Breast Cancer Xenografts Research Articles

Novel Chiral Ru(II) Complexes as Potential c-myc G-quadruplex DNA Stabilizers Inducing DNA Damage to Suppress Triple-Negative Breast Cancer Progression.

Currently, effective drugs for triple-negative breast cancer (TNBC) are lacking in clinics. c-myc is one of the core members during TNBC tumorigenesis, and G-rich sequences in the promoter region can form a G-quadruplex conformation, indicating that the c-myc inhibitor is a possible strategy to fight cancer. Herein, a series of chiral ruthenium(II) complexes ([Ru(bpy)2(DPPZ-R)](ClO4)2, Λ/Δ-1: R = -H, Λ/Δ-2: R = -Br, Λ/Δ-3: R = -C≡C(C6H4)NH2) were researched based on their interaction with c-myc G-quadruplex DNA. Λ-3 and Δ-3 show high affinity and stability to decrease their replication. Additional studies showed that Λ-3 and Δ-3 exhibit higher inhibition against different tumor cells than other molecules. Δ-3 decreases the viability of MDA-MB-231 cells with an IC50 of 25.51 μM, which is comparable with that of cisplatin, with an IC50 of 25.9 μM. Moreover, Δ-3 exhibits acceptable cytotoxic activity against MDA-MB-231 cells in a zebrafish xenograft breast cancer model. Further studies suggested that Δ-3 decreases the viability of MDA-MB-231 cells predominantly through DNA-damage-mediated apoptosis, which may be because Δ-3 can induce DNA damage. In summary, the results indicate that Ru(II) complexes containing alkinyl groups can be developed as c-myc G-quadruplex DNA binders to block TNBC progression.

Doxorubicin resistance in breast cancer xenografts and cell lines can be counterweighted by microRNA-140-3p, through PD-L1 suppression.

Doxorubicin, a first-line chemotherapeutic drug for breast cancer, kills cancer cells by inducing DNA-crosslinking damage. Dysregulated micro-RNA (miRNA) is associated with the drug resistance of tumors. However, little is known about the effect of miRNA-140-3p on DOX resistance of breast cancer. The miRNA microarray was used to sequence the transcripts of DOX-chemoresistant breast cancer tissues and DOX-chemosensitive tissues. Then, the breast cancer tissue chip in the GEO database was also analyzed to screen the target gene. Flow cytometry, in situ hybridisation (ISH), immunohistochemistry (IHC), Western blot, cell proliferation assay, real-time PCR analyses (qRT-PCR), and pull-down assay were used to explore the effects of miRNA-140-3p and programmed death ligand-1 (PD-L1) on the chemoresistance of DOX-resistant breast cancer cells treated with DOX. In vivo, the DOX-resistant breast cancer cell lines treated with miRNA-140-3p overexpression were injected subcutaneously into mice to construct breast cancer subcutaneous xenograft tumor models. Based on miRNA microarray, GEO database, and bioinformatics analysis, it was found that miRNA-140-3p and PD-L1 are the core molecules in the DOX resistance regulatory network in breast cancer, and lower miRNA-140-3p and higher PD-L1 expression levels were observed in DOX-resistant breast cancer tissues and cells. IHC results showed that compared with breast cancer tissues with high miRNA-140-3p expression, PD-L1 protein expression levels in breast cancer tissues with low miRNA-140-3p were significantly higher (P<0.01). Moreover, compared with DOX-sensitive tissues, the levels of PD-L1 protein expression in DOX-resistant tissues were significantly higher (P<0.01). In in vitro and in vivo experiments, the introduction of miRNA-140-3p decreased PD-L1 expression. Mechanically, we found that the MCF-7/DOX and HS598T/DOX cells pretreated with miRNA-140-3p inhibitor or exosomes containing PD-L1 have higher stemness and lower apoptosis rate, which can be abrogated by co-treating cells with anti-PD-L1 antibody or miRNA-140-3p mimic. MiRNA-140-3p can suppress PD-L1 expression in breast cancer cell-derived exosomes, thereby attenuating the chemoresistance induced by DOX in breast cancer.

