Effects of coenzyme Q10 supplementation on inflammation, angiogenesis, and oxidative stress in breast cancer patients: a systematic review and meta-analysis of randomized controlled- trials.

BACKGROUND/OBJECTIVE: Systemic inflammation and oxidative stress (OS) are associated with breast cancer. CoQ10 as an adjuvant treatment with conventional anti-cancer chemotherapy has been demonstrated to help in the inflammatory process and OS. This systematic review and meta-analysis of randomized clinical trials (RCTs) aimed to evaluate the efficacy of CoQ10 supplementation on levels of inflammatory markers, OS parameters, and matrix metalloproteinases/tissue inhibitor of metalloproteinases (MMPs/TIMPs) in patients with breast cancer. METHODS: A systematic literature search was carried out using electronic databases, including PubMed, Web of Science, Scopus, Google Scholar, and Embase, up to December 2020 to identify eligible RCTs evaluating the effect of CoQ10 supplementation on OS biomarkers, inflammatory cytokines, and MMPs/TIMPs. From 827 potential reports, 5 eligible studies consisting of 9 trials were finally included in the current meta-analysis. Quality assessment and heterogeneity tests of the selected trials were performed using the PRISMA checklist protocol and the I2 statistic, respectively. Fixed and random-effects models were assessed based on the heterogeneity tests, and pooled data were determined as the standardized mean difference (SMD) with a 95% confidence interval (CI). RESULTS: Our meta-analysis of the pooled findings for inflammatory biomarkers of OS and MMPs showed that CoQ10 supplementation (100 mg/day for 45-90 days) significantly decreased the levels of VEGF [SMD: - 1.88, 95% CI: (- 2. 62 to - 1.13); I2 = 93.1%, p < 0.001], IL-8 [SMD: - 2.24, 95% CI: (- 2.68 to - 1.8); I2 = 79.6%, p = 0.001], MMP-2 [SMD: - 1.49, 95% CI: (- 1.85 to - 1.14); I2 = 76.3%, p = 0.005] and MMP-9 [SMD: - 1.58, 95% CI: (- 1.97 to - 1.19); I2 = 79.6%, p = 0.002], but no significant difference was observed between CoQ10 supplementation and control group on TNF-α [SMD: - 2.30, 95% CI: (- 2.50 to - 2.11); I2 = 21.8%, p = 0.280], IL-6 [SMD: - 1.56, 95% CI: (- 1.73 to - 1.39); I2 = 0.0%, p = 0.683], IL-1ß [SMD: - 3.34, 95% CI: (- 3.58 to - 3.11); I2 = 0.0%, p = 0.561], catalase (CAT) [SMD: 1.40, 95% CI: (1.15 to 1.65); I2 = 0.0%, p = 0.598], superoxide dismutase (SOD) [SMD: 2.42, 95% CI: (2.12 to 2.71); I2 = 0.0%, p = 0.986], glutathione peroxidase (GPx) [SMD: 2.80, 95% CI: (2.49 to 3.11); I2 = 0.0%, p = 0.543]], glutathione (GSH) [SMD: 4.71, 95% CI: (4.26 to 5.16); I2 = 6.1%, p = 0.302] and thiobarbituric acid reactive substances (TBARS) [SMD: - 3.20, 95% CI: (- 3.53 to - 2.86); I2 = 29.7%, p = 0.233]. CONCLUSION: Overall, the findings showed that CoQ10 supplementation reduced some of the important markers of inflammation and MMPs in patients with breast cancer. However, further studies with controlled trials for other types of cancer are needed to better understand and confirm the effect of CoQ10 on tumor therapy.

Realgar Nanoparticles Inhibit Migration, Invasion and Metastasis in a Mouse Model of Breast Cancer by Suppressing Matrix Metalloproteinases and Angiogenesis.

