scholarly journals Exploring the Application of Bifunctional Metal Chelators in Treating Triple-Negative Breast Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Kuo Li ◽  
Youjiu Zhang ◽  
Xiaomei Wang ◽  
Ran Zhu ◽  
Changsheng Ma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Body Weight ◽  
Cell Viability ◽  
Triple Negative Breast Cancer ◽  
Nude Mice ◽  
Triple Negative ◽  
Cell Activity ◽  
The Body ◽  
Cell Binding ◽  
Binding Rate

Purpose: In this study, we independently synthesised and labelled a novel bidentate bifunctional chelating agent, 177Lu-3,4-HOPO-Cetuximab, that achieved tight binding between targeting and radioactivity, and evaluated its targeted killing ability of cells in vitro and in vivo.Method: 3,4-HOPO was successfully synthesised through a series of chemical steps using malt phenol as the raw material, which was then coupled with Cetuximab labelled with 177Lu. 177Lu-3,4-HOPO-Cetuximab and 177Lu-DOTA-Cetuximab was tested for its cell viability and cell-binding rate after different times and at different doses by CCK-8 and cell-binding experiments. 177Lu-3,4-HOPO-Cetuximab (~500 μCi) and 177Lu-DOTA-Cetuximab (~500 μCi) were injected into the tail vein of a subcutaneous metastasis mouse model of triple-negative breast cancer with a single injection, and tumour volume growth and body weight changes were regularly monitored for 20 days. The radioactivity distribution in nude mice was analysed after sacrifice, and the treated and untreated tumour tissues were analysed by HE staining.Result: The cell viability of 177Lu-3,4-HOPO-Cetuximab declined exponentially after treatment for 48 h at 50 Bq/mL to 500 kBq/mL, respectively; the cell activity was slowed down from 8 to 96 h at a dose of 500 kBq; while the binding rate of 4T1 cells in 177Lu-3,4-HOPO-Cetuximab from 1 to 24 h, respectively, increased logarithmically, which was similar with 177Lu-DOTA-Cetuximab. After 20 days of treatment, the body weight of nude mice with 177Lu-3,4-HOPO-Cetuximab and 177Lu-DOTA-Cetuximab were hardly changed, while the body weight with physiological saline decreased significantly. The tumour inhibition rate of the 177Lu-3,4-HOPO-Cetuximab and 177Lu-DOTA-Cetuximab were (37.03 ± 11.16)% and (38.7 ± 5.1)%; HE staining showed that tumour cells were affected by the action of 177Lu causing necrosis.Conclusion: The experiments showed that 177Lu-3,4-HOPO-Cetuximab has a certain targeted therapeutic ability for triple-negative breast cancer, and it is expected to become a potential targeted nuclear medicine treatment for triple-negative breast cancer.

Abstract 17055: Novel Dual mTOR Inhibitor/AMPK Activator Mitigates Doxorubicin Cardiotoxicity and Potentiates Its Chemotherapeutic Efficacy Against Triple Negative Breast Cancer

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Anindita Das ◽  
Sahak Hovsepian ◽  
Sayantanee Das ◽  
Arun Samidurai ◽  
Adolfo G Mauro ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Body Weight ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Mtor Inhibitor ◽  
Triple Negative ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Chemotherapeutic Efficacy