EPH/Ephrin-Targeting Treatment in Breast Cancer: A New Chapter in Breast Cancer Therapy

Breast cancer (BC) is the most common malignant tumor in women. Erythropoietin-producing hepatocellular receptors (EPHs), receptor tyrosine kinases binding the membrane-bound proteins ephrins, are differentially expressed in BC, and correlate with carcinogenesis and tumor progression. With a view to examining available therapeutics targeting the EPH/ephrin system in BC, a literature review was conducted, using the MEDLINE, LIVIVO, and Google Scholar databases. EPHA2 is the most studied EPH/ephrin target in BC treatment. The targeting of EPHA2, EPHA10, EPHB4, ephrin-A2, ephrin-A4, as well as ephrin-B2 in BC cells or xenograft models is associated with apoptosis induction, tumor regression, anticancer immune response activation, and impaired cell motility. In conclusion, EPHs/ephrins seem to represent promising future treatment targets in BC.

DAB2IP attenuates chemoresistance of triple-negative breast cancer through sequestration of RAC1 to prevent β-catenin nuclear accumulation.

Although chemotherapy, the most widely used systemic treatment in triple-negative breast cancer (TNBC), markedly improved the patients' outcome, chemoresistance always occurs. This study purposed to explore new therapeutic strategies for the treatment of chemoresistance. The expression and prognostic value of DAB2IP were investigated in TNBC tissues and cell lines. Low DAB2IP expression predicted high mortality risk in TNBC. Inhibition of DAB2IP expression conferred cancer stem cell capacity and chemoresistance in TNBC cell lines. Using murine breast cancer (BC) xenograft models, we evaluated the association with DAB2IP and chemoresistance. DAB2IP inhibited TNBC tumourigenesis and chemoresistance in vivo. Further, we revealed that DAB2IP inhibited β-catenin nuclear transport through competitive interaction with RAC1 and decreased β-catenin accumulation in the cell nucleus. Finally, we found that the DNA methylation level was negatively associated with DAB2IP expression in TNBC. Inhibition of DNA methylation restored the DAB2IP expression and attenuated chemoresistance in TNBC. We revealed that DAB2IP attenuates chemoresistance of TNBC via inhibition of RAC1-mediated β-catenin nuclear accumulation. Decitabine treatment results in re-expression of DAB2IP by inhibiting DNA methylation and could be a potential therapeutic strategy for chemoresistance in TNBC.

Gibberellin derivative GA-13315 overcomes multidrug resistance in breast cancer by up-regulating BMP6 expression.

Chemoresistance represents a major obstacle in breast cancer treatment. Bone morphogenetic protein 6 (BMP6) was reported to participate in the occurrence and development of various tumors. In the present study, the results of transcriptome sequencing, qRT-PCR and western blot analysis revealed that BMP6 was down-regulated in multidrug resistant MCF-7/Adr breast cancer cells and BMP6 overexpression sensitized MCF-7/Adr cells to chemotherapeutic drugs, indicating that BMP6 downregulation was involved in the mechanisms of multidrug resistance (MDR) of MCF-7/Adr breast cancer cells. GA-13315 (GA5) is a new tetracyclic diterpenoid selected from a series of gibberellin derivatives. Here, we found that GA5 exhibited more potent anti-tumor activity in multidrug resistant MCF-7/Adr breast cancer cells and xenografts, indicating that GA5 could overcome MDR. Mechanistically, GA5 increased BMP6 expression, and BPM6 knockdown partially reversed the inhibitory effect of GA5 on cell proliferation. Furthermore, we found that ERK phosphorylation and P-gp expression were increased in MCF-7/Adr cells when compared with MCF-7 cells. Either overexpression of BMP6 or treatment the cells with GA5 significantly decreased ERK phosphorylation and P-gp expression, indicating that GA5 reversed MDR of MCF-7/Adr cells by upregulating BMP6, thereby inhibiting the activation of ERK signaling pathway and reducing P-gp expression. Collectively, our present study demonstrated that the MDR of MCF-7/Adr cells was closely related to the low expression of BMP6, and revealed the molecular mechanisms by which GA5 overcame MDR in breast cancer, providing evidence in supporting the development of GA5 to be a promising agent for overcoming MDR in clinical cancer therapy in the future.