BACKGROUND: Realgar, a traditional Chinese medicine, has shown antitumor efficacy in several tumor types. We previously showed that realgar nanoparticles (nano-realgar) had significant antileukemia, anti-lung cancer and anti-liver cancer effects. In addition, the anti-tumor effects of nanorealgar were significantly better than those of ordinary realgar. OBJECTIVE: To explore the inhibitory effects and molecular mechanisms of nano-realgar on the migration, invasion and metastasis of mouse breast cancer cells. METHODS: Wound-healing migration assays and Transwell invasion assays were carried out to determine the effects of nano-realgar on breast cancer cell (4T1) migration and invasion. The expression levels of matrix metalloproteinase (MMP)-2 and -9 were measured by Western blot. A murine breast cancer metastasis model was established, administered nano-realgar for 32 days and monitored for tumor growth and metastasis by an in vivo optical imaging system. Finally, living imaging and hematoxylin and eosin (HE) staining were used to measure the morphology and pathology of lung and liver cancer cell metastases, respectively. Angiogenesis was assessed by CD34 immunohistochemistry. RESULTS: Nano-realgar significantly inhibited the migration and invasion of breast cancer 4T1 cells and the expression of MMP-2 and -9. Meanwhile, nano-realgar effectively suppressed the abilities of tumor growth, metastasis and angiogenesis in the murine breast cancer metastasis model in a time- and dosedependent manner. CONCLUSION: Nano-realgar significantly inhibited migration and invasion of mouse breast cancer cells in vitro as well as pulmonary and hepatic metastasis in vivo, which may be closely correlated with the downexpression of MMP-2 and -9 and suppression of tumor neovascularization.

Modulation of MMP-2 and -9 secretion by cytokines, inducers and inhibitors in human melanoma A-2058 cells.

Melanoma, an extremely aggressive cancer, causes the most skin cancer-related deaths, due to metastasis to other areas of the body, such as lymph nodes, lungs, liver, brain or bone. It is characterized by high levels of matrix metalloproteinase (MMP)-2 and -9 secretions that degrade the extracellular matrix and basement membrane, allowing cancer cells to spread to distal organs. Various cytokines, mitogens, growth factors, inducers and inhibitors control MMP activities. We investigated the roles of these in regulation of MMP-2 and -9 in human melanoma A-2058 cells. Human A-2058 cells were grown in DMEM supplemented with 15% FBS and antibiotics in 24-well tissue culture plates. At near confluence, the cells were washed with PBS and incubated in serum-free media with phorbol 12-myristate 13-acetate (PMA) at 10, 25, 50 and 100 ng/ml; TNF-α and IL-1ß at 0.1, 1, 10 and 25 ng/ml; LPS at 10, 25, 50 and 100 µg/ml; epigallocatechin gallate (EGCG) and doxycycline (Dox) at 10, 25, 50 and 100 µM without and with PMA; a nutrient mixture (NM) containing lysine, proline, ascorbic acid and green tea extract without and with PMA at 10, 50, 100, 500 and 1,000 µg/ml; actinomycin D and cyclohexamide at 2 and 4 µM; retinoic acid and dexamethasone at 50 µM. After 24 h the media were removed and analyzed for MMP-2 and MMP-9 by zymography and densitometry. Melanoma A-2058 demonstrated strong expression of MMP-2 and slight expression of MMP-9. PMA at 100 ng/ml showed no effect on MMP-2 secretion but potently upregulated MMP-9 secretion to 400% that of control. TNF-α showed no significant overall effect on expression of MMP-2 but potent dose-dependent increased MMP-9 secretion with 200% of control at 25 ng/ml. IL-1ß showed no significant effect on MMP-2 or MMP-9 secretion by A-2058 cells, except at 25 ng/ml where MMP-2 level was reduced by ~40% and MMP-9 secretion ~50%. LPS treatment showed no significant effect on MMP-2 secretion and enhanced MMP-9 secretion up to 25 µg/ml followed by decreased level. EGCG, NM and doxycycline, without and with PMA, downregulated the expression of MMP-2 and MMP-9 in a dose-dependent manner. Actinomycin D, cyclohexamide and retinoic acid had inhibitory effects on MMP-2, while dexamethasone showed slight stimulatory effect on MMP-2 secretion. Our results showed that select cytokines, mitogens and inhibitors modulated A-2058 MMP-2 and MMP-9 expression. They suggest the clinical potential of MMP inhibitors, especially the non-toxic ones, such as the nutrient mixture and its component EGCG in management of melanoma.

