scholarly journals Combined CB2 receptor agonist and photodynamic therapy synergistically inhibit tumor growth in triple negative breast cancer

2018 ◽  
Vol 24 ◽  
pp. 185-191 ◽  
Author(s):  
Jiliang Zhang ◽  
Shaojuan Zhang ◽  
Yang Liu ◽  
Meng Su ◽  
Xiaoxi Ling ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Photodynamic Therapy ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Receptor Agonist ◽  
Triple Negative ◽  
Cb2 Receptor ◽  
Inhibit Tumor Growth

scholarly journals Edelfosine nanoemulsions inhibit tumor growth of triple negative breast cancer in zebrafish xenograft model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sofia M. Saraiva ◽  
Carlha Gutiérrez-Lovera ◽  
Jeannette Martínez-Val ◽  
Sainza Lores ◽  
Belén L. Bouzo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Xenograft Model ◽  
Skin Barrier ◽  
Zebrafish Embryos ◽  
Biorelevant Media

AbstractTriple negative breast cancer (TNBC) is known for being very aggressive, heterogeneous and highly metastatic. The standard of care treatment is still chemotherapy, with adjacent toxicity and low efficacy, highlighting the need for alternative and more effective therapeutic strategies. Edelfosine, an alkyl-lysophospholipid, has proved to be a promising therapy for several cancer types, upon delivery in lipid nanoparticles. Therefore, the objective of this work was to explore the potential of edelfosine for the treatment of TNBC. Edelfosine nanoemulsions (ET-NEs) composed by edelfosine, Miglyol 812 and phosphatidylcholine as excipients, due to their good safety profile, presented an average size of about 120 nm and a neutral zeta potential, and were stable in biorelevant media. The ability of ET-NEs to interrupt tumor growth in TNBC was demonstrated both in vitro, using a highly aggressive and invasive TNBC cell line, and in vivo, using zebrafish embryos. Importantly, ET-NEs were able to penetrate through the skin barrier of MDA-MB 231 xenografted zebrafish embryos, into the yolk sac, leading to an effective decrease of highly aggressive and invasive tumoral cells’ proliferation. Altogether the results demonstrate the potential of ET-NEs for the development of new therapeutic approaches for TNBC.

scholarly journals The extracellular-regulated protein kinase 5 (ERK5) enhances metastatic burden in triple-negative breast cancer through focal adhesion protein kinase (FAK)-mediated regulation of cell adhesion

Oncogene ◽  
2021 ◽  
Author(s):  
Qiuping Xu ◽  
Jingwei Zhang ◽  
Brian A. Telfer ◽  
Hao Zhang ◽  
Nisha Ali ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Kinase ◽  
Tumor Growth ◽  
Focal Adhesion ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Adhesion Protein ◽  
Focal Adhesion Protein

AbstractThere is overwhelming clinical evidence that the extracellular-regulated protein kinase 5 (ERK5) is significantly dysregulated in human breast cancer. However, there is no definite understanding of the requirement of ERK5 in tumor growth and metastasis due to very limited characterization of the pathway in disease models. In this study, we report that a high level of ERK5 is a predictive marker of metastatic breast cancer. Mechanistically, our in vitro data revealed that ERK5 was critical for maintaining the invasive capability of triple-negative breast cancer (TNBC) cells through focal adhesion protein kinase (FAK) activation. Specifically, we found that phosphorylation of FAK at Tyr397 was controlled by a kinase-independent function of ERK5. Accordingly, silencing ERK5 in mammary tumor grafts impaired FAK phosphorylation at Tyr397 and suppressed TNBC cell metastasis to the lung without preventing tumor growth. Collectively, these results establish a functional relationship between ERK5 and FAK signaling in promoting malignancy. Thus, targeting the oncogenic ERK5-FAK axis represents a promising therapeutic strategy for breast cancer exhibiting aggressive clinical behavior.

scholarly journals The targetable nanoparticle BAF312@cRGD-CaP-NP represses tumor growth and angiogenesis by downregulating the S1PR1/P-STAT3/VEGFA axis in triple-negative breast cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ke Gong ◽  
Juyang Jiao ◽  
Chaoqun Xu ◽  
Yang Dong ◽  
Dongxiao Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Umbilical Vein ◽  
Phosphate Ions ◽  
Sphingosine 1 Phosphate ◽  
Umbilical Vein Endothelial Cells ◽  
Endothelial Growth Factor