A diverse treatment with the extract of Euphorbia fischeriana Steud. and Ziziphus jujuba Mill. for breast cancer nude mice of MCF-7 (ER+) cells or MDA-MB-453 (ER-) cells via modulation of the PI3k/Akt signalling pathway

BackgroundThe extract of Euphorbia fischeriana Steud. and Ziziphus jujuba Mill. (ESZM) is a formula composed of Euphorbia fischeriana Steud. (E. fischeriana) and Ziziphus jujuba Mill. (Z. jujuba). Previous studies have shown that the ESZM extract has good anti-breast cancer effects in vitro. However, its in vivo therapeutic efficacy and underlying mechanism are still unclear, particularly for different subtypes of breast cancer. Our study aimed to investigate the pharmacological effects and the underlying molecular mechanism of the ESZM extract on growth inhibition and apoptosis in breast cancer nude mice of MCF-7 (ER+) cells or MDA-MB-453 (ER-) cells MethodologyIn this paper, growth inhibition, cell cycle arrest and apoptosis of tumour tissues treated with the ESZM extract in ER(+) or ER(-) breast cancer xenografts were determined based on the tumour inhibition rates, using a cycle analysis kit, Annexin V-FITC/PI and Hoechst 33,342/PI staining and TEM observations, and a TUNEL test. The related gene and protein expression levels were measured using a qRT-PCR assay, Western blotting, immunohistochemistry and immunofluorescence. Serum biochemistry tests and H&E staining were performed to evaluate the toxicity of the ESZM extract. ResultsThe results showed that the ESZM extract could inhibit the cell growth, block the cell cycle at the G2/M phase, and induce the apoptosis of subcutaneously transplanted tumours, especially of ER(-) breast cancer transplanted tumours. Furthermore, we demonstrated that the polyjuice could down-regulate or up-regulate the expression of the Bcl-2 family factors and of PI3k/Akt pathway-related signalling molecules in vivo. The ESZM extract increased the levels of ALT, AST, Cr and BUN, and increased the hepatic and renal toxicity in cancer-bearing mice. Conclusionsthese experimental results indicate that the ESZM extract has significant anti-breast cancer effects, particularly in ER(-) breast cancer xenografts, which might be implemented through the mitochondrion-dependant and the PI3k/Akt signalling pathways. The toxicity tests showed that the ESZM extract may have hepatorenal toxicity. Finally, we believe that the ESZM extract can be developed as a novel therapeutic option for the treatment of breast carcinoma.

Leveraging a Dual Variable Domain Immunoglobulin to Create a Site-Specifically Modified Radioimmunoconjugate.

