Candidate For Breast Cancer Research Articles

Adiponectin receptor agonist as potential therapeutic candidate for breast cancer associated with obesity

Adiponectin receptor agonist as potential therapeutic candidate for breast cancer associated with obesity

The Importance of Suppressing Pathological Periostin Splicing Variants with Exon 17 in Both Stroma and Cancer.

Periostin (POSTN) is a type of matrix protein that functions by binding to other matrix proteins, cell surface receptors, or other molecules, such as cytokines and proteases. POSTN has four major splicing variants (PN1-4), which are primarily expressed in fibroblasts and cancer. We have reported that we should inhibit pathological POSTN (PN1-3), but not physiological POSTN (PN4). In particular, pathological POSTN with exon 17 is present in both stroma and cancer, but it is unclear whether the stroma or cancer pathological POSTN should be suppressed. We transplanted 4T1 cells (breast cancer) secreting POSTN with exon 17 into 17KO mice lacking POSTN exon 17 to suppress stromal POSTN with exon 17. The results show that 17KO mice had smaller primary tumors and fewer metastases. Furthermore, to suppress cancer POSTN with exon 17, 4T1 cells transfected with POSTN exon 17 skipping oligo or control oligo were transplanted from the tail vein into the lungs. The results show that POSTN exon 17 skipping oligo significantly suppressed lung metastasis. These findings suggest that it is important to suppress POSTN exon 17 in both stroma and cancer. Antibody targeting POSTN exon 17 may be a therapeutic candidate for breast cancer.

Bovine serum albumin-coated ZIF-8 nanoparticles to enhance antitumor and antimetastatic activity of methotrexate: in vitro and in vivo study

In this study, a bovine serum albumin-decorated zeolitic imidazolate framework (ZIF-8@BSA) was used to enhance the anticancer and antimetastatic properties of methotrexate. SEM, DLS, FT-IR, and XRD confirmed the physicochemical suitability of the developed nanoparticles. According to the SEM analysis, the mean size of ZIF-8 nanoparticles was 68.5 ± 13.31 nm. The loading capacity and encapsulation efficiency of MTX@ZIF-8@BSA were 28.77 ± 2.54% and 96.3 ± 0.67%, respectively. According to the in vitro hemolysis test, MTX@ZIF-8@BSA showed excellent blood compatibility. MTX@ZIF-8@BSA exhibited pH sensitivity, releasing more MTX at pH 5.4 (1.73 times) than at pH 7.4. The IC50 value of MTX@ZIF-8@BSA on 4T1 cells was 32.7 ± 7.3 µg/mL after 48 h of treatment, outperforming compared to free MTX with an IC50 value of 53.3 ± 3.7 µg/mL. Treatment with MTX@ZIF-8@BSA resulted in superior tumor growth suppression in tumor-bearing mice than free MTX. Furthermore, based on histopathology tests, MTX@ZIF-8@BSA reduced the metastasis in lung and liver tissues. While there was not any noticeable toxicity in the vital organs of MTX@ZIF-8@BSA-receiving mice, free methotrexate resulted in severe toxicity in the kidneys and liver. According to the preliminary in vitro and in vivo findings, MTX@ZIF-8@BSA presents an attractive drug delivery system candidate for breast cancer due to its enhanced antitumor efficacy and lower toxicity.

Design, synthesis and biological evaluation of piperine derivatives as potent antitumor agents

A series of piperine derivatives were designed and successfully synthesized. The antitumor activities of these compounds against 293 T human normal cells, as well as MDA-MB-231 (breast) and Hela (cervical) cancer cell lines, were assessed through the MTT assay. Notably, compound H7 exhibited moderate activity, displaying reduced toxicity towards non-tumor 293 T cells while potently enhancing the antiproliferative effects in Hela and MDA-MB-231 cells. The IC50 values were determined to be 147.45 ± 6.05 μM, 11.86 ± 0.32 μM, and 10.50 ± 3.74 μM for the respective cell lines. In subsequent mechanistic investigations, compound H7 demonstrated a dose-dependent inhibition of clone formation, migration, and adhesion in Hela cells. At a concentration of 15 μM, its inhibitory effect on Hela cell function surpassed that of both piperine and 5-Fu. Furthermore, compound H7 exhibited promising antitumor activity in vivo, as evidenced by significant inhibition of tumor angiogenesis and reduction in tumor weight in a chicken embryo model. These findings provide a valuable scientific foundation for the development of novel and efficacious antitumor agents, particularly highlighting the potential of compound H7 as a therapeutic candidate for cervical cancer and breast cancer.

