lignans and Triple-Negative-Breast-Neoplasms

The potential of combination therapy using nanoparticle delivery systems in improving triple-negative breast cancer treatment efficacy remains to be explored. Here, we report a novel nanoparticle system using a cholesterol biguanide conjugate hydrochloride (CBH) as both a drug and carrier to load magnolol (MAG). Poly(ethylene glycol)-poly(lactic-co-glycolic acid) (mPEG-PLGA) and aminoethyl anisamide-poly(ethylene glycol)-poly(lactic-co-glycolic acid) (AEAA-PEG-PLGA) were added to form nanoparticles. Nanoparticles accumulated most in tumor tissues when the weight ratio of AEAA-PEG-PLGA to mPEG-PLGA was 4:1. MAG and CBH exerted a synergistic inhibitory effect on 4 T1 cells. An in vitro study showed that nanoparticles displayed the highest tumor cell uptake rate, highest apoptosis rate, and strongest inhibitory effect on tumor cell migration and monoclonal formation. CBH might promote nanoparticle uptake by cells and lysosomal escape. After intravenous administration to mice with 4 T1 breast tumors in situ, the nanoparticles inhibited tumor growth without obvious toxicity. Western blot results showed that nanoparticles altered the levels of p53, p-AKT, and p-AMPK in the tumor tissue. Moreover, cell apoptosis was found in the same area of H&E-stained and TUNEL-stained tumors treated with the nanoparticles. Collectively, this nanoparticle system provides a novel combination drug delivery strategy for treating triple-negative breast cancer.

Topics: Animals; Biguanides; Biphenyl Compounds; Cell Line, Tumor; Drug Carriers; Humans; Lignans; Mice; Nanoparticles; Polyethylene Glycols; Triple Negative Breast Neoplasms

Magnolol (MAG), a biphenolic neolignan, has various biological activities including antitumor effects. In this study, 15 MAG derivatives were semi-synthesized and evaluated for their in vitro anticancer activities. From these derivatives, compound

Topics: Antineoplastic Agents; Biphenyl Compounds; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Screening Assays, Antitumor; Female; Humans; Lignans; Neoplasm Invasiveness; Triple Negative Breast Neoplasms

Arctigenin is a natural lignan that is found in burdock with anti‑viral, ‑oxidative, ‑inflammatory and anti‑tumor activities. In the current study, the effect of arctigenin on metastatic potential was examined in 4T‑1 mouse triple‑negative breast cancer cells. The results indicated that arctigenin inhibited cell motility and invasiveness, which was determined using wound healing and transwell invasion assays. Arctigenin suppressed matrix metalloprotease‑9 (MMP‑9) activity via gelatin zymography, and protein expression of cyclooxygenase‑2 (COX‑2) and MMP‑3. Furthermore, arctigenin attenuated the mRNA expression of metastatic factors, including MMP‑9, MMP‑3 and COX‑2. Based on these results, the effect of arctigenin on the mitogen‑activated protein kinase (MAPK)/activating protein‑1 (AP‑1) signaling pathway was assessed in an attempt to identify the regulatory mechanism responsible for its anti‑metastatic effects. Arctigenin was demonstrated to inhibit the phosphorylation of extracellular signal‑regulated protein kinase (ERK) and c‑Jun N‑terminal kinase (JNK), and the nuclear translocations of the AP‑1 subunits, c‑Jun and c‑Fos. In summary, the present study demonstrated that in 4T‑1 mouse triple‑negative breast cancer cells the anti‑metastatic effect of arctigenin is mediated by the inhibition of MMP‑9 activity and by the inhibition of the metastasis‑enhancing factors MMP‑9, MMP‑3 and COX‑2, due to the suppression of the MAPK/AP‑1 signaling pathway. The results of the current study demonstrated that arctigenin exhibits a potential for preventing cell migration and invasion in triple negative breast cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Arctium; Cell Line, Tumor; Cell Movement; Female; Furans; Humans; Lignans; MAP Kinase Signaling System; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Mice; Neoplasm Invasiveness; Phosphorylation; Signal Transduction; Transcription Factor AP-1; Triple Negative Breast Neoplasms

