ascorbic-acid and Triple-Negative-Breast-Neoplasms

Topics: Antioxidants; Apoptosis; Ascorbic Acid; Cell Line, Tumor; Female; Flow Cytometry; Humans; Immunohistochemistry; Membrane Potential, Mitochondrial; Mitochondria; Oxidative Stress; Reactive Oxygen Species; Signal Transduction; Superoxide Dismutase; Triple Negative Breast Neoplasms

Topics: Aminopyridines; Animals; Apoptosis; Ascorbic Acid; Cell Line, Tumor; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Histone Code; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Morpholines; Phosphoinositide-3 Kinase Inhibitors; Precision Medicine; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Compared with photon-induced binary cancer therapy, such as photothermal therapy (PTT) and photodynamic therapy (PDT), boron neutron capture therapy (BNCT) emerges as an alternative noninvasive treatment strategy that could overcome the shallow penetration of light. One key factor in performing successful BNCT is to accumulate a sufficient amount of B-10 (>20 ppm) within tumor cells, which has been a long-standing challenge for small-molecule-based boron drugs. Boron nitride nanoparticles (BNNPs) are promising boron carriers due to their high boron content and good biocompatibility, as certain types of BNNPs can undergo rapid degradation under physiological conditions. To design an on-demand degradable boron carrier, BNNPs were coated by a phase-transitioned lysozyme (PTL) that protects BNNPs from hydrolysis during blood circulation and can be readily removed by vitamin C after neutron capture therapy. According to PET imaging, the coated BNNPs exhibited high tumor boron accumulation while maintaining a good tumor to nontumor ratio. Tail-vein injections of vitamin C were followed by neutron irradiation, and BNNPs were found to be rapidly cleared from major organs according to

Topics: Animals; Ascorbic Acid; Boron Compounds; Boron Neutron Capture Therapy; Cell Line, Tumor; Copper Radioisotopes; Endocytosis; Female; Humans; Mice, Inbred BALB C; Muramidase; Nanoparticles; Positron-Emission Tomography; Tissue Distribution; Triple Negative Breast Neoplasms

Vitamin C supplementation has been shown to decrease triple-negative breast cancer (TNBC) metastasis. However, the molecular mechanism whereby vitamin C inhibits metastasis remains elusive. It has been postulated that vitamin C reduces the levels of HIF-1α, the master regulator of metastasis, by promoting its hydroxylation and degradation. Here, we show that vitamin C at 100 µM, a concentration achievable in the plasma in vivo by oral administration, blocks TNBC cell migration and invasion in vitro. The protein level of HIF-1α remains largely unchanged in cultured TNBC cells and xenografts, partially due to its upregulated transcription by vitamin C, suggesting that HIF-1α unlikely mediates the action of vitamin C on metastasis. Vitamin C treatment upregulates the expression of synaptopodin 2 and downregulates the expression of the transcription coactivator

Topics: Actins; Adaptor Proteins, Signal Transducing; Ascorbic Acid; Cell Line, Tumor; Cell Movement; Dietary Supplements; Down-Regulation; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Microfilament Proteins; Neoplasm Metastasis; Transcription Factors; Triple Negative Breast Neoplasms; Up-Regulation; Vitamins; YAP-Signaling Proteins

Cancer cells from different origins exhibit various basal redox statuses and thus respond differently to intrinsic or extrinsic oxidative stress. These intricate characteristics condition the success of redox-based anticancer therapies that capitalize on the ability of reactive oxygen species to achieve selective and efficient cancer cell killing.. Redox biology methods, stable isotope labeling by amino acids in cell culture (SILAC)-based proteomics, and bioinformatics pattern comparisons were used to decipher the underlying mechanisms for differential response of lung and breast cancer cell models to redox-modulating molecule auranofin (AUF) and to combinations of AUF and vitamin C (VC). The in vivo effect of AUF, VC, and two AUF/VC combinations on mice bearing MDA-MB-231 xenografts (n = 5 mice per group) was also evaluated. All statistical tests were two-sided.. AUF targeted simultaneously the thioredoxin and glutathione antioxidant systems. AUF/VC combinations exerted a synergistic and hydrogen peroxide (H2O2)-mediated cytotoxicity toward MDA-MB-231 cells and other breast cancer cell lines. The anticancer potential of AUF/VC combinations was validated in vivo on MDA-MB-231 xenografts in mice without notable side effects. On day 14 of treatments, mean (SD) tumor volumes for the vehicle-treated control group and the two AUF/VC combination-treated groups (A/V1 and A/V2) were 197.67 (24.28) mm3, 15.66 (10.90) mm3, and 10.23 (7.30)mm3, respectively; adjusted P values of the differences between mean tumor volumes of vehicle vs A/V1 groups and vehicle vs A/V2 groups were both less than .001. SILAC proteomics, bioinformatics analysis, and functional experiments linked prostaglandin reductase 1 (PTGR1) expression levels with breast cancer cell sensitivity to AUF/VC combinations.. The combination of AUF and VC, two commonly available drugs, could be efficient against triple-negative breast cancer and potentially other cancers with similar redox properties and PTGR1 expression levels. The redox-based anticancer activity of this combination and the discriminatory potential of PTGR1 expression are worth further assessment in preclinical and clinical studies.