Site-specifically modified radioimmunoconjugates exhibit superior in vitro and in vivo behavior compared to analogues synthesized via traditional stochastic methods. However, the development of approaches to site-specific bioconjugation that combine high levels of selectivity, simple reaction conditions, and clinical translatability remains a challenge. Herein, we describe a novel solution to this problem: the use of dual-variable domain immunoglobulins (DVD-IgG). More specifically, we report the synthesis, in vitro evaluation, and in vivo validation of a 177Lu-labeled radioimmunoconjugate based on HER2DVD, a DVD-IgG containing the HER2-targeting variable domains of trastuzumab and the catalytic variable domains of IgG h38C2. To this end, we first modified HER2DVD with a phenyloxadiazolyl methlysulfone-modified variant of the chelator CHX-A″-DTPA (PODS-CHX-A''-DTPA) and verified the site-specificity of the conjugation for the reactive lysines within the catalytic domains via chemical assay, MALDI-ToF mass spectrometry, and SDS-PAGE. The chelator-bearing immunoconjugate was subsequently labeled with [177Lu]Lu3+ to produce the completed radioimmunoconjugate, [177Lu]Lu-CHX-A″-DTPAPODS-HER2DVD, in >80% radiochemical conversion and a specific activity of 29.5 ± 7.1 GBq/μmol. [177Lu]Lu-CHX-A″-DTPAPODS-HER2DVD did not form aggregates upon prolonged incubation in human serum, displayed 87% stability to demetalation over a 7 days of incubation in serum, and exhibited an immunoreactive fraction of 0.95 with HER2-coated beads. Finally, we compared the pharmacokinetic profile of [177Lu]Lu-CHX-A″-DTPAPODS-HER2DVD to that of a 177Lu-labeled variant of trastuzumab in mice bearing subcutaneous HER2-expressing BT-474 human breast cancer xenografts. The in vivo performance of [177Lu]Lu-CHX-A″-DTPAPODS-HER2DVD matched that of 177Lu-labeled trastuzumab, with the former producing a tumoral activity concentration of 34.1 ± 12.1 %ID/g at 168 h and tumor-to-blood, tumor-to-liver, and tumor-to-kidney activity concentration ratios of 10.5, 9.6, and 21.8, respectively, at the same time point. Importantly, the DVD-IgG did not exhibit a substantially longer serum half-life than the traditional IgG despite its significantly larger size (202 kDa for the former vs 148 kDa for the latter). Taken together, these data suggest that DVD-IgGs represent a viable platform for the future development of highly effective site-specifically labeled radioimmunoconjugates for diagnostic imaging, theranostic imaging, and radioimmunotherapy.

Effect of histone deacetylase 8 gene deletion on breast cancer cellular mechanism in vitro and in vivo study

BackgroundTriple-negative breast cancer (TNBC) is the most aggressive type of cancer without any approved targeted therapy. Epigenetic processes have a pivotal role in cancer cell progression and while histone deacetylase 8 (HDAC8) has been proven as a potential oncogene in breast cancer, its underlying molecular mechanism is not known. Therefore, the present study, aimed to evaluate the underlying mechanism of the HDAC8 carcinogenesis in breast cancer progression. MethodsThe potential role of HDAC8 in cancer cell processes such as apoptosis, invasion, migration, angiogenesis, and cancer stem cells (CSCs) markers were evaluated by using flow cytometry Annexin V-FITC/propidium iodide (PI), reverse transcription-polymerase chain reaction (RT-qPCR), Matrigel-coated transwell plates and wound healing assay on both cell lines. The impact of HDAC8 on tumor development was also studied using a breast cancer xenograft model. ResultsHDAC8 expression was significantly downregulated in the cell lines, post-transfection with KO-vector. Downregulation of HDAC8 dramatically decreased cell migration, angiogenesis, and invasion while inducing apoptosis in MDAMB-468 and MDA-MB-231 cell lines. HDAC8 knocked out TNBC cell lines had lower levels of cancer stemness markers, such as prominin-1 (CD133), CD44, BMI1, and Aldehyde dehydrogenase 1 (ALDH1). Additionally, the knockout of HDAC8 inhibited tumor growth in a breast cancer xenograft model. ConclusionThe findings show that knocking out HDAC8 retains several anticancer actions in BC cells, such as inducing apoptosis, reducing migration, invasion, angiogenesis and removing CSCs markers.

A cytotoxic survey on 2-amino-1H-imidazol based synthetic marine sponge alkaloid analogues.

Here, we describe the synthesis and biologic activity evaluation of 20 novel synthetic marine sponge alkaloid analogues with 2-amino-1H-imidazol (2-AI) core. Cytotoxicity was tested on murine 4T1 breast cancer, A549 human lung cancer, and HL-60 human myeloid leukemia cells by the resazurin assay. A total of 18 of 20 compounds showed cytotoxic effect on the cancer cell lines with different potential. Viability of healthy human fibroblasts and peripheral blood mononuclear cells upon treatment was less hampered compared to cancer cell lines supporting tumor cell specific cytotoxicity of our compounds. The most cytotoxic compounds resulted the following IC50 values 28: 2.91 µM on HL-60 cells, and 29: 3.1 µM on 4T1 cells. The A549 cells were less sensitive to the treatments with IC50 15 µM for both 28 and 29. Flow cytometry demonstrated the apoptotic effect of the most active seven compounds inducing phosphatidylserine exposure and sub-G1 fragmentation of nuclear DNA. Cell cycle arrest was also observed. Four compounds caused depolarization of the mitochondrial membrane potential as an early event of apoptosis. Two lead compounds inhibited tumor growth in vivo in the 4T1 triple negative breast cancer and A549 human lung adenocarcinoma xenograft models. Novel marine sponge alkaloid analogues are demonstrated as potential anticancer agents for further development.

