stilbenes and Triple-Negative-Breast-Neoplasms

Topics: Animals; Humans; Liposomes; Mice; Polyethylene Glycols; Stilbenes; Triple Negative Breast Neoplasms

Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) with potential clinical benefits for all stages of breast cancer. TAM is primarily metabolized to more potent metabolites via polymorphic CYP2D6. This affects the clinical outcome of TAM treatment. Herein we report novel TAM analogues that can avoid metabolism via CYP2D6. The novel analogues bear a flexible skeleton. Compounds have either an ester group on ring C or homodiaminoalkoxy groups on rings B and C. Compound 6 (E/Z-4-[1-[4-(2-diethylaminoethoxy)phenyl]-3-(4-methoxyphenyl)-2-methyl[propenyl]phenol) was found to be ten-fold more potent than TAM on MCF-7 cells (GI

Topics: Breast Neoplasms; Female; Humans; MCF-7 Cells; Stilbenes; Tamoxifen; Triple Negative Breast Neoplasms

Triple-negative breast cancer (TNBC) is unresponsive to typical hormonal treatments, causing it to be one of the deadliest forms of breast cancer. Investigating alternative therapies to increase survival rates for this disease is essential. The goal of this study was to assess cytotoxicity and apoptosis mechanisms of prenylated stilbenoids in TNBC cells. The prenylated stilbenoids arachidin-1 (A-1) and arachidin-3 (A-3) are analogs of resveratrol (RES) produced in peanut upon biotic stress. The anticancer activity of A-1 and A-3 isolated from peanut hairy root cultures was determined in TNBC cell lines MDA-MB-231 and MDA-MB-436. After 24 h of treatment, A-1 exhibited higher cytotoxicity than A-3 and RES with approximately 11-fold and six-fold lower IC

Topics: Antineoplastic Agents, Phytogenic; Arachis; Caspase 9; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; G2 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Plant Roots; Poly(ADP-ribose) Polymerases; Stilbenes; Triple Negative Breast Neoplasms

Monotherapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) still leads to incomplete responses in most EGFR-mutation positive non-small cell lung cancer (NSCLC) patients, often due to acquired resistance through activation of parallel compensatory pathways. We have previously shown that co-targeting EGFR, signal transducer and activator of transcription 3 (STAT3), and Src-yes-associated protein 1 (YAP1) was highly synergistic in vitro and in vivo. In the present study, we treated EGFR-mutation positive cell lines with the combination of osimertinib plus a natural compound, pterostilbene, which has been reported to abrogate Src and STAT3 activation.

Topics: Acrylamides; Adaptor Proteins, Signal Transducing; Aniline Compounds; Antigens, Neoplasm; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Adhesion Molecules; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; Humans; Phosphorylation; STAT3 Transcription Factor; Stilbenes; Transcription Factors; Triple Negative Breast Neoplasms; YAP-Signaling Proteins

Resveratrol, a plant‑derived stilbene compound, has exhibited anticancerous properties, including breast cancer. Stilbenes have a molecular structure highly similar to estrogen and have the ability to bind estrogen receptors and regulate activity. Numerous studies have demonstrated the effectiveness of resveratrol in estrogen receptor‑positive (ER‑positive) subtypes of breast cancer, yet the effects in ER‑negative subtypes, including triple‑negative breast cancer (TNBC), have been limited. In the present study, resveratrol and 28 analogues were tested on a panel of ER‑positive and TNBC cell lines to determine effects on cell viability. Several compounds exhibited significant impacts on cell viability and suggested changes in cell morphology, with high potency of select compounds compared to resveratrol observed in a dose‑dependent manner. Due to the lack of estrogen receptors in TNBC and the estrogenic nature of stilbenes, regulation of breast cancer‑associated cellular pathways was assessed for five analogues shown to significantly inhibit cell viability. Top regulated pathways included apoptosis (confirmed by caspase assay) and DNA damage repair. Overall, our results indicated several resveratrol analogues to be active in ER‑negative phenotypes, acting through an ER receptor‑independent manner, supporting further investigation into their mechanism of action and use as potential chemotherapeutics in higher‑risk breast cancer cases.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA Damage; DNA Repair; Estrogen Receptor alpha; Female; Humans; Resveratrol; Signal Transduction; Stilbenes; Triple Negative Breast Neoplasms