Molecular expression, purification and structural characterization of recombinant L-Glutaminase from Streptomyces roseolus

The present research reports the anti-cancer potential of recombinant L-Glutaminase from Streptomyces roseolus. L-Glutaminase gene was synthesized by codon-optimization, cloned and successfully expressed in E. coli BL21 (DE3). Affinity purified recombinant L-Glutaminase revealed a molecular mass of 32 kDa. Purified recombinant L-Glutaminase revealed stability at pH 7.0–8.0 with optimum activity at 70 °C further indicating its thermostable nature based on thermodynamic characterization. Recombinant L-Glutaminase exhibited profound stability in the presence of several biochemical parameters and demonstrated its metalloenzyme nature and was also found to be highly specific towards favorable substrate (l-Glutamine) based on kinetics. It demonstrated antioxidant property and pronounced cytotoxic effect against breast cancer (MCF-7 cell lines) in a dose dependent behavior with IC50 of 40.68 μg/mL. Matrix-assisted laser desorption ionization-time of flight-mass spectroscopy (MALDI-TOF-MS) analysis of desired mass peaks ascertained the recombinant L-Glutaminase identity. N-terminal amino acid sequence characterization through Edman degradation revealed highest resemblance for L-glutaminase within the Streptomyces sp. family. The purified protein was characterized structurally and functionally by employing spectroscopic methods like Raman, circular dichroism and nuclear magnetic resonance. The thermostability was assessed by thermogravimetric analysis. The outcomes of the study, suggests the promising application of recombinant L-Glutaminase as targeted therapeutic candidate for breast cancer.

A new TROP2-targeting antibody-drug conjugate shows potent antitumor efficacy in breast and lung cancers

Trophoblast cell surface antigen 2 (Trop2) is considered to be an attractive therapeutic target in cancer treatments. We previously generated a new humanized anti-Trop2 antibody named hIMB1636, and designated it as an ideal targeting carrier for cancer therapy. Lidamycin (LDM) is a new antitumor antibiotic, containing an active enediyne chromophore (AE) and a noncovalently bound apoprotein (LDP). AE and LDP can be separated and reassembled, and the reassembled LDM possesses cytotoxicity similar to that of native LDM; this has made LDM attractive in the preparation of gene-engineering drugs. We herein firstly prepared a new fusion protein hIMB1636-LDP composed of hIMB1636 and LDP by genetic engineering. This construct showed potent binding activities to recombinant antigen with a KD value of 4.57 nM, exhibited binding to Trop2-positive cancer cells and internalization and transport to lysosomes, and demonstrated powerful tumor-targeting ability in vivo. We then obtained the antibody-drug conjugate (ADC) hIMB1636-LDP-AE by molecular reconstitution. In vitro, hIMB1636-LDP-AE inhibited the proliferation, migration, and tumorsphere formation of tumor cells with half-maximal inhibitory concentration (IC50) values at the sub-nanomolar level. Mechanistically, hIMB1636-LDP-AE induced apoptosis and cell-cycle arrest. In vivo, hIMB1636-LDP-AE also inhibited the growth of breast and lung cancers in xenograft models. Moreover, compared to sacituzumab govitecan, hIMB1636-LDP-AE showed more potent antitumor activity and significantly lower myelotoxicity in tumors with moderate Trop2 expression. This study fully revealed the potent antitumor efficacy of hIMB1636-LDP-AE, and also provided a new preparation method for LDM-based ADC, as well as a promising candidate for breast cancer and lung cancer therapeutics.

Network-Derived Radioresistant Breast Cancer Target with Candidate Inhibitors from Brown Algae: A Sequential Assessment from Target Selection to Quantum Chemical Calculation.

