BackgroundTriple-negative breast cancer (TNBC) is one of the most difficult subtypes of breast cancer to treat due to its aggressive, metastatic behavior, and a lack of a targeted therapy. Trivalent arsenic derivatives (arsenite, AsIII) with remarkable clinical efficacy in acute promyelocytic leukemia has been demonstrated to exhibit inhibitory effect against breast cancer cells. To provide novel insight into the development of new therapeutic strategies, antitumor activity of AsIII and tetrandrine (Tetra), a Chinese plant-derived alkaloid, against the TNBC cell line MDA-MB-231 in vitro and in vivo was investigated.MethodsCytotoxicity was evaluated using cell viability, lactate dehydrogenase leakage and cell cycle assay. Alterations of genes related to cell proliferation and death were analyzed using western blotting. In vivo antitumor activity of AsIII alone or in combination with Tetra was studied using MDA-MB-231 xenografts in nude mice.ResultsSynergistic cytotoxic effects of two drugs were observed in the cells. In vivo study also showed that co-administration of AsIII and Tetra significantly reduced tumor volume and weight, directly supporting its in vitro antitumor activity. No deaths and reduction of body-weight were observed after a long-term co-administration, indicating its good tolerability. S-phase arrest associated with the upregulation of FOXO3a, p27 along with decreased Cyclin D1 expression was observed in the cells treated with the combined regimen. A substantial upregulated p21 expression and downregulated phospho-FOXO3a and Cyclin D1 expression was observed in the tumor tissues of mice co-administered with AsIII and Tetra. Autophagy induction was observed in the combination treatment in vitro and in vivo. The addition of wortmannin, a potent autophagy inhibitor, significantly rescued MDA-MB-231 cells from their cytotoxicity of AsIII and Tetra.ConclusionsS-phase arrest, autophagic and necrotic cell death contribute to the cytocidal effects of the combined regimen of AsIII and Tetra. Considering our previous study showing synergistic cytotoxic effects of the combined regimen in estrogen receptor-positive breast cancer cell line MCF-7, these results suggest that development of the combination regimen of AsIII plus Tetra may offer many benefits to patients with different types of breast cancer.
To provide novel insight into the development of new therapeutic strategies to combat breast cancer using trivalent arsenic (AsIII)-based combination therapy, the cytotoxicity of a combination of AsIII and tetrandrine (Tetra), a Chinese plant-derived alkaloid, was investigated in the human breast cancer cell line MCF-7. Cytotoxicity was evaluated using cell viability, colony formation, wound healing, lactate dehydrogenase leakage and cell cycle assay. Alterations of genes associated with cell proliferation and death were analyzed using real-time PCR and western blotting. Intracellular arsenic accumulation (As[i]) was also determined. Tetra significantly enhanced the cytotoxicity of AsIII in MCF-7 cells in a synergistic manner. The combined treatment upregulated the expression level of FOXO3a, and subsequently resulted in a concomitant increase in the expression levels of p21, p27, and decrease of cycline D1, which occurred in parallel with G0/G1 phase arrest. Autophagy induction was also observed in the combination treatment. Importantly, combining AsIII with Tetra exhibited a synergistic inhibitory effect on the expression level of survivin. Furthermore, enhanced As[i] along with synergistic cytotoxicity was observed in MCF-7 cells treated with AsIII combined with Tetra or Ko134, an inhibitor of breast cancer resistance protein (BCRP), suggesting that Tetra or the BCRP inhibitor probably intervened in the occurrence of resistance to arsenic therapy by enhancing the As[i] via modulation of multidrug efflux transporters. These results may provide a rational molecular basis for the combination regimen of AsIII plus Tetra, facilitating the development of AsIII-based anticancer strategies and combination therapies for patients with solid tumors, especially breast cancer.