Inhibition of Breast Cancer Metastasis by Presurgical Treatment with an Oral Matrix Metalloproteinase Inhibitor: A Preclinical Proof-of-Principle Study.

Breast cancer has the second highest death toll in women worldwide, despite significant progress in early diagnosis and treatments. The main cause of death is metastatic disease. Matrix metalloproteinases (MMP) are required for the initial steps of metastasis, and have therefore been considered as ideal pharmacologic targets for antimetastatic therapy. However, clinical trials of MMP inhibitors were unsuccessful. These trials were conducted in patients with advanced disease, beyond the stage when these compounds could have been effective. We hypothesized that early treatment with a selective MMP inhibitor between the time of diagnosis and definitive surgery, the so-called "window-of-opportunity," can inhibit metastasis and thereby improve survival. To investigate our hypothesis, we used the 4T1 mouse model of aggressive mammary carcinoma. We treated the animals with SD-7300, an oral inhibitor of MMP-2, -9, and -13, starting after the initial detection of the primary tumor. Seven days later, the primary tumors were excised and analyzed for MMP activity, and the SD-7300 treatment was discontinued. After 4 weeks, the animals were sacrificed and their lungs analyzed histologically for number of metastases and metastatic burden (metastases' area/lung section area). SD-7300 treatment inhibited 70% to 80% of tumor-associated MMP activity (P = 0.0003), reduced metastasis number and metastatic burden by 50% to 60% (P = 0.002 and P = 0.0082, respectively), and increased survival (92% vs. 66.7%; P = 0.0409), relative to control vehicle. These results show that treatment of early invasive breast cancer with selective MMP inhibitors can lower the risk of recurrence and increase long-term disease-free survival. Mol Cancer Ther; 15(10); 2370-7. ©2016 AACR.

Administration of Danhong Injection to diabetic db/db mice inhibits the development of diabetic retinopathy and nephropathy.

Danhong Injection (DHI), a Chinese medicine for treatment of patients with coronary heart disease, inhibits primary abdominal aortic aneurysms in apoE deficient (apoE(-/-)) mice. Formation of microaneurysms plays an important role in the development of diabetic retinopathy and nephropathy. It remains unknown if DHI can reduce these diabetic complications. In this study, diabetic db/db mice in two groups were injected with saline and DHI, respectively, for 14 weeks. Blood and tissue samples were collected to determine serum glucose, lipids and tissue structure. DHI reduced diabetes-induced body weight gain, serum cholesterol and glucose levels. In retinas, DHI blocked the shrink of whole retina and retinal sub-layers by inhibiting expression of caspase 3, matrix metalloproteinase 2 (MMP-2) and MMP-9, accumulation of carbohydrate macromolecules and formation of acellular capillaries. DHI improved renal functions by inhibiting mesangial matrix expansion, expression of vascular endothelial growth factor A, fibronectin and advanced glycation end products in kidneys. Mechanistically, DHI induced expression of glucokinase, AMPKα/phosphorylated AMPKα, insulin receptor substrate 1, fibroblast growth factor 21 and peroxisome proliferator-activated γ. Expression of genes responsible for energy expenditure was also activated by DHI. Therefore, DHI inhibits diabetic retinopathy and nephropathy by ameliorating glucose metabolism and demonstrates a potential application in clinics.

Shikonin blocks migration and invasion of human breast cancer cells through inhibition of matrix metalloproteinase-9 activation.