Despite significant progress in early detection and treatment, a few aggressive breast cancers still exhibit resistance to therapy. This study aimed to identify a therapeutic target for radioresistant breast cancer (RRbc) through a protein network from breast cancer genes and to evaluate potent phytochemicals against the identified target. Our approach includes the integration of differential expression genes from expression datasets to create a protein network and to use survival analysis to identify the crucial RRbc protein in order to discover a therapeutic target. Next, the phytochemicals sourced from brown algae were screened through molecular docking, ADME (absorption, distribution, metabolism, and excretion), molecular dynamics (MD) simulation, MM-GBSA, and quantum mechanics against the identified target. As a result of our protein network investigation, the proto-oncogene c-KIT (KIT) protein was identified as a potent radioresistant breast cancer target. Further, phytochemical screening establishes that nahocol-A1 from brown algae has high binding characteristics (-8.56 kcal/mol) against the KIT protein. Then, quantum chemical analysis of nahocol-A1 provided insights into its electronic properties favorable for protein binding. Also, MD simulation comprehends the conformational stability of the KIT-nahocol-A1 complex. Overall, our findings suggest nahocol-A1 could serve as a promising therapeutic candidate for radioresistant breast cancer.

Toxicological profiling of a de novo synthesized benzimidazole derivative with potent and selective proapoptotic potentials against breast cancer.

This study aimed to investigate the toxicological profile of 1-(6-(1H-benzo[d]imidazole-2-yl)-2-methylpyridin-3-yl) ethanone (BMPE), both in vitro and in vivo. The proapoptotic/necrotic and cell cycle arrest potentials of BMPE were assessed in MCF-7cell line. The in vivo toxicology was assessed in female Balb/c mice by repeated dosing of 5, 25, and 50mg/kg for 21 consecutive days, then different biochemical, inflammatory, and oxidative markers were assessed in sera/tissue homogenates of treated animals. The new derivative showed a potent selective cytotoxicity against malignant cell lines with IC50 value 0.2μM/mL, while the cytotoxic effect on normal Wi-38cells was observed at IC50 value 0.4μM/mL; i.e. twofold the effective anticancer dose. BMPE exhibited an early DNA fragmentation-derived cell apoptosis observed at the G0/G1 checkpoint. In vivo, BMPE was biochemically/immunologically tolerable at a pharmacological dose range of 5-25mg/kg, with no significant rates of mortality/morbidity and minimal-to-moderate histopathological alterations recorded. The new derivative represents an attractive therapeutic candidate for breast cancer, considering its noticeable modulatory effect on the oxidative-inflammatory axis that would relate to its potent antitumor effect.

CYD0281, a Bcl-2 BH4 domain antagonist, inhibits tumor angiogenesis and breast cancer tumor growth

BackgroundB-cell lymphoma 2 (Bcl-2) family proteins are key regulators of apoptosis, which possess four conserved Bcl-2 homologies (BH) domains. Among the BH domains, the BH3 domain is considered as a potent ‘death domain’ while the BH4 domain is required for anti-apoptotic activity. Bcl-2 can be converted to a pro-apoptotic molecule through the removal or mutation of the BH4 domain. Bcl-2 is considered as an inducer of angiogenesis, which can promote tumor vascular network formation and further afford nutrients and oxygen to promote tumor progression. However, whether disrupting the function of the BH4 domain to convert Bcl-2 into a pro-apoptotic molecule could make Bcl-2 possess the potential for anti-angiogenic therapy remains to be defined.MethodsCYD0281 was designed and synthesized according to the lead structure of BDA-366, and its function on inducing a conformational change of Bcl-2 was further evaluated via immunoprecipitation (IP) and immunofluorescence (IF) assays. Moreover, the function of CYD0281 on apoptosis of endothelial cells was analyzed via cell viability, flow cytometry, and western blotting assays. Additionally, the role of CYD0281 on angiogenesis in vitro was determined via endothelial cell migration and tube formation assays and rat aortic ring assay. Chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models, breast cancer cell xenograft tumor on CAM and in mouse models as well as the Matrigel plug angiogenesis assay were used to explore the effects of CYD0281 on angiogenesis in vivo.ResultsWe identified a novel potent small-molecule Bcl-2-BH4 domain antagonist, CYD0281, which exhibited significant anti-angiogenic effects both in vitro and in vivo, and further inhibited breast cancer tumor growth. CYD0281 was found to induce conformational changes in Bcl-2 through the exposure of the BH3 domain and convert Bcl-2 from an anti-apoptotic molecule into a cell death inducer, thereby resulting in the apoptosis of vascular endothelial cells.ConclusionsThis study has revealed CYD0281 as a novel Bcl-2-BH4 antagonist that induces conformational changes of Bcl-2 to convert to a pro-apoptotic molecule. Our findings indicate that CYD0281 plays a crucial role in anti-angiogenesis and may be further developed as a potential anti-tumor drug candidate for breast cancer. This work also provides a potential anti-angiogenic strategy for breast cancer treatment.

