Antitumor Effects In Breast Cancer Research Articles

Honokiol Exhibits Anti-Tumor Effects in Breast Cancer by Modulating the miR-148a-5p-CYP1B1 Axis.

Breast cancer (BC) is the most frequently diagnosed malignancy in female patients. There is a significant lack of therapeutic strategies for BC, particularly triple-negative breast cancer (TNBC). Honokiol (HNK), a lignin extracted from the Magnolia genus plant, has demonstrated numerous pharmacological effects. Therefore, this study aims to investigate the antitumor effect of HNK on BC cells and employ high-throughput sequencing to elucidate its potential mechanism. We found that HNK significantly inhibited proliferation and induced apoptosis on BC cell lines in a dose-dependent manner. Moreover, HNK treatment suppressed migration and colony formation and initiated the intrinsic apoptotic pathway specifically in MDA-MB-231 cells. High-throughput sequencing and bioinformatics analysis revealed that miR-148a-5p expression was significantly up-regulated, whereas CYP1B1 expression was down-regulated following HNK treatment. Importantly, survival analysis based on TCGA database showed high miR-148a-5p expression was correlated with a better prognosis for BC patients. Inhibition of miR-148a-5p by inhibitor not only increased cell viability but also attenuated apoptosis induced by HNK.Finally, a strong synergistic effect between HNK and paclitaxel was observed in vitro. In conclusion, our study validated the antitumor efficacy of HNK against human BC cells and elucidated its underlying mechanism through high-throughput sequencing, thereby providing compelling evidence for further exploration of the potential clinical application of HNK towards the treatment of BC.

Nischarin inhibits the epithelial-mesenchymal transition process and angiogenesis in breast cancer cells by inactivating FAK/ERK signaling pathway via EGF like repeats and discoidin domains 3.

Our previous study has demonstrated that Nischarin (NISCH) exerts its antitumor effects in breast cancer (BC) by suppressing cell migration and invasion. This study aims to explore the underlying mechanism through which NISCH functions in BC. The relevance between EGF Like Repeats and Discoidin Domains 3 (EDIL3) mRNA expression and the overall survival of tumor patients was depicted by the Kaplan-Meier curve. The findings revealed that overexpressed NISCH attenuated cell motility and colony-forming capacities of Hs578T cells, yet silenced NISCH in MDA-MB-231 cells led to contrasting results. Western blot (WB) analysis indicated that overexpression of NISCH significantly down-regulated the Vimentin and Slug expression, and inactivated the FAK/ERK signaling pathway. RNA sequencing (RNA-seq) was performed in NISCH-overexpressed Hs578T cells and the control cells to analyze differentially expressed genes (DeGs), and the results showed a significant down-regulation of EDIL3 mRNA level upon overexpression of NISCH. Subsequent functional analyses demonstrated that overexpression of EDIL3 attenuated the inhibitory effect of NISCH on cell migration, invasion, colony formation, and tube formation. In summary, our finding preliminarily revealed that NISCH inhibits the epithelial-mesenchymal transition (EMT) process and angiogenesis in BC cells by down-regulating EDIL3 to inactivate the FAK/ERK signaling pathway, thereby suppressing the progression of BC. Our results hold promise for contributing to the deep understanding of BC pathogenesis and identifying new therapeutic strategies for clinical application.

Deguelin and Paclitaxel Loaded PEG-PCL Nano-Micelles for Suppressing the Proliferation and Inducing Apoptosis of Breast Cancer Cells.