Background: Doxorubicin (DOX) is a first-line anticancer drug for the treatment of triple negative breast cancer (TNBC). However, its dose-dependent delayed and progressive cardiotoxicity limits its therapeutic application. NovoMedix (NM922) is a novel dual mTOR inhibitor/AMPK activator that was shown to attenuate adverse cardiac remodeling and fibrosis in a pressure-overload mouse model of heart failure. We investigated whether combination therapy with DOX and NM922 exhibits synergistic chemotherapeutic effect while mitigating DOX cardiotoxicity. Methods & Results: Tumors were generated in athymic female BALB/cAnNCr-nu/nu mice by implanting MDA-MB-231 cells into the rear right flank. Mice with tumors (volume≈200mm 3 ) were randomized into 6 groups and treated as follows: 1) Control (n=10); 2) DOX (3 mg/kg; i.p. twice weekly, total 15 mg/kg; n=10); 3) NM922 (25 mg/kg/d; p.o. n=5); 4) DOX+NM922 (25 mg/kg/d; p.o. n=15); 5) NM922 (100 mg/kg/d; p.o. n=5); 6) DOX+NM922 (100 mg/kg/d; p.o. n=15). Tumor size, body weight and cardiac function were assessed throughout the study. DOX alone, and to a significant extent when in combination with NM922 (25 mg/kg) reduced tumor growth compared to control. NM922 (100 mg/kg) with/without DOX significantly reduced tumor growth as compared to DOX alone (Fig A). DOX caused reduction in body weight and survival of tumor-bearing mice. NM922 did not prevent DOX-induced cachexia, but significantly improved survival in DOX-treated mice (Fig B). DOX treatment caused a significant decline in left ventricular ejection fraction compared to control over 3 weeks, which was ameliorated with NM922 (100 mg/kg) co-treatment (Fig C&D). Conclusion: Our results suggest that NM922 may potentiate the chemotherapeutic efficacy of DOX in TNBC, while mitigating its cardiotoxicity. Moreover, these findings advocate the potential efficacy of utilizing lower DOX dosages when combined with NM922, which would have significant clinical implications.

scholarly journals APR-246 alone and in combination with a phosphatidylserine-targeting antibody inhibits lung metastasis of human triple-negative breast cancer cells in nude mice

2019 ◽  
Vol Volume 11 ◽  
pp. 249-259
Author(s):  
Yayun Liang ◽  
Cynthia Besch-Williford ◽  
Matthew T Cook ◽  
Anthony Belenchia ◽  
Rolf A Brekken ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Lung Metastasis ◽  
Triple Negative Breast Cancer ◽  
Nude Mice ◽  
Breast Cancer Cells ◽  
Triple Negative

scholarly journals LXR-inverse agonism stimulates immune-mediated tumor destruction by enhancing CD8 T-cell activity in triple negative breast cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Katherine J. Carpenter ◽  
Aurore-Cecile Valfort ◽  
Nick Steinauer ◽  
Arindam Chatterjee ◽  
Suomia Abuirqeba ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Cell ◽  
Cell Activity ◽  
Cd8 T Cell ◽  
Tumor Immune Evasion ◽  
Tumor Destruction ◽  
Immune Mediated

AbstractTriple-negative breast cancer (TNBC) is a highly aggressive subtype that is untreatable with hormonal or HER2-targeted therapies and is also typically unresponsive to checkpoint-blockade immunotherapy. Within the tumor microenvironment dysregulated immune cell metabolism has emerged as a key mechanism of tumor immune-evasion. We have discovered that the Liver-X-Receptors (LXRα and LXRβ), nuclear receptors known to regulate lipid metabolism and tumor-immune interaction, are highly activated in TNBC tumor associated myeloid cells. We therefore theorized that inhibiting LXR would induce immune-mediated TNBC-tumor clearance. Here we show that pharmacological inhibition of LXR activity induces tumor destruction primarily through stimulation of CD8+ T-cell cytotoxic activity and mitochondrial metabolism. Our results imply that LXR inverse agonists may be a promising new class of TNBC immunotherapies.

scholarly journals Evaluation of chidamide and PFI-1 as a combination therapy for triple-negative breast cancer

2020 ◽  
Vol 19 (2) ◽  
pp. 259-264
Author(s):  
Nong Lin ◽  
Qiaolu Yang ◽  
Tong Xu ◽  
Lianguo Shi
Keyword(s):  
Breast Cancer ◽  
Combination Therapy ◽  
Cell Viability ◽  
Breast Cancer Cell ◽  
Triple Negative Breast Cancer ◽  
Histone Deacetylases ◽  
Triple Negative ◽  
Inhibitory Effect