Programmed death ligand 1 (PD-L1) is overexpressed in some metastatic breast cancer subtypes, specifically triple-negative breast cancer (TNBC). This feature can assist in the eradication of anti-tumor immunity, thereby enhancing the survival of the tumor. This study aims to explore how sesamin affects PD-L1 expression in breast cancer cells and its related molecular mechanisms. We found high levels of expression of PD-L1 in both mRNA and protein levels in the TNBC cell line, MDA-MB231, but not in the luminal type-breast cancer cell line, MCF-7. We then demonstrated the tumor suppressive effect of sesamin, which induced the inhibition of cell proliferation in MDA-MB231 cells. Additionally, sesamin triggered PD-L1 downregulation (both mRNA and protein) through the inhibition of AKT, NF-κB and JAK/Stat signaling in MDA-MB231 cells. Moreover, the migration ability of MDA-MB231 cells was effectively diminished by sesamin via inhibition of the activation of MMP-9 and MMP-2. In summary, this study demonstrated that sesamin suppresses MDA-MB231 breast cancer cells' proliferation and migration; and decreases the expression of PD-L1 via the downregulation of AKT, NF-κB, and JAK/Stat signaling. Therefore, sesamin may be an effective alternative and novel therapeutic option for immunotherapy in breast cancer cells with high PD-L1 expression.

Topics: Adenocarcinoma; B7-H1 Antigen; Biomarkers, Tumor; Breast Neoplasms; Cell Proliferation; Dioxoles; Female; Humans; Janus Kinases; Lignans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; MCF-7 Cells; NF-kappa B; Proto-Oncogene Proteins c-akt; Signal Transduction; STAT Transcription Factors; Triple Negative Breast Neoplasms; Up-Regulation

Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking prognostic and effective therapeutic targets currently. In this study, we evaluated the toxic potential of schisandrin A (SchA), a bioactive phytochemical found in Schisandra chinensis in TNBC. The anti-cancer effect and underlying mechanism of SchA on MDA-MB-231 and BT-549 cells were determined in vitro and in xenograft mouse model. Our data show that SchA markedly inhibited the growth of TNBC cells via induction of cell cycle arrest and cell apoptosis. Moreover, over activation of Wnt signaling was observed in TNBC cells, which was significantly suppressed by the treatment of SchA. Also, SchA treatment activated ER stress in TNBC cells. Finally, we verified these inhibitory effects of SchA in the MDA-MB-231 xenograft mouse model. In conclusion, SchA effectively inhibited TNBC in preclinical models by inducing cell cycle arrest and apoptosis via regulating Wnt/ER stress signaling pathway. All of these data indicate that SchA could be a potential candidate for the treatment of TNBC.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cyclooctanes; Endoplasmic Reticulum Stress; Female; Humans; Lignans; Mice; Polycyclic Compounds; Schisandra; Triple Negative Breast Neoplasms; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

Triple negative breast cancer (TNBC) is an aggressive subgroup of human breast cancer. In this study, we have examined the potential of Schisandrin B (Sch B), a bioactive chemical compound found in Schisandra chinensis, against TNBC. We used MDA-MB-231, BT-549, and MDA-MB-468 TNBC cells and immunodeficient mice to study the effect of Sch B. Our results show that Sch B inhibits TNBC growth by inducing cell cycle arrest and by triggering apoptotic death. Sch B also inhibited the migration and colony formation of tumor cells, and prevented the growth of TNBC cells in mice. We found that these inhibitory activities were mediated through suppression of signal transducer and activator of transcription-3 (STAT3) phosphorylation and nuclear translocation. Taken together, our studies show that Sch B has potent anti-tumor activity against TNBC via a novel mechanism involving STAT3 inactivation.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cyclooctanes; Dose-Response Relationship, Drug; Female; Humans; Lignans; Mice; Mice, Inbred BALB C; Mice, Nude; Polycyclic Compounds; STAT3 Transcription Factor; Triple Negative Breast Neoplasms; Tumor Burden; Xenograft Model Antitumor Assays