Deguelin (DGL) is a natural flavonoid reported to exhibit antitumor effects in breast cancer (BC). PEG-PCL (Polyethylene Glycol- Polycaprolactone), as polymeric micelles, has biodegradability and biocompatibility. The aim of this study was to investigate whether the nanoparticular delivery system, PEG-PCL could improve the bioavailability of DGL for suppressing proliferation of BC cells. PEG-PCL polymers were first prepared by ring-opening polymerization, and DGL and paclitaxel (PTX)-loaded PEG-PCL nano-micelles were formulated via the film dispersion method. The composition and molecular weight of PEG-PCL were analyzed by nuclear magnetic resonance and fourier Transform infrared spectroscopy (FTIR) spectra. Particle size, surface potential and hemolytic activity of micelles were assessed by dynamic light scattering, transmission electron microscopy and hemolysis assay, respectively. Then proliferation and apoptosis of MDA-MB-231 and MDA-MB-468 cells were tested with Edu staining, CCK-8, TUNEL staining, and Flow cytometer. Caspase 3 expression was also assessed by Western blot. Our results first indicated that PEG2000-PCL2000 was successfully synthesized. DGL and PTX-loaded PEG-PCL nano-micelles were rounded in shape with a particle size of 35.78 ± 0.35 nm and a surface potential of 2.84 ± 0.27 mV. The micelles had minimal hemolytic activity. Besides, we proved that DGL and PTX-loaded PEG-PCL nano-micelles could suppress proliferation and induce apoptosis in BC cells. The DGL and PTX-loaded PEG-PCL nano-micelles constructed in this study had a prominent inhibitory role on proliferation and a remarkable promotional role on apoptosis in BC cells. This study proposes that nano-micelles formed by PEG-PCL can enhance the cytotoxicity of Paclitaxel against breast cancer cells, and concurrently, the loading of Deguelin may further inhibit cell proliferation. This presents a potential for the development of a novel therapeutic strategy.

Sphingomyelin synthase 2 promotes the stemness of breast cancer cells via modulating NF-κB signaling pathway

ObjectivesMulti-drug resistance (MDR) to chemotherapy is the main obstacle influencing the anti-tumor effect in breast cancer, which might lead to the metastasis and recurrence of cancer. Until now, there are still no effective methods that can overcome MDR. In this study, we aimed to investigate the role of sphingomyelin synthase 2 (SMS2) in breast cancer resistance.MethodsQuantitative RT-PCR analysis was performed to assess changes in mRNA expression. Western blot analysis was performed to detect protein expression. Inhibitory concentration value of adriamycin (ADR) was evaluated using CCK 8 assay. The stemness ability of breast cancer cells was assessed by spheroid-formation assay. Immunofluorescence staining was conducted to show the cellular distribution of proteins. Breast tumor masses were harvested from the xenograft tumor mouse model.ResultsSMS2 overexpression increased the IC50 values of breast cancer cells. SMS2 decreased the CD24 transcription level but increased the transcription levels of stemness-related genes including CD44, ALDH, OCT 4 and SOX2 in breast cancer cells. SMS2 overexpression promoted the nuclear translocation of phosphorylated NF-κB, while suppression of SMS2 could inhibit the NF-κB pathway.ConclusionsSMS2 increased the stemness of breast cancer cells via NF-κB signaling pathway, leading to resistance to the chemotherapeutic drug ADR. Thus, SMS2 might play a critical role in the development of breast cancer resistance, which is a previously unrecognized mechanism in breast cancer MDR development.

Targeted Inhibition of p21 Promotes the Growth of Breast Cancer Cells and Impairs the Tumor-Killing Effect of the Vaccinia Virus.

Vaccinia virus is widely used as an oncolytic agent for human cancer therapy, and several versions of vaccinia virus have demonstrated robust antitumor effects in breast cancer. Most vaccinia viruses are modified by thymidine kinase (TK) deletion. The function of the cyclin-dependent kinase inhibitor p21 in breast cancer remains controversial. We explored the impact of p21 gene knockdown (KD) on breast cancer cells and whether p21 KD interferes with the antitumor effect of TK-negative vaccinia virus. p21 KD MDA-MB-231 and p21 KD MCF-7 cells were prepared, and cell proliferation and migration rates were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and scratch healing assays. The tumor growth of xenografts originating from p21KD MDA-MB-231 cells and control cells was compared in a mouse model. The colony formation and sphere-forming abilities of p21 KD breast cancer cells were also determined using low-melting agarose and serum-free culture. The tumor-killing effect of the vaccinia virus was determined in breast cancer cells and mouse models using an MTT assay and tumor cell xenografts. p21 KD increased the growth and migration of MDA-MB-231 and MCF-7 cells and promoted the cell growth of MDA-MB-231 cells in mice, while decreasing the colony formation and sphere formation abilities. Expression of TK was reduced in p21 KD MDA-MB-231 cells. Oncolytic effects of both wild-type and TK-deleted vaccinia viruses were attenuated in p21KD MDA-MB-231 cells. The tumor-killing effect of TK-deleted vaccinia virus was also weakened in xenografted mice bearing p21 KD MDA-MB-231 cells. Targeted inhibition of p21 accelerates the proliferation and migration of breast cancer cells and impairs the tumor-killing effect of vaccinia virus, suggesting that p21 levels in cancer cells interfere with vaccinia virus oncolytic therapy.