Physiologically-based pharmacokinetic/pharmacodynamic modeling to predict tumor growth inhibition and the efficacious dose of selective estrogen receptor degraders in humans.

GDC-9545 (giredestrant) is a highly potent, nonsteroidal, oral selective estrogen receptor antagonist and degrader that is being developed as a best-in-class drug candidate for early-stage and advanced drug-resistant breast cancer. GDC-9545 was designed to improve the poor absorption and metabolism of its predecessor GDC-0927, for which development was halted due to a high pill burden. This study aimed to develop physiologically-based pharmacokinetic/pharmacodynamic (PBPK-PD) models to characterize the relationships between oral exposure of GDC-9545 and GDC-0927 and tumor regression in HCI-013 tumor-bearing mice, and to translate these PK-PD relationships to a projected human efficacious dose by integrating clinical PK data. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the animal and human Simcyp V20 Simulator (Certara) and adequately described each compound's systemic drug concentrations and antitumor activity in the dose-ranging xenograft experiments in mice. The established PK-PD relationship was translated to a human efficacious dose by substituting mouse PK for human PK. PBPK input values for human clearance were predicted using allometry and in vitro in vivo extrapolation approaches and human volume of distribution was predicted from simple allometry or tissue composition equations. The integrated human PBPK-PD model was used to simulate TGI at clinically relevant doses. Translating the murine PBPK-PD relationship to a human efficacious dose projected a much lower efficacious dose for GDC-9545 than GDC-0927. Additional sensitivity analysis of key parameters in the PK-PD model demonstrated that the lower efficacious dose of GDC-9545 is a result of improvements in clearance and absorption. The presented PBPK-PD methodology can be applied to support lead optimization and clinical development of many drug candidates in discovery or early development programs.

A review on Forkhead Box A1 (FOXA1) gene; A potent candidate for prostate and breast cancer

A review on Forkhead Box A1 (FOXA1) gene; A potent candidate for prostate and breast cancer

Silver(I) Complexes Based on Oxadiazole-Functionalized α-Aminophosphonate: Synthesis, Structural Study, and Biological Activities.

Two silver(I) complexes, bis{diethyl[(5-phenyl-1,3,4-oxadiazol-2-yl-κN3:κN4-amino) (4-trifluoromethylphenyl)methyl]phosphonate-(tetrafluoroborato-κF)}-di-silver(I) and tetrakis-{diethyl[(5-phenyl-1,3,4-oxadiazol-2-yl-κN3-amino)(4-trifluoromethylphenyl)methyl]phosphonate} silver(I) tetrafluoroborate, were prepared starting from the diethyl[(5-phenyl-1,3,4-oxadiazol-2-yl-amino)(4-trifluoromethylphenyl)methyl]phosphonate (1) ligand and AgBF4 salt in Ag/ligand ratios of 1/1 and 1/4, respectively. The structure, stoichiometry, and geometry of the silver complexes were fully characterized by elemental analyses, infrared, single-crystal X-ray diffraction studies, multinuclear NMR, and mass spectroscopies. The binuclear complex ([Ag2(1)2(BF4)2]; 2) crystallizes in the monoclinic asymmetric space group P21/c and contains two silver atoms adopting a {AgN2F} planar trigonal geometry, which are simultaneously bridged by two oxadiazole rings of two ligands, while the mononuclear complex ([Ag(1)4]BF4; 3) crystallizes in the non-usual cubic space group Fd-3c in which the silver atom binds to four distinct electronically enriched nitrogen atoms of the oxadiazole ring, in a slightly distorted {AgN4} tetrahedral geometry. The α-aminophosphonate and the monomeric silver complex were evaluated in vitro against MCF-7 and PANC-1 cell lines. The silver complex is promising as a drug candidate for breast cancer and the pancreatic duct with half-maximal inhibitory concentration (IC50) values of 8.3 ± 1.0 and 14.4 ± 0.6 μM, respectively. Additionally, the interactions of the ligand and the mononuclear complex with Vascular Endothelial Growth Factor Receptor-2 and DNA were evaluated by molecular docking methods.