Shikonin, a natural naphthoquinone isolated from a traditional Chinese medicinal herb, has been reported to promote tumor cell death. However, there are few reports concerning its effect on metastasis-related cell invasion and migration behavior. In the present study, we investigated the effect of shikonin on human breast cancer invasion and migration. We found that shikonin inhibited phorbol 12-myristate 13-acetate (PMA)-induced cell migration and invasion in MCF-7 breast cancer cells, which was correlated with modulation of matrix metalloproteinase-9 (MMP-9) through suppression of both expression and proteolytic and promoter activity. We also found that shikonin inhibited both MMP-9 expression and promoter activity in MDA-MB­231 cells with high metastatic potential. These results indicated that shikonin induces the suppression of migration and invasion through modulation of MMP-9 in human breast cancer cells. Therefore, shikonin may be a potential anticancer drug for human breast cancer therapy.

Doxycycline-loaded ß-tricalcium phosphate release following EDTA root surface etching improved the clinical outcomes in chronic periodontitis: an in vivo study.

BACKGROUND: The main objective of the present study is to quantify doxycycline (DOX) release from ß-tricalcium phosphate (ß-TCP) after EDTA root surface treatment. METHODS: Thirty systemically healthy patients with ≥1 paired contralateral interproximal intrabony defect ≥4 mm deep along with an interproximal probing depth ≥6 mm and clinical attachment level ≥4 mm were randomized into two groups. Group 1 (G1) consisted of sites treated with open flap debridement followed by placement of DOX blended with ß-TCP (DOX-ß-TCP), whereas group 2 (G2) sites were treated with flap surgery followed by the placement of DOX blended with ß-TCP after EDTA etching of the exposed root surfaces (DOX-ß-TCP + EDTA). Samples of gingival crevicular fluid (GCF) were obtained 1, 3, 7, 14, and 21 days after surgery. Quantitative measurements of DOX were taken with high-performance liquid chromatography. Clinical evaluation and follow-up for 6 months were performed. RESULTS: At 21 days, the DOX-ß-TCP + EDTA-treated group showed a 194.7 µg/mL value. The DOX-ß-TCP + EDTA-treated group retained more DOX during the periods of 3, 7, 10, 14, and 21 days than the DOX-ß-TCP-treated group. Six months after therapy, DOX-ß-TCP + EDTA-treated sites showed more significant clinical improvements compared to DOX-ß-TCP-treated sites (P ≤ 0.05). CONCLUSIONS: EDTA root surface etching enhances DOX availability in the GCF following its release from ß-TCP as a drug carrier.

HDAC inhibitors augmented cell migration and metastasis through induction of PKCs leading to identification of low toxicity modalities for combination cancer therapy.

PURPOSE: Histone deacetylase inhibitors (HDACi) are actively explored as new-generation epigenetic drugs but have low efficacy in cancer monotherapy. To reveal new mechanism for combination therapy, we show that HDACi induce cell death but simultaneously activate tumor-progressive genes to ruin therapeutic efficacy. Combined treatments to target tumorigenesis and HDACi-activated metastasis with low toxic modalities could develop new strategies for long-term cancer therapy. EXPERIMENTAL DESIGN: Because metastasis is the major cause of cancer mortality, we measured cell migration activity and profiled metastasis-related gene expressions in HDACi-treated cancer cells. We developed low toxic combination modalities targeting tumorigenesis and HDACi-activated metastasis for preclinical therapies in mice. RESULTS: We showed that cell migration activity was dramatically and dose dependently enhanced by various classes of HDACi treatments in 13 of 30 examined human breast, gastric, liver, and lung cancer cell lines. Tumor metastasis was also enhanced in HDACi-treated mice. HDACi treatments activated multiple PKCs and downstream substrates along with upregulated proapoptotic p21. For targeting tumorigenesis and metastasis with immediate clinical impact, we showed that new modalities of HDACi combined drugs with PKC inhibitory agent, curcumin or tamoxifen, not only suppressed HDACi-activated tumor progressive proteins and cell migration in vitro but also inhibited tumor growth and metastasis in vivo. CONCLUSION: Treatments of different structural classes of HDACi simultaneously induced cell death and promoted cell migration and metastasis in multiple cancer cell types. Suppression of HDACi-induced PKCs leads to development of low toxic and long-term therapeutic strategies to potentially treat cancer as a chronic disease.