VPS34-IN1 induces apoptosis of ER+ breast cancer cells via activating PERK/ATF4/CHOP pathway

VPS34-IN1 is a specific selective inhibitor of Class III Phosphatidylinositol 3-kinase (PI3K) and has been shown to exhibit a significant antitumor effect in leukemia and liver cancer. In current study, we focused on the anticancer effect and potential mechanism of VPS34-IN1 in estrogen receptor positive (ER+ ) breast cancer. Our results revealed that VPS34-IN1 inhibited the viability of ER+ breast cancer cells in vitro and in vivo. Flow cytometry and western blot analyses showed that VPS34-IN1 treatment induced breast cancer cell apopotosis. Interestingly, VPS34-IN1 treatment activated protein kinase R (PKR)-like ER kinase (PERK) branch of endoplasmic reticulum (ER) stress. Furthermore, knockdown of PERK by siRNA or inhibition of PERK activity by chemical inhibitor GSK2656157 could attenuate VPS34-IN1-mediated apoptosis in ER+ breast cancer cells. Collectively, VPS34-IN1 has an antitumor effect in breast cancer, and it may result from activating PERK/ATF4/CHOP pathway of ER stress to induce cell apoptosis. These findings broaden our understanding of the anti-breast cancer effects and mechanisms of VPS34-IN1 and provide new ideas and reference directions for the treatment of ER+ breast cancer.

Natural Compounds, Optimal Combination of Brusatol and Polydatin Promote Anti-Tumor Effect in Breast Cancer by Targeting Nrf2 Signaling Pathway.

Triple-negative breast cancer (TNBC) has been clearly recognized as a heterogeneous tumor with the worst prognosis among the subtypes of breast cancer (BC). The advent and application of current small-molecule drugs for treating TNBC, as well as other novel inhibitors, among others, have made treatment options for TNBC more selective. However, there are still problems, such as poor patient tolerance, large administration doses, high dosing frequency, and toxic side effects, necessitating the development of more efficient and less toxic treatment strategies. High expression of Nrf2, a vital antioxidant transcription factor, often promotes tumor progression, and it is also one of the most effective targets in BC therapy. We found that in MDA-MB-231 cells and SUM159 cells, brusatol (BRU) combined with polydatin (PD) could significantly inhibit cell proliferation in vitro, significantly downregulate the expression of Nrf2 protein as well as the expression of downstream related target genes Heme Oxygenase-1 (HO-1) and NAD(P)H dehydrogenase, quinone 1 (NQO1), and promote reactive oxygen species (ROS) levels to further strengthen the anti-tumor effect. Furthermore, we discovered in our in vivo experiments that by reducing the drug dosage three times, we could significantly reduce tumor cell growth while avoiding toxic side effects, providing a treatment method with greater clinical application value for TNBC treatment.

Piperine has anti-tumor effects in breast cancer by inducing mitochondrial apoptosis pathway

Piperine has anti-tumor effects in breast cancer by inducing mitochondrial apoptosis pathway

Panobinostat inhibits breast cancer progression via Vps34-mediated exosomal pathway.

Exosomes play crucial roles in intercellular communication, including tumormetastasis. Panobinostat (LBH589), a histone deacetylases (HDAC) inhibitor, is an emerging anti-tumor drug with promising efficacy in cancer therapy. This study was set out from recent evidence that exosome was a mechanism of intercellular drug transfer with significant pharmacological consequences. It enlightened us LBH589 might regulate tumor growth through exosomal secretion. Here we demonstrated LBH589 induced autophagy and facilitated secretory autophagy. Furthermore, LBH589 dose- and time-dependently stimulated exosomal release mediated by Vps34/Rab5C pathway, documented by the ablation of Vps34 and/or Rab5C in breast cancer cells. Additionally, the findings also presented LBH589 inhibited breast cancer progression via exosomes. Altogether, we revealed a novel mechanism of LBH589 in exosome-mediated anti-tumor effects in breast cancer. The schematic diagram of signaling pathways involved in the suppression of breast cancer progression by LBH589 via exosomes.

Silibinin exhibits anti-tumor effects in a breast cancer stem cell model by targeting stemness and induction of differentiation and apoptosis.