The present study examined the effects of tetrandrine suppressing proliferation, targeting LC3, p62, and Beclin-1 autophagy genes by inhibiting PI3K/AKT/mTOR signaling in Triple-negative breast cancer (TNBC) MDA-MB-231 cell. Cell viability and apoptosis were evaluated by MTT and Annexin-V/PI double staining. Cytotoxicity was determined with LDH assay. Western Blot and Immunofluorescence were used to measure the protein levels of p62/SQSTM1, Beclin1, LC3-II/LC3-I, and PTEN/PI3K/AKT/mTOR signaling. Results showed that tetrandrine inhibited the MDA-MB-231 cell proliferation and induced the apoptosis. Tetrandrine at doses of 12.8, 16.1, and 25.7μmol/L showed significant cytotoxicity on MDA-MB-231 cells (p<0.01). Tetrandrine induced MDA-MB-231 cell autophagy by decreasing p62/SQSTM1 expression, improving the expression of Beclin1 and LC3-II/LC3-I (p<0.01), inhibiting the PI3K/AKT /mTOR pathway by downregulating the expression of p-AKT ser473/AKT, p-PI3K/PI3K p110α, and p-mTOR ser2448/mTOR and upregulating PTEN expression. These findings revealed that tetrandrine could suppress proliferation and induce autophagy in MDA-MB-231 cell by inhibiting the PI3K/AKT/mTOR pathway and might be a promising anti-triple-negative breast cancer drug.
Objective: To evaluate the effect of moxibustion on relieving breast cancer–related lymphedema. Materials and Methods: A randomized controlled trial was conducted in our institution from March 2016 to March 2017. All patients (N = 48) with cancer-related lymphedema were allocated to 2 groups: a treatment group, in which moxibustion was performed, and a control group, in which pneumatic circulation was performed with compression garments worn every day. Therapeutic efficacy was evaluated by measuring arm circumference (wrist crease, 10 cm proximal to wrist crease, elbow crease, and 10 cm proximal to elbow crease) and determining the Revised Piper Fatigue Scale score and Visual Analog Scale score for swelling before and after treatment. Results: All patients were treated for 4 consecutive weeks. Compared with 0 week after treatment, the affected-side arm circumference after 4 weeks’ treatment decreased in both treatment and control groups; the difference value in the treatment group was superior to that in the control group. Compared with the controls, moxibustion resulted in a lower Visual Analog Scale score. The Revised Piper Fatigue total scores were improved in both the moxibustion and control group, and there was no significant difference between the 2 groups. Moxibustion reduced the behavioral, sensory, emotional, and cognitive Revised Piper Fatigue scores, but only the behavioral and sensory scores improved in the control group. Conclusion: Moxibustion has potential effect on breast cancer–related lymphedema. We present promising preliminary data for larger randomized trials to enable accurate evaluation of moxibustion as a lymphedema treatment.
Background: Breast cancer has become one of the most common malignant tumors in women owing to its increasing incidence each year. Clinical studies have shown that Cinnamomum cassia (L.) J. Presl (cinnamon) has a positive influence on the prevention and treatment of breast cancer.Aim: We aimed to screen the potential targets of cinnamon in the treatment of breast cancer through network pharmacology and explore its potential therapeutic mechanism through cell experiments.Methods: We used the TCMSP, TCM Database @ Taiwan, and TCMID websites and established the active ingredient and target database of cinnamon. Thereafter, we used the GeneCards and OMIM databases to establish a breast cancer-related target database, which matched the cinnamon target database. Based on the matching results, the STRING database was used to analyze the interaction between the targets, and the biological information annotation database was used to analyze the biological process of the target (gene ontology) and the pathway enrichment of Kyoto Encyclopedia of Genes and Genomes (KEGG). After establishing the layout of the analysis, we used Cytoscape 3.6.0 software for network analysis. Finally, the cell experiment was used to verify the anti-breast cancer effect of cinnamaldehyde.Results: Our research showed that the main components of cinnamon, including cinnamaldehyde, can play a role in the treatment of breast cancer through 59 possible important targets. Subsequently, enrichment analysis by gene ontology and Kyoto Encyclopedia of Genes and Genomes showed that 83 cell biological processes and 37 pathways were associated with breast cancer (p < 0.05), including the peroxisome proliferator-activated receptor and PI3K-Akt pathway, which are closely related to tumor cell apoptosis. In vitro cell verification experiments showed that cinnamaldehyde can significantly inhibit cell proliferation, change cell morphology, inhibit cell migration and invasion ability, and promote cell apoptosis.Conclusion: Our results showed that cinnamaldehyde is a potential novel drug for the treatment and prevention of breast cancer.
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