various clinical MDR Gram-positive bacteria, persisters and biofilms, with low frequencies of resistance development. Moreover, nigericin exhibited favorable in vivo efficacy in deep-seated mouse biofilm, murine skin and bloodstream infection models. With Staphylococcus aureus, nigericin disrupted ATP production and electron transport chain; cell death was associated with altered membrane structure and permeability. Obtaining nigericin-resistant/tolerant mutants required multiple rounds of challenge, and, cross-resistance to members of several antimicrobial classes was absent, probably due to distinct nigericin action with the GraSR two-component regulatory system. Thus, our work reveals that nigericin is a promising antibiotic candidate for the treatment of chronic or recurrent infections caused by Gram-positive bacteria.[6]

C40H67NAO11

746.9432

746.458

C, 64.32; H, 9.04; Na, 3.08; O, 23.56

28643-80-3

Nigericin;28380-24-7

34230

White to off-white solid powder

1.19g/cm3

779.9ºC at 760mmHg

226.9ºC

4.26E-28mmHg at 25°C

Streptomyces, Streptomyces violaceusniger, and Streptomyces hygroscopicus

4.37

3

11

9

51

1230

19

C[C@H]1CC[C@@H](O[C@H]1[C@@H](C)C(=O)[O-])C[C@@H]2C[C@H]([C@H]([C@@]3(O2)[C@@H](C[C@@](O3)(C)[C@H]4CC[C@@](O4)(C)[C@H]5[C@H](C[C@@H](O5)[C@@H]6[C@H](C[C@H]([C@@](O6)(CO)O)C)C)C)C)C)OC.[Na+]

MOYOTUKECQMGHE-PDEFJWSRSA-M

InChI=1S/C40H68O11.Na/c1-21-11-12-28(46-33(21)26(6)36(42)43)17-29-18-30(45-10)27(7)40(48-29)25(5)19-38(9,51-40)32-13-14-37(8,49-32)35-23(3)16-31(47-35)34-22(2)15-24(4)39(44,20-41)50-34;/h21-35,41,44H,11-20H2,1-10H3,(H,42,43);/q;+1/p-1/t21-,22-,23-,24+,25+,26+,27+,28+,29+,30+,31+,32+,33+,34-,35+,37-,38-,39-,40+;/m0./s1

sodium (R)-2-((2R,3S,6R)-6-(((2S,4R,5R,7R,9R,10R)-2-((2S,2'R,3'S,5R,5'R)-5'-((2S,3S,5R,6R)-6-hydroxy-6-(hydroxymethyl)-3,5-dimethyltetrahydro-2H-pyran-2-yl)-2,3'-dimethyloctahydro-[2,2'-bifuran]-5-yl)-9-methoxy-2,4,10-trimethyl-1,6-dioxaspiro[4.5]decan-7-yl)methyl)-3-methyltetrahydro-2H-pyran-2-yl)propanoate

Helixin C; Azalomycin M; Nigericin sodium; Nigericin sodium salt; 28643-80-3; Sodium nigericin; Nigericin (sodium salt); NIGERICIN, MONOSODIUM SALT; Antibiotic K178; UNII-DGN38HI976; Nigericin sodium; Polyetherin A

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Ethanol :≥ 50 mg/mL (~66.94 mM)
DMSO : ~11.76 mg/mL (~15.74 mM )

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.35 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (3.35 mM) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (3.35 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)