Introduction: Malignant breast cancer (BC) frequently contains a rare population of cells called cancer stem cells which underlie tumor relapse and metastasis, and targeting these cells may improve treatment options and outcomes for patients with BC. The aim of the present study was to determine the effect of silibinin on the self-renewal capacity, tumorgenicity, and metastatic potential of mammospheres. Methods: The effect of silibinin on viability and proliferation of MCF-7, MDA-MB-231 mammospheres, and MDA-MB-468 cell aggregation was determined after 72-120 hours of treatment. Colony and sphere formation ability, and the expression of stemness, differentiation, and epithelial-mesenchymal-transition (EMT)-associated genes were assessed by reverse transcription-quantitative polymerase chain reaction (qRT-PCR) in mammospheres treated with an IC50 dose of silibinin. Additionally, the antitumor capacity of silibinin was assessed in vivo, in mice. Results: The results of the present study showed that silibinin decreased the viability of all mammospheres derived from MCF-7, MDA-MB-231, and MDA-MB-468 cell aggregation in a dose-dependent manner. Colony and sphere-forming ability, as well as the expression of genes associated with EMT were reduced in mammospheres treated with silibinin. Additionally, the expression of genes associated with stemness and metastasis was also decreased and the expression of genes associated with differentiation were increased. Intra-tumoral injection of 2 mg/kg silibinin decreased tumor volumes in mice by 2.8 fold. Conclusion: The present study demonstrated that silibinin may have exerted its anti-tumor effects in BC by targeting the BC stem cells, reducing the tumorgenicity and metastasis. Therefore, silibinin may be a potential adjuvant for treatment of BC.

Strengthening of antitumor effects in breast cancer from a novel B7-H4- and CD3-targeting bispecific antibody by an oncolytic virus.

BackgroundFor programmed cell death protein 1/programmed death-ligand 1 (PD-L1)-positive triple-negative breast cancer (TNBC), the addition of immune checkpoint inhibitors (ICIs) to chemotherapy has been shown to increase the objective response rate (ORR) by only 13.4–16.3%. Thus, examining converting tumor immunogenicity and targeting novel pathways may be needed to improve response to immunotherapy. B7-H4 is an emerging target for breast cancer immunotherapy. However, the antitumor effect of B7-H4 is unstable during cell generation and further research is necessary to strengthen the antitumor efficacy of B7-H4.MethodsTo explore the potential of B7-H4-targeted immunotherapy of breast cancer, current study generated four monoclonal antibodies (mAbs) against B7-H4 through immunization of mice followed by phage display technology. T cell-engaged bispecific antibodies and immunotoxins were created based on these mAbs. To evaluate the anti-tumor activity of B7-H4-targeting bispecific antibody and immunotoxin, the anti-tumor efficacy test in vitro and in mice models in vivo were performed. Moreover, to boost the efficacy, oncolytic virus herpes simplex virus type 2 (HSV-2) was combined with the bispecific antibody and tested in mice models.ResultsRigorous in vitro cytotoxicity assay showed that both B7-H4 bispecific antibodies and immunotoxins were toxic to B7-H4 positive cells, with the former being more potent. However, in vivo studies showed that immunotoxin was slightly more effective in suppressing tumor growth. Further, bispecific antibody combined with oncolytic virus HSV-2 revealed a synergistic effect in suppressing tumor growth without causing obvious adverse effects.ConclusionsCollectively, our findings uncover a novel strategy of combining oncolytic virus HSV-2 with bispecific antibody reinforce antitumor immune response, which warranted further translational investigation.

Platelet-Derived miR-126-3p Directly Targets AKT2 and Exerts Anti-Tumor Effects in Breast Cancer Cells: Further Insights in Platelet-Cancer Interplay.

Among the surrounding cells influencing tumor biology, platelets are recognized as novel players as they release microvesicles (MVs) that, once delivered to cancer cells, modulate signaling pathways related to cell growth and dissemination. We have previously shown that physiological delivery of platelet MVs enriched in miR-126 exerted anti-tumor effects in different breast cancer (BC) cell lines. Here, we seek further insight by identifying AKT2 kinase as a novel miR-126-3p direct target, as assessed by bioinformatic analysis and validated by luciferase assay. Both ectopic expression and platelet MV-mediated delivery of miR-126-3p downregulated AKT2 expression, thus suppressing proliferating and invading properties, in either triple negative (BT549 cells) or less aggressive Luminal A (MCF-7 cells) BC subtypes. Accordingly, as shown by bioinformatic analysis, both high miR-126 and low AKT2 levels were associated with favorable long-term prognosis in BC patients. Our results, together with the literature data, indicate that miR-126-3p exerts suppressor activity by specifically targeting components of the PIK3/AKT signaling cascade. Therefore, management of platelet-derived MV production and selective delivery of miR-126-3p to tumor cells may represent a useful tool in multimodal therapeutic approaches in BC patients.