Purpose: To evaluate the in vitro and in vivo effects of the combination therapy of histone deacetylases (HDAsC) inhibitor, chidamide, and bromodomain-containing proteins (BETs) inhibitor, PFI-1, on triplenegative breast cancer (TNBC). Methods: Four distinct breast cancer cell lines and one TNBC mouse model were treated with vehicle, chidamide, PFI-1 alone, or chidamide and PFI-1. The inhibitory effect of chidamide or PFI-1 on HDACs and BETs was assessed by HDAC enzyme inhibition and AlphaScreen assays. Cell viability was determined by MTT assay while protein expression of p-STAT3 was evaluated by western blotting and immunohistochemistry (IHC) staining assay. Results: Chidamide exerted inhibitory effect on HDACs while PFI-1 inhibited BET proteins. The threedimensional model demonstrated the interactions between chidamide and HDAC2, and between PFI-1 and BRD4. Chidamide or PFI-1 exerted inhibitory effects on breast cancer cell proliferation in vitro. However, the combination of PFI-1 and chidamide significantly inhibit MDA-MB-231 cell viability, and decrease the expression of p-STAT3, when compared to that treated with chidamide or PFI-1 alone. Moreover, the combined inhibitory effect of PFI-1 and chidamide on tumor growth was also found in the in vivo mice experiments. Conclusion: The combination of chidamide and PFI-1 is a potential is a potential therapeutic strategy for the management of TNBC. Keywords: Triple-negative breast cancer, Histone deacetylases, Bromodomain

scholarly journals Role of GPX4-Mediated Ferroptosis in the Sensitivity of Triple Negative Breast Cancer Cells to Gefitinib

2020 ◽  
Author(s):  
Xiang Song ◽  
Xinzhao Wang ◽  
Zhaoyun Liu ◽  
Zhiyong Yu
Keyword(s):  
Breast Cancer ◽  
Cell Viability ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Tumor Model ◽  
Tunel Staining ◽  
Ki 67 ◽  
In Vivo Experiments ◽  
Related Proteins

Abstract Background: Gefitinib exhibits antitumor activity in the patients with breast cancer, but the resistance to gefitinib in triple negative breast cancer (TNBC) is a new concern. Glutathione peroxidase 4 (GPX4) is a leading regulator of ferroptosis, which is of importance for the survival of TNBC cells. This study investigated GPX4-mediated ferroptosis in gefitinib sensitivity in TNBC.Methods: Gefitinib resistant TNBC cells MDA-MB-231/Gef and HS578T/Gef were constructed, and treated with lentivirus sh-GPX4 and ferroptosis inhibitor ferrostatin-1. GPX4 expression, cell viability and apoptosis were detected. Malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS) levels were evaluated. The levels of ferroptosis-related proteins ACSL4, PTGS2, NOX1 and FTH1 were detected. Subcutaneous tumor model was established in nude mice, and gefitinib was intraperitoneally injected. Apoptosis was detected by TUNEL staining and Ki-67 expression was detected by immunohistochemistry.Results: GPX4 was increased in gefitinib-resistant cells. After silencing GPX4, the inhibition rate of cell viability increased, the limitation of colony formation ability reduced, apoptosis rate increased, and the sensitivity of cells to gefitinib was improved. After silencing GPX4, MDA level and ROS production were significantly increased, while GSH level was decreased. Silencing GPX4 promoted ferroptosis. After inhibition of ferroptosis by ferrostatin-1, it revealed that inhibition of GPX4 promoted gefitinib sensitivity by promoting cell ferroptosis. In vivo experiments also showed that inhibition of GPX4 enhanced the anticancer effect of gefitinib through promoting ferroptosis.Conclusion: Inhibition of GPX4 stimulated ferroptosis and thus enhanced TNBC cell sensitivity to gefitinib.

scholarly journals The Valuable Role of Holo-lactoferrin in Ferroptosis and Its Application in Radiotherapy of Triple Negative Breast Cancer (P05-014-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Zheng Zhang ◽  
Jiaying Xu ◽  
Li Qiang Qin ◽  
Yang Kai
Keyword(s):  
Breast Cancer ◽  
Cell Viability ◽  
Triple Negative Breast Cancer ◽  
Natural Science ◽  
Triple Negative ◽  
Academic Program ◽  
Jiangsu Province ◽  
Ros Generation ◽  
Mcf 7