Topics: A549 Cells; Animals; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Auranofin; Cell Line, Tumor; Female; Glutathione; Human Umbilical Vein Endothelial Cells; Humans; Mice; Oxidative Stress; Proteome; Random Allocation; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Bromodomain and extra-terminal inhibitors (BETi) have shown efficacy for the treatment of aggressive triple negative breast cancer (TNBC). However, BETi are plagued by a narrow therapeutic window as manifested by severe toxicities at effective doses. Therefore, it is a limitation to their clinical implementation in patient care.. The impact of vitamin C on the efficacy of small compounds including BETi was assessed by high-throughput screening. Co-treatment of TNBC by BETi especially JQ1 and vitamin C was evaluated in vitro and in vivo.. High-throughput screening revealed that vitamin C improves the efficacy of a number of structurally-unrelated BETi including JQ1, I-BET762, I-BET151, and CPI-203 in treating TNBC cells. The synergy between BETi and vitamin C is due to suppressed histone acetylation (H3ac and H4ac), which is in turn caused by upregulated histone deacetylase 1 (HDAC1) expression upon vitamin C addition. Treatment with JQ1 at lower doses together with vitamin C induces apoptosis and inhibits the clonogenic ability of cultured TNBC cells. Oral vitamin C supplementation renders a sub-therapeutic dose of JQ1 able to inhibit human TNBC xenograft growth and metastasis in mice.. Vitamin C expands the therapeutic window of BETi by sensitizing TNBC to BETi. Using vitamin C as a co-treatment, lower doses of BETi could be used to achieve an increased therapeutic index in patients, which will translate to a reduced side effect profile. FUND: University of Miami Sylvester Comprehensive Cancer Center, Bankhead Coley Cancer Research program (7BC10), Flight Attendant Medical Research Institute, and NIH R21CA191668 (to GW) and 1R56AG061911 (to CW and CHV).

Topics: Acetylation; Animals; Antineoplastic Agents; Apoptosis; Ascorbic Acid; Azepines; Cell Line, Tumor; Dietary Supplements; Disease Models, Animal; Drug Synergism; Female; Gene Expression Profiling; Gene Silencing; Histone Deacetylase 1; Humans; Mice; Proteins; Triazoles; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Methotrexate (MTX) is widely used as both an anticancer and anti-rheumatoid arthritis drug. Although MTX has been used to inhibit the growth of many cancer cells, it cannot effectively inhibit growth of triple-negative breast cancer cells (TNBC cells). Vitamin C is an antioxidant that can prevent oxidative stress. In addition, vitamin C has been applied as adjunct treatment for growth inhibition of cancer cells. Recent studies indicated that combined treatment with vitamin C and MTX may inhibit MCF-7 and MDA-MB-231 breast cancer cell growth through G2/M elongation. However, the mechanisms remain unknown. The aim of the present study was to determine whether combined treatment with low-dose vitamin C and MTX inhibits TNBC cell growth and to investigate the mechanisms of vitamin C/MTX-induced cytotoxicity. Neither low-dose vitamin C alone nor MTX alone inhibited TNBC cell growth. However, combined low-dose vitamin C and MTX had synergistic anti-proliferative/cytotoxic effects on TNBC cells. In addition, co-treatment increased H2O2 levels and activated both caspase-3 and p38 cell death pathways.

Topics: Ascorbic Acid; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Drug Therapy, Combination; Female; Gene Expression Regulation, Neoplastic; Humans; Hydrogen Peroxide; MAP Kinase Signaling System; MCF-7 Cells; Methotrexate; Triple Negative Breast Neoplasms