Therapeutic efficacy of the humanized JAA-F11 anti-Thomsen-Friedenreich antibody constructs H2aL2a and H3L3 in human breast and lung cancer xenograft models.

The Thomsen-Friedenreich antigen (TF-Ag-α) is found on ~85% of human carcinomas but is cryptic on normal tissue. The humanized highly specific hJAA-F11-H2aL2a and -H3L3 antibodies target TF-Ag-α without binding to TF-Ag-beta (found on surface glycolipids of some normal cells). The relative affinity of H3L3 is 17 times that of H2aL2a, which would seem to favor superior efficacy, however, increased affinity can result in less tumor penetration. To assess the potential therapeutic efficacy of these antibodies, four human cancer- mouse xenograft models were treated with H2aL2a and H3L3.The tumor xenograft models used were human non-small cell lung cancer, H520, and small cell lung cancer, HTB171 in nude mice and human triple negative breast cancer, MDA-MB-231 and HCC1806 in SCID mice. H2aL2a significantly decreased tumor growth in both breast and both lung cancer models. H2aL2a showed statistically equal or better efficacy than H3L3 and has superior production capabilities. These results suggest that H2aL2a may be superior as a naked antibody, as an antibody drug conjugate or as a radiolabeled antibody, however the higher affinity of H3L3 may lead to better efficacy in bi-specific therapies in which the binding is decreased due to the presence of only one TF-Ag-α binding site.

Biomimetic hybrid-cell membrane nanoparticles loaded with panaxytriol for breast cancer combinational therapy

Breast cancer is the most prevalent cancer with an unfavorable prognosis in women, which seriously threatened women’s health worldwide. In our previous study, a phytoconstituent, panaxytriol (PA), isolated from a Tujia ethnomedicine Panax japonicus, showed excellent inhibitory effects on APE1 activity, an enzyme tightly related with the development of breast cancer. Considering the tumor cell-killing ability and poor bioavailability of PA in vivo, Prussian blue nanoparticles with dopamine surface modification were applied to enhance its therapeutic efficacy against breast cancer by combining with photodynamic agent of indocyanine green. The hybrid-cell membrane (microphage and erythrocyte membranes) camouflage of the nano-delivery system significantly improved the solubility and targeting ability to tumor regions with increased immune evasion. This Prussian blue nanoparticle-based biomimetic formulation, introduced via tail vein administration, was validated as an efficient PA delivery vehicle for inhibiting the growth of breast cancer xenografts in nude mice. Molecular experiments revealed that the antitumor activity was mediated through cell proliferation inhibition and apoptosis induction. Our results prove that comprehensive therapy combining PA with nanomaterials may provide an effective strategy for treating breast cancer in vivo.

Vicinal Diaryl-Substituted Isoxazole and Pyrazole Derivatives with In Vitro Growth Inhibitory and In Vivo Antitumor Activity.

The vicinal diaryl heterocyclic framework has been widely used for the development of compounds with significant bioactivities. In this study, a series of diaryl heterocycles were designed and synthesized based on an in-house diaryl isoxazole derivative (9), and most of the newly synthesized derivatives demonstrated moderate to good antiproliferative activities against a panel of hepatocellular carcinoma and breast cancer cells, exemplified with the diaryl isoxazole 11 and the diaryl pyrazole 85 with IC50 values in the range of 0.7–9.5 μM. Treatments with both 11 and 85 induced apoptosis in these tumor cells, and they displayed antitumor activity in vivo in the Mahlavu hepatocellular carcinoma and the MDA-MB-231 breast cancer xenograft models, indicating that these compounds could be considered as leads for further development of antitumor agents. Important structural features of this compound class for the antitumor activity have also been proposed, which warrant further exploration to guide the design of new and more potent diaryl heterocycles.