Abstract Objectives Holo-lactoferrin (Holo-Lf) is one kind of iron-saturated form of lactoferrin. Our study is to observe the role of Holo-Lf in ferroptosis and radiotherapy of breast cancer. Methods Triple negative breast cancer (TMBC) cells MDA-MB-231 and non-TMBC cells MCF-7 cells were treated with Apo-Lf and Holo-Lf, separately. After 24 h, cell viability was determined by CCK-8. To observe the role of Holo-Lf in ferroptosis, MDA-MB-231 and MCF-7 cells were treated with Apo-Lf, Holo-Lf in combine with ferroptosis activator Erastin. After 24 h, cells were incubated with PI and ROS probe. The fluorescence intensity of PI and ROS were examined by CLSM. Besides, cells also collected for the detection of GPX-4 expression. To demonstrate the H2O2 catalytic effect of Holo-Lf, MDA-MB-231 cells were incubated with 1 mM H2O2 after treated with Holo-Lf, and followed by a 4 Gy radiation. Finally, the ROS of cells and cell viability were detected by CCK-8 and CLSM. Results Cell viability of MDA-MB-231was significantly inhibited by Holo-Lf. After combined with Erastin, the cell viability was further inhibited. Notably, the fluorescence of PI and ROS in cells treated with Holo-Lf and Erastin were higher than other groups. By contrast, Apo-Lf significant lower the fluorescence of PI in MDA-MB-231 cells and decrease the generation of ROS in MDA-MB-231 cells. However, these results were not obtained in MCF-7 cells. Additionally, the expression of GPX-4 both in MDA-MB-231 and MCF-7 cells were significant down regulated by the treatment of Holo-Lf. As a contrast, Apo-Lf could significant up regulated the expression of GPX-4 in both cells. Besides, the ROS generation of MDA-MB-231 cells treated with Holo-Lf and H2O2 combined with 4 Gy radiation were significantly higher than cells in other groups. Conclusions Holo-Lf can specially enhance the ferroptosis of Erastin to MDA-MB-231 cells. Holo-Lf also can relieve the hypoxia microenvironment and enhance the inhibition effect of radiotherapy to MDA-MB-231 cells. Funding Sources This work was supported in part by the Outstanding Youth Science Foundation, the National Natural Science Foundation of China, the National Natural Science Foundation of Jiangsu Province, Postgraduate Research & Practice Innovation Program of Jiangsu Province, and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). Supporting Tables, Images and/or Graphs

Hydroxytyrosol and Oleuropein Inhibit Migration and Invasion of MDA-MB-231 Triple-Negative Breast Cancer Cell via Induction of Autophagy

2020 ◽  
Vol 19 (16) ◽  
pp. 1983-1990 ◽  
Author(s):  
Hui-Yuan Lu ◽  
Jian-Sheng Zhu ◽  
Zhan Zhang ◽  
Wei-Jian Shen ◽  
Shan Jiang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Viability ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Chemotherapeutic Agents ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Cell Migration And Invasion

Background: Breast Cancer (BC) is the leading cause of cancer-related deaths among women. As such, novel chemotherapeutic agents are urgently needed, especially for Triple-Negative Breast Cancer (TNBC). Hydroxytyrosol (HT) and Oleuropein (OL) are rich in olive oil, which is associated with a low occurrence of BC. However, the effects and mechanisms of action of HT and OL in BC cells are still unclear. This study aimed to explore the molecular mechanisms underlying the antitumor effect of HT and OL in TNBC. Methods: TNBC MDA-MB-231 cells were treated with HT and OL in combination with Hepatocyte Growth Factor (HGF), rapamycin (Rapa, an inducer of autophagy) or 3-methyladenine (3-MA, an inhibitor of autophagy). Cell viability, migration, invasion, and autophagy signaling were analyzed by scratch assays, transwell migration assays, and Western blot analysis. Results: Treatment with HT or OL reduced MDA-MB-231 cell viability in a dose-dependent manner. MDAMB- 231 cells were more sensitive to HT treatment than OL treatment. Rapa treatment could significantly block HGF-induced MDA-MB-231 cell migration and invasion, suggesting that inhibition of autophagy could promote migration and invasion. Moreover, HT or OL treatment significantly suppressed HGF or 3-MA induced cell migration and invasion by reversing LC3-II/LC3-I and Beclin-1 downregulation and reversing p62 upregulation. Conclusion: These data indicated that HT and OL may inhibit migration and invasion of TNBC cells by activating autophagy. These findings provide potential therapeutic strategies that target autophagy to limit the pathogenesis and progression of BC.

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