BAY-885, a mitogen-activated protein kinase kinase 5 inhibitor, induces apoptosis by regulating the endoplasmic reticulum stress/Mcl-1/Bim pathway in breast cancer cells

ABSTRACT The mitogen-activated protein kinase kinase 5 (MEK5)/extracellular signal-regulated kinase 5 (ERK5) axis has been reported to promote tumorigenesis in breast cancer (BC). Therefore, targeting the MEK5/ERK5 axis is a potential strategy against BC. BAY-885 is a novel inhibitor of ERK5; however, to date, its anti-tumor effects in BC have not been investigated. This study aimed to assess the anti-tumor effects of BAY-885 in BC and identify its underlying mechanisms of action. Unlike other ERK5 inhibitors, which frequently failed to mimic ERK5 genetic ablation phenotypes, the BAY-885 treatment effectively recapitulated ERK5 depletion effects in BC cells. Results revealed that BAY-885 affected the viability and induced apoptosis in BC cells. Moreover, the BAY-885-mediated downregulation of myeloid cell leukemia-1 (Mcl-1) and upregulation of Bim were dependent on ERK5 inhibition. Furthermore, BAY-885 triggered activation of endoplasmic reticulum (ER) stress, which further led to the upregulation of Bim and downregulation of Mcl-1. ER stress was induced in an ERK5 inhibition-dependent manner. These findings suggested that BAY-885 induced apoptosis in BC cells via ER stress/Mcl-1/Bim axis, suggesting that BAY-885 may serve as a therapeutic agent for BC.

TRIM72 exerts antitumor effects in breast cancer and modulates lactate production and MCT4 promoter activity by interacting with PPP3CA.

A hypoxic tumor microenvironment (TME) promotes cancer progression, yet its value as a therapeutic target remains underexploited. Tripartite motif-containing 72 (TRIM72) may protect cells against various stresses including hypoxia. Recently, low TRIM72 expression has been implicated in cancer progression. However, the biological role and molecular mechanism of TRIM72 in breast cancer (BC) remain unclear. Herein, we analyzed the TRIM72 expression in BC tissue and cell lines by western blot (WB) and quantitative reverse transcription-PCR. We established the overexpression of TRIM72 using plasmids and lentiviral-mediated upregulation, as well as downregulation of protein phosphatase 3 catalytic subunit alpha (PPP3CA) by siRNA. The tumor-suppressive roles of TRIM72 were assessed on BT549 and MDA-MB-231 cells by MTS, Transwell, and flow cytometry assays in vitro and in xenografted tumors in vivo. The molecular mechanism of TRIM72 was investigated by luciferase reporter and co-immunoprecipitation (Co-IP) assay. Lactate production was measured by ELISA under hypoxic environments induced by CoCl2. Moreover, the expression of PI3K/Akt/mTOR pathway-associated proteins was detected by WB in BC cells. Results showed that TRIM72 was downregulated in BC. Overexpression of TRIM72 inhibited tumor proliferation and invasion in vitro and in a xenograft tumor model. Mechanistically, PPP3CA altered the inhibitory effects of TRIM72 on hypoxia-induced lactate production and monocarboxylate transporter 4-promoter activity, as well as the effect of the PI3K/Akt/mTOR signaling pathway. Our study suggests that TRIM72 modulates the TME and plays tumor-suppressive roles in BC progression. Therefore, TRIM72 may serve as a potential therapeutic target in BC.

The Combined Use of Orf Virus and PAK4 Inhibitor Exerts Anti-tumor Effect in Breast Cancer.