337 (PB117) - Identification and molecular characterization of invasive lobular breast cancer models in a panel of 180 breast XPDX models

Background: Invasive lobular and ductal breast tumors have distinct histologies and clinical presentation. Invasive lobular cancer (ILC) characteristics include somatic alterations in the CDH1 gene leading to loss of E-cadherin expression, low HER2 expression, frequent loss of PTEN, increased AKT expression and mutations in PIK3CA, TBX3 and FOXA1 genes. Invasive ductal cancers (IDC) express E-cadherin and more often include HER2+ cancers and ESR1 mutations. The XenoSTART Patient-Derived Xenograft (XPDX) breast cancer platform includes over 180 models spanning all subtypes characterized with immunohistochemistry (IHC) including ERα, PR and HER2 protein levels, genomic and transcriptomic sequencing and in in vivo drug sensitivity. To further annotate our platform, we classified each breast XPDX model as ILC or IDC based on clinical history, E-cadherin staining, presence of variants in target genes and HER2 expression or amplification. Methods: XPDX models were established and validated as previously described and further characterized using IHC to determine E-cadherin protein levels (Abcam a-Rabbit ab15148). Analysis was performed on WES to identify variants in CDH1, PIK3CA, TBX3, FOXA1 and PTEN. RNAseq data was used to determine expression levels of AKT and HER2. Clinical histology data was also used for ILC versus IDC classification. Resulting models classified as ILC by our analysis were histologically confirmed by a clinical pathologist. Results: 180 breast models were examined by IHC and 25/180 (14%) lacked E-cadherin staining. Six of these 25 models (24%) reported CDH1 variants including deletions, frameshifts and point mutations. PIK3CA mutations, most notably H1047R, were reported in 5/25 models and FOXA1 (Q209E) was co-mutated in 2 of these models (ST2167 and ST2167/TDR). High AKT1 expression was reported in 5/25 models. While most E-cadherin-negative models were from clinically HER2 negative patients, 4/25 were from clinically HER2+ patients and corresponding models retained HER2 staining and amplification. 3/25 models were clinically classified as metaplastic and did not contain any target gene variant. Conclusion: We screened 180 models in our XPDX breast cancer platform and identified at least twenty-two ILC models based on E-cadherin staining, genomics and clinical histology, and confirmed heterogeneity of this subtype of breast cancer. Additonal analysis is underway to compare sensitivity of chemotherapy and targeted agents in ILC and IDC-classified breast models. No conflict of interest.

Tumor growth monitoring in breast cancer xenografts: A good technique for a strong ethic.

PurposeAlthough recent regulations improved conditions of laboratory animals, their use remains essential in cancer research to determine treatment efficacy. In most cases, such experiments are performed on xenografted animals for which tumor volume is mostly estimated from caliper measurements. However, many formulas have been employed for this estimation and no standardization is available yet.MethodsUsing previous animal studies, we compared all formulas used by the scientific community in 2019. Data were collected from 93 mice orthotopically xenografted with human breast cancer cells. All formulas were evaluated and ranked based on correlation and lower mean relative error. They were then used in a Gompertz quantitative model of tumor growth.ResultsSeven formulas for tumor volume estimation were identified and a statistically significant difference was observed among them (ANOVA test, p < 2.10−16), with the ellipsoid formula (1/6 π × L × W × (L + W)/2) being the most accurate (mean relative error = 0.272 ± 0.201). This was confirmed by the mathematical modeling analysis where this formula resulted in the smallest estimated residual variability. Interestingly, such result was no longer valid for tumors over 1968 ± 425 mg, for which a cubic formula (L x W x H) should be preferred.Main findingsWhen considering that tumor volume remains under 1500mm3, to limit animal stress, improve tumor growth monitoring and go toward mathematic models, the following formula 1/6 π × L × W x (L + W)/2 should be preferred.