Programmed cell death ligand 1 (PD‑L1) expressed in cancer cells interacting with its receptor programmed cell death 1 (PD‑1) expressed in immune cells represents a regulatory axis linked to the suppression and evasion of host immune functions. The blockade of PD‑1/PD‑L1 interaction using monoclonal antibodies has emerged as an effective therapy for several solid tumors; however, durable response has been observed in a subset of patients with PD‑L1-positive tumors. Thus, the understanding of the mechanisms responsible for the expression of PD‑L1 in tumor cells may help to improve the response to PD‑L1 blockade therapies. In this study, we investigated whether resveratrol, a grape-derived stilbenoid with immunoregulatory activity, modulates the expression of PD‑L1 in breast and colorectal cancer cells. The surface expression of PD‑L1 was determined by flow cytometry in cancer cells treated with resveratrol and/or piceatannol. Each stilbenoid alone induced PD‑L1 and when used in combination, elicited a synergistic upregulation of PD‑L1 in some cell lines. The induction of PD‑L1 by the combined use of stilbenoids was most pronounced in the Cal51 triple-negative breast cancer (TNBC) and SW620 colon cancer cells. The observed induction of PD‑L1 was transcriptionally mediated by nuclear factor (NF)-κB, as shown by NF‑κB reporter assays, the nuclear accumulation of the p65 subunit of NF‑κB, inhibition by the IKK inhibitor, BMS‑345541, and histone the modification inhibitors, resminostat, entinostat or anacardic acid. Combined treatment with resveratrol and piceatannol also decreased tumor cell survival as indicated by the upregulation of the DNA damaging marker, γH2AX, the cleavage of caspase 3, the downregulation of the survival markers, p38-MAPK/c‑Myc, and G1-to-S cell cycle arrest.

Topics: Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Cell Line, Tumor; Cell Survival; Colonic Neoplasms; E1A-Associated p300 Protein; Female; G1 Phase Cell Cycle Checkpoints; Histone Deacetylases; Humans; NF-kappa B; Programmed Cell Death 1 Receptor; Resveratrol; Signal Transduction; Stilbenes; Treatment Outcome; Triple Negative Breast Neoplasms; Up-Regulation

Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) is nontoxic to normal cells and preferentially cytotoxic to cancer cells. Recent data suggest that malignant breast cancer cells often become resistant to TRAIL. Pterostilbene (PTER), a naturally occurring analogue of resveratrol found in blueberries, is known to induce cancer cells to undergo apoptosis. In the present study, we examined whether PTER affects TRAIL-induced apoptosis and its mechanism in TRAIL-resistant triple negative breast cancer (TNBC) cells. Our data indicated that PTER induced apoptosis (14.68 ± 3.78% for 40 μM PTER vs 1.98 ± 0.25% for control, p < 0.01) in TNBC cells and enhanced TRAIL-induced apoptosis in TRAIL-resistant TNBC cells (18.45 ± 4.65% for 40 μM PTER vs 29.38 ± 6.35% for combination of 40 μM PTER and 100 ng/mL TRAIL, p < 0.01). We demonstrated that PTER induced death receptors DR5 and DR4 as well as decreased decoy receptor DcR-1 and DcR-2 expression. PTER also decreased the antiapoptotic proteins c-FLIPS/L, Bcl-Xl, Bcl-2, survivin, and XIAP. PTER induced the cleavage of bid protein and caused proapoptotic Bax accumulation. Moreover, we found that PTER induced the expression of DR4 and DR5 through the reactive oxygen species (ROS)/ endoplasmic reticulum (ER) stress/ERK 1/2 and p38/C/EBP-homologous protein (CHOP) signaling pathways. Overall, our results showed that PTER potentiated TRAIL-induced apoptosis via ROS-mediated CHOP activation leading to the expression of DR4 and DR5.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cell Survival; Down-Regulation; Humans; Reactive Oxygen Species; Receptors, Death Domain; Receptors, TNF-Related Apoptosis-Inducing Ligand; Signal Transduction; Stilbenes; TNF-Related Apoptosis-Inducing Ligand; Triple Negative Breast Neoplasms