The parapoxvirus Orf virus (ORFV) has long been recognized as one of the valuable vectors in researches of oncolytic virus. In order to develop a potential therapeutic strategy for breast cancer based on the oncolytic virotherapy via ORFV, firstly we explore the oncolytic effects of ORFV. Our research showed that ORFV exerts anti-tumor effects in vitro by inducing breast cancer cell G2/M phase arrest and cell apoptosis. In vivo experiments were carried out, in which we treated 4T1 tumor-bearing BALB/C mice via intratumoral injection of ORFV. ORFV can exert anti-tumor activity by regulating tumor microenvironment (TME) and inducing a host immune response plus directly oncolytic effect. The CRISPR-Cas9 knockout library targeting 507 kinases was used to screen out PAK4, which is beneficial to the anti-tumor effect of ORFV on breast cancer cells. PF-3758309 is a potent PAK4-targeted inhibitor. Co-using of ORFV and PF-3758309 as a combination treatment produces its anti-tumor effects through inhibition of cell viability, induction of apoptosis and suppression of cell migration and invasion in vitro. The results of in vivo experiments showed that the tumor growth of mice in the combination treatment group was significantly inhibited, which proved that the combination treatment exerts an effective anti-tumor effect in vivo. In summary, we have clarified the oncolytic effect of ORFV on breast cancer, and found that the combination of ORFV and PAK4 inhibitor can effectively improve the oncolytic effect of ORFV. We hope our research could provide a new idea for the development of new treatment strategies for breast cancer.

Anti-Tumor Necrosis Factor Receptor 2 Antibody Combined With Anti-PD-L1 Therapy Exerts Robust Antitumor Effects in Breast Cancer.

Breast cancer is a leading type of malignant tumor in women; however, the immunotherapy in breast cancer is still underappreciated. In this study, we demonstrated that tumor necrosis factor receptor 2 (TNFR2) is highly expressed in both breast tumor tissue and tumor-infiltrating immunosuppressive CD4+Foxp3+ regulatory T cells (Tregs). We found that TNFR2 antagonistic antibody reduced Foxp3 expression and the proliferation of Tregs and impaired the inhibitory effect of Tregs on CD4+CD25– effector T (Teff) cells in a dose-dependent manner. The treatment of anti-TNFR2 antibody not only inhibited the proliferation of breast tumor cells in vitro but also suppressed the tumorigenesis of murine mammary carcinoma 4T1 cells in vivo. Mice recovered from tumor growth also developed 4T1-specific immunity. Furthermore, we demonstrated that anti-TNFR2 antibody in combination with anti-PD-L1 exhibited augmented antitumor effects than monotherapy. Anti-TNFR2 treatment also tended to increase the expression of proinflammatory cytokines in tumor tissues. In conclusion, our study suggests that TNFR2 antagonist could potentially offer a clinical benefit as a single agent or in combination with immune checkpoint blockade treatment for breast cancer immunotherapy.

Polysaccharides with Antitumor Effect in Breast Cancer: A Systematic Review of Non-Clinical Studies.

Purpose: To review the effects of polysaccharides and their proposed mechanisms of action in breast cancer experimental models. Data sources, selection, and extraction: Articles were selected by using PubMed, ScienceDirect, Scopus, and Medline, assessed from 1 May 2019 to 1 July 2020. The systematic review was registered in the International Prospective Register of Systematic Reviews (Prospero) under the number CRD42020169103. Results: Most of the studies explore algae polysaccharides (43.2%), followed by mushrooms (13.5%), plants (13.5%), fruits (10.8%), fungus (2.7%), bacteria, (2.7%), and sea animals (2.7%). A total of 8.1% investigated only in vitro models, 62.1% evaluated only in vivo models, and 29.7% evaluated in vitro and in vivo models. The mechanism of action involves apoptosis, inhibition of cellular proliferation, angiogenesis, and antimetastatic effects through multiple pathways. Conclusions: Findings included here support further investigations on the anti-tumor effect of polysaccharides. Some polysaccharides, such as fucoidan and β-glucans, deserve detailed and structured studies aiming at translational research on breast tumors, since they are already used in the clinical practice of other proposals of human health.

Novel Anti-FOLR1 Antibody-Drug Conjugate MORAb-202 in Breast Cancer and Non-Small Cell Lung Cancer Cells.