Preparation of DSPE-PEG-cRGD Modified Cationic Liposomes for Delivery of OC-2 shRNA and The Antitumor Effects on Breast Cancer.

Cationic liposome delivery of interfering RNA (shRNA) plays an important role in tumor therapy. The cyclic Arg-Gly-Asp (cRGD) modified cationic liposomes (cRGD-CL) were designed for targeted delivery of ONECUT2 (OC-2) shRNA (pshOC-2) to breast cancer cells. The characterization analysis of cationic liposome showed that the prepared cRGD-CL/pshOC-2 lipoplexes had uniform particle size (150 ± 1.02 nm), moderate zeta potential (19.8 ± 0.249 mV) and high encapsulation efficiency (up to 96%). The results of flow cytometer showed that the introduction of cRGD could significantly promote the liposomes targeting tumor cells. In MCF-7 cells, the pshOC-2 could down-regulate expression of OC-2 and result in cell apoptosis, inhibition of the wound healing, migration and cell colony formation, in which the signal pathways of Bcl-xL, Bcl-2 were inhibited and the signal pathways of Bax and Cleaved Caspase-3 were promoted. In MCF-7 xenograft mice, intravenous administration of cRGD-CL/pshOC-2 lipoplexes could effectively reduce the expression of OC-2 in tumors and result in apparently antitumor effects, which suggested that the lipoplexes might be deeply penetrated into tumor through receptor-mediated transcytosis. The results revealed that the cationic liposome (cRGD-CL) was an effective delivery system for OC-2 shRNA, which might be an effective therapeutic candidate for breast cancer.

High DNAJA4 expression correlates with poor survival outcomes in breast cancer

Abstract Background: DNAJA4 (PRO1472) is a heat shock protein that has been associated with several types of cancers, including breast cancer. We aimed to reveal the protein expression, clinical outcomes, and regulatory mechanisms of DNAJA4 gene in breast cancer by employing tissue microarrays, transcriptomic datasets, and in-silico tools. Methods: DNAJA4 protein expression and its clinical implications were evaluated by immunohistochemistry assay (normals = 32; tumors = 121). RNA-seq and DNA microarray datasets were analyzed by using breast cancer gene-expression miner (Bc-GenExMiner v4.8) to estimate the survival probabilities of breast cancer patients. DNAJA4 promoter methylation level was analyzed in clinical samples by UALCAN in-silico tool (normals = 97; tumors = 793). Results: DNAJA4 protein expression is significantly high in clinical breast cancer samples compared to the normal samples (P = 0.016). High DNAJA4 mRNA expression is correlated with poor overall survival (OS), disease-free survival (DFS), and distant metastasis-free survival (DMFS) in breast cancer patients (P < 0.05). Mutations or copy number variations of DNAJA4 are uncommon in clinical samples. Reduced promoter methylation was observed in clinical breast cancer samples. Conclusion: We suggest DNAJA4 expression as a new biomarker candidate for breast cancer. Promoter hypomethylation could be an important epigenetic factor in the upregulation of DNAJA4 expression in breast cancer.