The treatment of triple negative breast cancer (TNBC) is a significant challenge to cancer research. The lack of hormone receptors limits the treatment options available to patients with this diagnosis, forcing them to endure prolonged radiation and chemotherapy. Anti-angiogenesis is a chemotherapeutic strategy that targets the vasculature of tumors. Combretastatin A-4 (CA-4) is a well-known vasculature-disrupting agent, which has been shown to effectively kill a variety of cancers through inhibition of tubulin polymerization. Due to its toxicity, small molecule analogues of CA-4 have been sought out. We have designed a novel dual action CA-4 prodrug, YK-5-252, which releases the drug through a disulfide bond cleavage mechanism and contains a near-infrared (NIR) fluorophore, which allows fluorescence monitoring of cleavage. This disulfide linkage causes CA-4 to become effective only when released by glutathione (GSH) reducing the toxicity of the drug while simultaneously releasing the NIR fluorophore. Therefore the prodrug, YK-5-252, represents a novel CA-4 analogue which has reduced toxicity and can be used for theranostics imaging.

Topics: Benzopyrans; Cell Line, Tumor; Cell Proliferation; Flow Cytometry; Humans; Mass Spectrometry; Proton Magnetic Resonance Spectroscopy; Stilbenes; Theranostic Nanomedicine; Triple Negative Breast Neoplasms; Tubulin Modulators

Resveratrol (RSVL) a dietary phytochemical showed to enhance the efficacy of chemotherapeutic drugs. Recently, Salinomycin (SAL) has gained importance as cancer therapeutic value for breast cancer (BC), however, its superfluxious toxicity delimits the utility. Taking the advantage of RSVL, the therapeutic efficacy of RSVL and SAL combination was studied in vitro and in vivo system. Firstly, the synergistic combination dose of RSVL and SAL was calculated and further, the efficacy was examined by wound healing, and Western blots analysis. Further, in vivo study was performed to confirm the effect of colony formation and apoptosis detection by flow cytometry based assays. Further, the molecular mode of action was determined at both transcript and translational level by quantitative Real Time PCR combination in Ehrlich ascitic carcinoma model.The combination of IC20 (R20) of RSVL and IC10 (S10) dose of SAL showed best synergism (CI<1) with ∼5 fold dose advantage of SAL. Gene expression results at mRNA and protein level revealed that the unique combination of RSVL and SAL significantly inhibited epithelial mesenchymal transition (Fibronectin, Vimentin, N-Cadherin, and Slug); chronic inflammation (Cox2, NF-kB, p53), autophagy (Beclin and LC3) and apoptotic (Bax, Bcl-2) markers. Further, i n vivo study showed that low dose of SAL in combination with RSVL increased life span of Ehrlich ascitic mice. Overall, our study revealed that RSVL synergistically potentiated the anticancer potential of SAL against triple negative BC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Autophagy; Cadherins; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Epithelial-Mesenchymal Transition; Female; Humans; Mice; NF-kappa B; Pyrans; Resveratrol; Stilbenes; Triple Negative Breast Neoplasms

Breast cancer is the leading cause of cancer-related deaths among females in economically developing countries. Greater than 95% of breast malignancies are of epithelial origin; the induction of epithelial-to-mesenchymal transition (EMT) has been shown to initiate the metastatic process in breast carcinoma and remains the key target for drug development. Here, we examine the anti-metastatic potential of pterostilbene in modulating EMT process in breast cancer cells both in vitro and in vivo. The differential invasive ability among MCF7, Hs578t and MDA-MB-231 breast cancer cell lines were closely correlated with the expression of EMT markers, determined by Western blots and Matrigel-coated transwells assay. Pterostilbene inhibited the migratory and invasive potential of triple-negative MDA-MB-231 and Hs578t cells, accompanied by the up-regulation of E-cadherin and down-regulation of Snail, Slug, vimentin and ZEB1. Mechanistic investigations revealed a significant up-regulation of miR-205, which resulted in the reduction of Src expression in pterostilbene-treated breast cancer cells. Importantly, pterostilbene suppressed tumor growth and metastasis in MDA-MB-231-bearing NOD/SCID mice by reducing Src/Fak signaling; this observation was consistent with the negative correlations between miR-205 and Src expression in both normal and malignant breast tissues. Our findings provide supports for the usage of pterostilbene as an inhibitor of EMT process and potential candidate for adjuvant therapy.