Antibody–drug conjugates (ADCs), which are currently being developed, may become promising cancer therapeutics. Folate receptor α (FOLR1), a glycosylphosphatidylinositol-anchored membrane protein, is an attractive target of ADCs, as it is largely absent from normal tissues but is overexpressed in malignant tumors of epithelial origin, including ovarian, lung, and breast cancer. In this study, we tested the effects of novel anti-FOLR1 antibody–eribulin conjugate MORAb-202 in breast cancer and non-small cell lung cancer (NSCLC) cell lines. FOLR1 expression, cell proliferation, bystander killing effects, and apoptosis were evaluated in seven breast cancer and nine NSCLC cell lines treated with MORAb-202. Tumor growth and FOLR1 expression were assessed in T47D and MCF7 orthotopic xenograft mouse models after a single intravenous administration of MORAb-202 (5 mg/kg). MORAb-202 was associated with inhibited cell proliferation, with specific selectivity toward FOLR1-expressing breast cancer cell lines. Eribulin, the payload of MORAb-202, was unleashed in HCC1954 cells, diffused into intercellular spaces, and then killed the non-FOLR1-expressing MCF7 cells in co-culture systems. In orthotopic xenograft mouse models, FOLR1-expressing T47D tumors and non-FOLR1-expressing MCF7 tumors were suppressed upon MORAb-202 administration. The novel anti-FOLR1 antibody–eribulin conjugate MORAb-202 has potential antitumor effects in breast cancer.

The efficacy of etanercept as anti-breast cancer treatment is attenuated by residing macrophages

BackgroundInteraction between microenvironment and breast cancer cells often is not considered at the early stages of drug development leading to failure of many drugs at later clinical stages. Etanercept is a TNF-alpha inhibitor that has been investigated for potential antitumor effect in breast cancer with conflicting results.MethodsSecretome data on MDA-MB-231 cancer cell-line were from public repositories and subjected to gene enrichment analyses. Since MDA-MB-231 cells secrete high levels of Granulocyte-Monocyte Colony Stimulating Factor, which activates macrophages to promote tumor growth, the effect of macrophage co-culturing on anticancer efficacy of Etanercept in breast cancer was evaluated using the Boolean network modeling and in vitro experiments including invasion, cell cycle, Annexin PI, and tetrazolium based viability assays and NFKB activity.ResultsThe secretome profile of MDA-MB-231 cells was similar to the expression of genes following treatment of breast cancer cells with TNF-α. Accordingly, inhibition of TNF-α by Etanercept decreased MDA-MB-231 cell survival, induced apoptosis and cell cycle arrest in vitro and inhibited NFKB activation. The inhibitory effect of Etanercept on cell viability, cell cycle progression, invasion and induction of apoptosis decreased following co-culturing of the cancer cells with macrophages. The Boolean network modeling of the changes in the dynamics of intracellular signaling pathways revealed NFKB activation by secretome of macrophages, leading to a decreased efficacy of Etanercept, suggesting NFKB inhibition as an alternative approach to inhibit cancer cell growth in the presence of macrophage crosstalk.ConclusionThis study indicates that the effect of Etanercept may be influenced by residing macrophages in tumor microenvironment, and suggests a method to predict the effect of drugs in the presence of stromal cells to guide experimental designs in drug development.

Antitumor activity of vibrio sp. isolated biopolymers in induced breast cancer in rats.

To evaluate the antitumor activity of the raw extract from biopolymers isolated from the Vibrio sp. marine bacteria in breast cancer induced by N-Methyl-N-nitrosourea (MNU) in rats. The Vibrio sp. marine bacteria was cultured for seven days, then the raw supernatant was filtered, precipitated and concentrated. MNU was administered in a single dose of 50 mg/kg to 39 Holtzman rats and were daily treated for 9 weeks orally: G1 (n = 13): 0.1 mL/100 g of saline solution; G2 (n = 13): 20 mg/kg of raw extract from Vibrio sp. biopolymers; G3 (n = 13): 100 mg/kg of tamoxifen; G4 (n = 11) received no MNU and only 0.1 mL/100 g of saline solution. Body weight and the appearance of breast tumors identified by palpation were assessed weekly, as well as histopathological examination at the end of treatment. Seventy-seven percent of the rats in the G1 group developed tumors from week 7 onwards in an average of 2.2 tumors per animal; in contrast to the group treated with the raw biopolymer extract and tamoxifen; where only one rat (8%) in each group developed tumors after week nine of induction (p = 0.001). The histopathological results support that all the removed tumors correspond to breast ductal adenocarcinoma with different patterns: solid, papillary and cystic. Likewise, necrotic foci were evidenced in 30% of the tumors of the G1 group. The raw extract of biopolymers isolated from Vibrio sp. present antitumor effect in breast cancer induced in rats.