Histocompatibility Minor 13 (HM13), targeted by miR-760, exerts oncogenic role in breast cancer by suppressing autophagy and activating PI3K-AKT-mTOR pathway

Histocompatibility Minor 13 (HM13) is reported to participate in regulating multiple cancers. In the present study, we uncovered that HM13 was highly expressed in breast cancer and correlated with worse prognosis. Downregulation of HM13 could suppress breast cancer cell proliferation and metastasis abilities. Tumorigenicity mediated by HM13 was also observed in the xenograft model. Knockdown of HM13 could activate autophagy by inducing endoplasmic reticulum (ER) stress. Moreover, further experiments demonstrated that downregulated HM13 could inhibit PI3K-AKT-mTOR pathway. We then verified that HM13 was a direct target of miR-760 functioned as a tumor -suppressor in breast cancer. And the tumor suppressive effects of miR-760 could be partially reversed by HM13. Taken together, these findings elucidated that HM13, targeted by miR-760, could play an oncogenic role in breast cancer by inducing autophagic inhibition and facilitating PI3K-AKT-mTOR pathway. Our findings suggested HM13 could act as a novel therapeutic target candidate for breast cancer and supported the idea that autophagy inducers might represent a new approach to treat breast cancer.

Tonkinensine B induces apoptosis through mitochondrial dysfunction and inactivation of the PI3K/AKT pathway in triple-negative breast cancer cells.

Tonkinensine B, a novel compound with cytisine-pterocarpan skeleton isolated from the root of Sophora tonkinensis Gagnep, was reported to have a significant antitumor effect. The effect and intrinsic mechanism of tonkinensine B on tumour need to be further investigated. With the help of cell cytotoxicity, the effect of tonkinensine B on MDA-MB-231 cells was investigated. By observing mitochondrial function changes, the intrinsic mechanism was further studied. The levels of key apoptosis-associated proteins Bcl-2, Bax, caspase-9, caspase-3 and AKT in MDA-MB-231 cells were analysed to determine whether tonkinensine B caused apoptosis via the mitochondrial pathway. After treated with tonkinensine B, MDA-MB-231 cells multiplication was repressed, and the decreased mitochondrial membrane potential, loss of ATP synthesis and elevated ROS generation were detected. Furthermore, the proportions of Bax/Bcl-2, cleaved caspase-3 and caspase-9 proteins production were up-regulated, indicating that tonkinensine B acted on intrinsic mitochondrial-mediated apoptosis pathway. In addition, tonkinensine B also reduced phosphorylation levels of AKT, and thus the activation of apoptosis might likewise be correlated with the inhibition of the PI3K/AKT pathway. Tonkinensine B may be a hopeful candidate for human triple-negative breast cancer, and further structural optimization is expected to improve its anti-tumour activity.

Design of multifunctional ethosomes for topical fenretinide delivery and breast cancer chemoprevention

Fenretinide (FENR) is a chemopreventive drug candidate for breast cancer. However, it is an off-the-shelf drug mainly due to its high hydrophobicity and low bioavailability. Herein, we employed a quality by design (QbD) approach to tune ethosomes for innovative FENR topical administration and breast cancer chemoprevention. Ethosomes were selected based on their ability to incorporate poorly soluble drugs and improve their penetration in the skin. Mixed systems (micelles and vesicles) and binary systems (containing ethanol and propylene glycol) were produced by ethanol injection (EI) and film hydration (FH) based on QbD. Skin penetration was assayed using porcine ear skin as model, while cytotoxicity was assayed in tumor (MCF-7) and non-tumor (MCF-10A) cells. For EI, higher values of temperature increased size and PDI; adjustment of the stirring speed and flow rate enabled the obtainment of ethosomes of 200–400 nm (PDI ≤ 0.3) and zeta potential of −18 to −20 mV. For FH, increasing the stirring speed reduced size, but extrusion was necessary to obtain systems of 100–150 nm (PDI < 0.2). The incorporation of FENR was maximized in binary systems, reaching ~50%. Compared to the control solution, mixed and binary systems increased FENR delivery into the epidermis+dermis by 3–4- and 5-fold, respectively. Only binary systems increased drug delivery across the skin and did not reduce the viability of MCF-10A cells, suggesting tolerability. In conclusion, QbD enabled the optimization of ethosomes, and FENR incorporation into an aqueous-based delivery system capable of enhancing skin penetration without compromising the in vitro cytotoxicity and selectivity against cancer cells.