Topics: Animals; Cadherins; Cell Line, Tumor; Down-Regulation; Epithelial-Mesenchymal Transition; Female; Focal Adhesion Kinase 1; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; MCF-7 Cells; Mice; Mice, Inbred NOD; Mice, SCID; MicroRNAs; Neoplasm Metastasis; Proto-Oncogene Proteins c-akt; RNA, Small Interfering; Signal Transduction; src-Family Kinases; Stilbenes; Transcription Factors; Triple Negative Breast Neoplasms; Up-Regulation; Vimentin; Xenograft Model Antitumor Assays; Zinc Finger E-box-Binding Homeobox 1

Nutrition is believed to be a primary contributor in regulating gene expression by affecting epigenetic pathways such as DNA methylation and histone modification. Resveratrol and pterostilbene are phytoalexins produced by plants as part of their defense system. These two bioactive compounds when used alone have been shown to alter genetic and epigenetic profiles of tumor cells, but the concentrations employed in various studies often far exceed physiologically achievable doses. Triple-negative breast cancer (TNBC) is an often fatal condition that may be prevented or treated through novel dietary-based approaches.. HCC1806 and MDA-MB-157 breast cancer cells were used as TNBC cell lines in this study. MCF10A cells were used as control breast epithelial cells to determine the safety of this dietary regimen. CompuSyn software was used to determine the combination index (CI) for drug combinations.. Combinatorial resveratrol and pterostilbene administered at close to physiologically relevant doses resulted in synergistic (CI <1) growth inhibition of TNBCs. SIRT1, a type III histone deacetylase (HDAC), was down-regulated in response to this combinatorial treatment. We further explored the effects of this novel combinatorial approach on DNA damage response by monitoring γ-H2AX and telomerase expression. With combination of these two compounds there was a significant decrease in these two proteins which might further resulted in significant growth inhibition, apoptosis and cell cycle arrest in HCC1806 and MDA-MB-157 breast cancer cells, while there was no significant effect on cellular viability, colony forming potential, morphology or apoptosis in control MCF10A breast epithelial cells. SIRT1 knockdown reproduced the effects of combinatorial resveratrol and pterostilbene-induced SIRT1 down-regulation through inhibition of both telomerase activity and γ-H2AX expression in HCC1806 breast cancer cells. As a part of the repair mechanisms and role of SIRT1 in recruiting DNMTs, the effects of this combination treatment was also explored on DNA methyltransferases (DNMTs) expression. Interestingly, the compounds resulted in a significant down-regulation of DNMT enzymes with no significant effects on DNMT enzyme expression in MCF10A control cells.. Collectively, these results provide new insights into the epigenetic mechanisms of a novel combinatorial nutrient control strategy that exhibits synergy and may contribute to future recalcitrant TNBC prevention and/or therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; DNA (Cytosine-5-)-Methyltransferases; DNA Damage; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Activation; Epigenesis, Genetic; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Histones; Humans; Receptor, ErbB-2; Resveratrol; Sirtuin 1; Stilbenes; Telomerase; Triple Negative Breast Neoplasms

High expression of vimentin, a canonical mesenchymal marker, is linked with poor prognosis in triple negative breast cancer (TNBC), implying that vimentin may be a potential biomarker in the application of TNBC therapy. Pterostilbene (PTE) has shown anti-invasion activity, and thus, we investigated whether PTE inhibited the epithelial-mesenchymal transition (EMT) in TNBC. Here, we show that PTE decreases the vimentin expression, but that the effect was transient. PTE stimulated Fas signaling, which drives EMT by the ERK1/2 and GSK3β/β-catenin pathways, supporting Fas signaling induction involved in EMT regulation. PTE also triggered autophagy in TNBC. The treatment of TNBC with 3-methyladenine an autophagy inhibitor, not only sustained PTE-inhibited EMT but also significantly promoted anti-proliferation, which indicates that autophagy plays a cyto-protective role and is associated with EMT. Taken together, these data showed that Fas signaling and autophagy accelerated the aggressiveness of TNBC. Inhibition of autophagy or Fas signaling may provide novel targets for TNBC therapy.

Topics: Adenine; Antineoplastic Agents, Phytogenic; Autophagy; beta Catenin; Cell Line, Tumor; Cell Proliferation; Epithelial-Mesenchymal Transition; fas Receptor; Female; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Signal Transduction; Stilbenes; Triple Negative Breast Neoplasms; Vimentin