We have shown that a novel STAT3 inhibitor arctigenin (Atn) induces significant cytotoxicity in triple-negative breast cancer (TNBC) cells. This study further delineated molecular mechanisms where by Atn triggered cytotoxicity in TNBC cells. We found Atn can also inhibit metastasis in TNBC cells through cancerous inhibitor of protein phosphatase 2A (CIP2A) pathway. CIP2A is an endogenous inhibitor of protein phosphatase 2A (PP2A), which can increase the migration and invasion of various cancer cells. PP2A is a tumor suppressor, which is functionally defective in various cancers. Atn-induced metastasis inhibition was associated with reactivation of PP2A, downregulation of CIP2A and Akt phosphorylation. Silencing CIP2A enhanced Atn-induced metastasis inhibition and apoptosis in TNBCs. Furthermore, ectopic expression of CIP2A or inhibition of PP2A in TNBC cells abolished the effects of Atn. In conclusion, we found that enhancement of PP2A activity by inhibition of CIP2A, at least in part, promotes the anti-metastasis effect induced by Atn. Our findings disclose the novel therapeutic mechanism of this targeted agent, and suggest the therapeutic potential and feasibility of developing PP2A enhancers as a novel anticancer strategy.

Topics: Antineoplastic Agents; Apoptosis; Autoantigens; Cell Line, Tumor; Down-Regulation; Furans; Humans; Intracellular Signaling Peptides and Proteins; Lignans; Membrane Proteins; Phosphorylation; Protein Phosphatase 2; Proto-Oncogene Proteins c-akt; RNA Interference; RNA, Small Interfering; Signal Transduction; STAT3 Transcription Factor; Triple Negative Breast Neoplasms

Triple-negative breast cancers (TNBCs) are the most aggressive and hard-to-treat breast tumors with poor prognosis, and exploration for novel therapeutic drugs is impending. Arctigenin (Atn), a bioactive lignan isolated from seeds of Arctium lappa L, has been reported to inhibit many cancer types; however, the effect of Atn on TNBC remains unclear. In this study, we demonstrated that Atn decreased proliferation, and induced apoptosis in TNBC cells. Furthermore, we explored the underlying mechanism of Atn inhibition on TNBC cells. Computational docking and affinity assay showed that Atn bound to the SH2 domain of STAT3. Atn inhibited STAT3 binding to genomic DNA by disrupting hydrogen bond linking between DNA and STAT3. In addition, Atn augmented Taxotere®-induced TNBC cell cytotoxicity. TNBC xenograft tests also confirmed the antitumor effect of Atn in vivo. These characteristics render Atn as a promising candidate drug for further development and for designing new effective STAT3 inhibitors.

Topics: Animals; Antineoplastic Agents; Apoptosis; Arctium; Asia, Eastern; Cell Line, Tumor; Cell Proliferation; DNA; Docetaxel; Drug Evaluation, Preclinical; Drug Synergism; Female; Fluorescent Antibody Technique; Furans; Humans; Hydrogen Bonding; Lignans; Mice, Nude; Molecular Docking Simulation; Plants, Medicinal; Protein Domains; Signal Transduction; STAT3 Transcription Factor; Taxoids; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Topics: Administration, Oral; Animals; Antineoplastic Agents; Apoptosis; Biological Availability; Biphenyl Compounds; Caco-2 Cells; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Female; Humans; Lignans; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Micelles; Nanoparticles; Particle Size; Structure-Activity Relationship; Surface Properties; Triple Negative Breast Neoplasms