Solid phase radiosynthesis of an olaparib derivative using 4-[18F] fluorobenzoic acid and in vivo evaluation in breast and prostate cancer xenograft models for PARP-1 expression

IntroductionSolid-phase synthesis and conjugation reactions of acids and amines using coupling reagents are common in organic synthesis, but rare in 18F radiochemistry. 4-[18F]Fluorobenzoic acid (FBA) is a useful building block, but is seldom used directly with coupling reagents for the preparation of 18F radiopharmaceuticals. To overcome the inconveniences associated with using [18F]FBA in conjugation reactions, we have developed a non-covalent solid-phase synthesis (SPS) strategy for the radiosynthesis of [18F]PARPi, a derivative of olaparib as a Poly (ADP-ribose) polymerase-1 (PARP-1) radioligand. MethodsFluoro-, bromo- and iodo-benzoic derivatives of olaparib were synthesized, and their PARP-1 affinities were measured using a recently developed cell culture-based competitive assay. To produce [18F]PARPi, [18F]FBA was radiosynthesized and purified using a cation-exchange cartridge, and then trapped by an anion-exchange resin cartridge, on which the solid-phase radiosynthesis was carried out to produce the desired product. [18F]PARPi was evaluated in vivo in breast and prostate xenograft tumor models by microPET imaging, biodistribution and autoradiography. ResultsThe best derivatives of olaparib were identified as compound 4, 7 and 8. [18F]4 ([18F]PARPi) was radiosynthesized in high radiochemical yield, high molar activity and high radiochemical purity using this SPS strategy. The in vivo evaluation of [18F]PARPi demonstrates the PARP-1 specific uptake of [18F]PARPi in the animal models. ConclusionsThis method is simple and efficient, having great potential for the synthesis of radiopharmaceuticals starting from [18F]FBA or other radiolabeled aromatic acids. Using [18F]PARPi prepared by this method, we demonstrated the promise of [18F]PARPi in the nuclear imaging of PARP-1 expression.

Tetrahydrocurcumin Chemosensitizes Breast Cancer to Albumin-Bound Paclitaxel by Enhancing SPARC Expression through Demethylation.

Paclitaxel is an effective chemotherapy drug for breast cancer (BC); however, drug resistance affects long-term clinical applications. In this study, we aimed to explore whether a natural compound, tetrahydrocurcumin (THC), could sensitize BC to albumin-bound paclitaxel (ab-PTX). The in vitro sensitization effect of THC to ab-PTX was evaluated in human BC cell lines, and in vivo chemosensitivity was measured using a xenograft BC tumor model. The expression of secreted protein acidic and rich in cysteine (SPARC), a speculated protein interacting with ab-PTX, was measured. Methylation-specific polymerase chain reaction (MSP) was used to further explore whether demethylation of SPARC by THC contributed to its chemosensitivity capabilities. Higher SPARC expression was correlated with a better prognosis in patients with BC. In vitro analysis showed THC enhanced the inhibitory effect of ab-PTX on BC cells and xenograft tumors and showed significant chemosensitivity. This enhancement mainly relied on upregulating the expression of SPARC through downregulating methylation of the SPARC gene. The demethylating agent, 5-Aza-2′-deoxycytidine (5-Aza-Cdr), decreased THC's chemosensitivity effect, further confirming this molecular mechanism. THC enhanced the inhibitory effect of ab-PTX in BC by downregulating methylation of the SPARC gene. Further, upregulated SPARC increased the efficacy of ab-PTX.

Resveratrol reverses TGF-β1-mediated invasion and metastasis of breast cancer cells via the SIRT3/AMPK/autophagy signal axis.