Synthesis and cytotoxic activity of N-(4-bromo)-benzoyl-N’phenylthiourea and 4-(tert-butyl)-N-benzoylurea on primary cells of HER2-Positive breast cancer

Many of the breast cancer treatments use chemotherapeutic agents in the form of synthetic drugs. Some thiourea and benzoylurea derivatives have been proven to inhibit the proliferation of breast cancer cells. Up until now, the derivation compounds are still being developed. In this study, we synthesized two compounds namely N-(4-bromo)-benzoyl-N'-phenylthiourea and 4-(tert-butyl)-N-benzoylurea. Before the two compounds were synthesized, the prediction of cytotoxic activity in silico was first performed by docking the synthesis compounds with the HER2 receptor (PDB code: 3PP0). The results of the in-silico test are Rerank Score (RS) value using the MVD program (Molegro Virtual Doker). Acyl nucleophilic substitution was carried out to synthesize the compounds. The structure of the synthesized compounds was identified using FTIR, 1H-NMR, 13C-NMR and Mass Spectrometry. In vitro cytotoxic activity was carried out on HER2-positive primary breast cancer cells and produced IC50 values. The results showed that the RS value of N-(4-bromo)-benzoyl-N'-phenylthiourea was smaller (-99.21kcal/mol) than 4-(tert-butyl)-N-benzoylurea (-88.86kcal/mol), meanwhile the RS value of hydroxyurea as a comparison compound which has a urea group and anticancer activity of -34.60kcal/mol. IC50 values of N-(4-bromo)-benzoyl-N’-phenylthiourea and 4-(tert-butyl)-N-benzoylurea were 0.54 mM and 0.61mM respectively. Hydroxyurea had an IC50 value of 11.61mM. It can be concluded that N-(4-bromo)-benzoyl-N’-phenylthiourea was more potent than 4-(tert-butyl)-N-benzoylurea so it can be developed further as an anticancer candidate for HER2-positive breast cancer.

Development of New Oncolytic Virotherapy Targeting Breast Cancer Using Coxsackievirus B3.

Breast cancer is the most common cancer in women worldwide, and triple-negative breast cancer (TNBC) is highly refractory to current standard therapies. Oncolytic virotherapy has recently gathered attention as a new treatment candidate for refractory cancers. We previously developed a new Coxsackievirus B3 (CVB3) virotherapy targeting lung cancers, and demonstrated that miRNA target sequence insertion into CVB3 reduced its pathogenicity, retaining its original oncolytic activity. In this study, we examined the oncolytic effects of CVB3 against breast cancer cells including TNBC cells. CVB3 infection killed breast cancer cells in a time- and titer-dependent manner, and induced apoptosis. Nude mice transplanted with human TNBC cells were successfully treated with both CVB3-WT and CVB3-HP. Importantly, mice treated with CVB3-HP showed very few adverse events. CVB3-HP is a strong oncolytic virus candidate for breast cancer, including TNBC, due to its remarkable oncolytic efficacy and improved safety profile.

Discovery of novel DNA methylation biomarkers for non-invasive sporadic breast cancer detection in the Latino population.

Human diversity is one of the main pitfalls in the development of robust worldwide biomarkers in oncology. Epigenetic variability across human populations is associated with different genetic backgrounds, as well as variable lifestyles and environmental exposures, each of which should be investigated. To identify potential non-invasive biomarkers of sporadic breast cancer in the Uruguayan population, we studied genome-wide DNA methylation using Illumina methylation arrays in leukocytes of 22 women with sporadic breast cancer and 10 healthy women in a case-control study. We described a panel of 38 differentially methylated CpG positions that was able to cluster breast cancer patients (BCP) and controls, and that also recapitulated methylation differences in 12 primary breast tumors and their matched normal breast tissue. Moving forward, we simplified the detection method to improve its applicability in a clinical setting and used an independent well-characterized cohort of 80 leukocyte DNA samples from BCP and 80 healthy controls to validate methylation results at specific cancer-related genes. Our investigations identified methylation at CYFIP1 as a novel epigenetic biomarker candidate for sporadic breast cancer in the Uruguayan population. These results provide a proof-of-concept for the design of larger studies aimed at validating biomarker panels for the Latin American population.