Resveratrol (Resv) has antitumorigenic and antimetastatic activities; however, the molecular mechanisms underlying the inhibitory effects of Resv on the invasion and metastasis of breast cancer cells are still a subject of debate. In our study, we demonstrated that Resv inhibited tumor cell proliferation and tumor growth. It also suppressed invasion and pulmonary metastasis of breast cancer by reversing the transforming growth factor beta 1 (TGF-β1)-mediated EMT process. Meanwhile, the anticarcinogenic effects of Resv were abolished by the autophagy blocker 3-methyladenine (3-MA) or Beclin 1 small interfering RNA. Moreover, Resv upregulated autophagy-related genes and protein levels and induced the formation of autophagosomes in 4T1 breast cancer cells and xenograft mice, suggesting that autophagy was involved in the anticarcinogenic activities of Resv in both models. In addition, Resv-induced autophagy by increasing the expression of SIRT3 and phosphorylated AMPK. SIRT3 knockdown reduced AMPK phosphorylation and autophagy-related proteins levels, and suppressed the anticancer effects of Resv, demonstrating that the inhibitory effects of Resv on tumor progression were mediated via the SIRT3/AMPK/autophagy pathway. Taken together, our study provided novel insight into the anticancer effects of Resv and revealed that targeting the SIRT3/AMPK/autophagy pathway can serve as a new therapeutic target against breast cancer.

Combination of a novel heat shock protein 90-targeted photodynamic therapy with PD-1/PD-L1 blockade induces potent systemic antitumor efficacy and abscopal effect against breast cancers

BackgroundWe previously demonstrated potent antitumor activity against human breast cancer xenografts using photodynamic therapy (PDT) targeting a novel tumor-specific photosensitizer (HS201), which binds heat shock protein 90 (HS201-PDT). However, induction...

Transcription factor-nucleosome dynamics from plasma cfDNA identifies ER-driven states in breast cancer.

Genome-wide binding profiles of estrogen receptor (ER) and FOXA1 reflect cancer state in ER+ breast cancer. However, routine profiling of tumor transcription factor (TF) binding is impractical in the clinic. Here, we show that plasma cell-free DNA (cfDNA) contains high-resolution ER and FOXA1 tumor binding profiles for breast cancer. Enrichment of TF footprints in plasma reflects the binding strength of the TF in originating tissue. We defined pure in vivo tumor TF signatures in plasma using ER+ breast cancer xenografts, which can distinguish xenografts with distinct ER states. Furthermore, state-specific ER-binding signatures can partition human breast tumors into groups with significantly different ER expression and mortality. Last, TF footprints in human plasma samples can identify the presence of ER+ breast cancer. Thus, plasma TF footprints enable minimally invasive mapping of the regulatory landscape of breast cancer in humans and open vast possibilities for clinical applications across multiple tumor types.

Pilot study of jadomycin B pharmacokinetics and anti-tumoral effects in zebrafish larvae and mouse breast cancer xenograft models.

Despite numerous therapeutic options, multidrug resistance (MDR) remains an obstacle to successful breast cancer therapy. Jadomycin B, a natural product derived from Streptomyces venezuelae ISP5230, maintains cytotoxicity in MDR human breast cancer cells. Our objectives were to evaluate the pharmacokinetics, toxicity, anti-tumoral, and anti-metastatic effects of jadomycin B in zebrafish larvae and mice. In a zebrafish larval xenograft model, jadomycin B significantly reduced the proliferation of human MDA-MB-231 cells at or below its maximum tolerated dose (40 µm). In female Balb/C mice, a single intraperitoneal dose (6mg/kg) was rapidly absorbed with a maximum serum concentration of 3.4±0.27 µm. Jadomycin B concentrations declined biphasically with an elimination half-life of 1.7±0.058h. In the 4T1 mouse mammary carcinoma model, jadomycin B (12mg/kg every 12h from day 6 to 15 after tumor cell injection) decreased primary tumor volume compared to vehicle control. Jadomycin B-treated mice did not exhibit weight loss, nor significant increases in biomarkers of impaired hepatic (alanine aminotransferase) and renal (creatinine) function. In conclusion, jadomycin B demonstrated a good safety profile and provided partial anti-tumoral effects, warranting further dose-escalation safety and efficacy studies in MDR breast cancer models.