Abstract Background Overexpressed vascular endothelial growth factor A (VEGFA) and phosphorylated signal transducer and activator of transcription 3 (P-STAT3) cause unrestricted tumor growth and angiogenesis of breast cancer (BRCA), especially triple-negative breast cancer (TNBC). Hence, novel treatment strategy is urgently needed. Results We found sphingosine 1 phosphate receptor 1 (S1PR1) can regulate P-STAT3/VEGFA. Database showed S1PR1 is highly expressed in BRCA and causes the poor prognosis of patients. Interrupting the expression of S1PR1 could inhibit the growth of human breast cancer cells (MCF-7 and MDA-MB-231) and suppress the angiogenesis of human umbilical vein endothelial cells (HUVECs) via affecting S1PR1/P-STAT3/VEGFA axis. Siponimod (BAF312) is a selective antagonist of S1PR1, which inhibits tumor growth and angiogenesis in vitro by downregulating the S1PR1/P-STAT3/VEGFA axis. We prepared pH-sensitive and tumor-targeted shell-core structure nanoparticles, in which hydrophilic PEG2000 modified with the cyclic Arg-Gly-Asp (cRGD) formed the shell, hydrophobic DSPE formed the core, and CaP (calcium and phosphate ions) was adsorbed onto the shell; the nanoparticles were used to deliver BAF312 (BAF312@cRGD-CaP-NPs). The size and potential of the nanoparticles were 109.9 ± 1.002 nm and − 10.6 ± 0.056 mV. The incorporation efficacy for BAF312 was 81.4%. Results confirmed BAF312@cRGD-CaP-NP could dramatically inhibit tumor growth and angiogenesis in vitro and in MDA-MB-231 tumor-bearing mice via downregulating the S1PR1/P-STAT3/VEGFA axis. Conclusions Our data suggest a potent role for BAF312@cRGD-CaP-NPs in treating BRCA, especially TNBC by downregulating the S1PR1/P-STAT3/VEGFA axis. Graphic abstract

scholarly journals Biomimetic oxygen delivery nanoparticles for enhancing photodynamic therapy in triple-negative breast cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hanyi Fang ◽  
Yongkang Gai ◽  
Sheng Wang ◽  
Qingyao Liu ◽  
Xiao Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Photodynamic Therapy ◽  
Cancer Cell ◽  
Triple Negative Breast Cancer ◽  
Oxygen Delivery ◽  
Therapeutic Efficacy ◽  
Triple Negative ◽  
Oxygen Solubility ◽  
Post Injection

Abstract Background Triple-negative breast cancer (TNBC) is a kind of aggressive breast cancer with a high rate of metastasis, poor overall survival time, and a low response to targeted therapies. To improve the therapeutic efficacy and overcome the drug resistance of TNBC treatments, here we developed the cancer cell membrane-coated oxygen delivery nanoprobe, CCm–HSA–ICG–PFTBA, which can improve the hypoxia at tumor sites and enhance the therapeutic efficacy of the photodynamic therapy (PDT), resulting in relieving the tumor growth in TNBC xenografts. Results The size of the CCm–HSA–ICG–PFTBA was 131.3 ± 1.08 nm. The in vitro 1O2 and ROS concentrations of the CCm–HSA–ICG–PFTBA group were both significantly higher than those of the other groups (P < 0.001). In vivo fluorescence imaging revealed that the best time window was at 24 h post-injection of the CCm–HSA–ICG–PFTBA. Both in vivo 18F-FMISO PET imaging and ex vivo immunofluorescence staining results exhibited that the tumor hypoxia was significantly improved at 24 h post-injection of the CCm–HSA–ICG–PFTBA. For in vivo PDT treatment, the tumor volume and weight of the CCm–HSA–ICG–PFTBA with NIR group were both the smallest among all the groups and significantly decreased compared to the untreated group (P < 0.01). No obvious biotoxicity was observed by the injection of CCm–HSA–ICG–PFTBA till 14 days. Conclusions By using the high oxygen solubility of perfluorocarbon (PFC) and the homologous targeting ability of cancer cell membranes, CCm–HSA–ICG–PFTBA can target tumor tissues, mitigate the hypoxia of the tumor microenvironment, and enhance the PDT efficacy in TNBC xenografts. Furthermore, the HSA, ICG, and PFC are all FDA-approved materials, which render the nanoparticles highly biocompatible and enhance the potential for clinical translation in the treatment of TNBC patients.

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 Biomimetic Oxygen Delivery Nanoparticles for Enhancing Photodynamic Therapy in Triple-negative Breast Cancer

2021 ◽  
Author(s):  
Hanyi Fang ◽  
Yongkang Gai ◽  
Sheng Wang ◽  
Qingyao Liu ◽  
Xiao Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Photodynamic Therapy ◽  
Cancer Cell ◽  
Triple Negative Breast Cancer ◽  
Oxygen Delivery ◽  
Therapeutic Efficacy ◽  
Triple Negative ◽  
Oxygen Solubility ◽  
Post Injection

Abstract Background Triple-negative breast cancer (TNBC) is a kind of aggressive breast cancer with a high rate of metastasis, poor overall survival time, and a low response to targeted therapies. To improve the therapeutic efficacy and overcome the drug resistance of TNBC treatments, here we developed the cancer cell membrane-coated oxygen delivery nanoprobe, CCm-HSA-ICG-PFTBA, which can improve the hypoxia at tumor sites and enhance the therapeutic efficacy of the photodynamic therapy (PDT), resulting in relieving the tumor growth in TNBC xenografts. Results The size of the CCm-HSA-ICG-PFTBA was 131.3 ± 1.08 nm. The in vitro 1O2 and ROS concentrations of the CCm-HSA-ICG-PFTBA group were both significantly higher than those of the other groups (P < 0.001). In vivo fluorescence imaging revealed that the best time window was at 24 h post-injection of the CCm-HSA-ICG-PFTBA. Both in vivo 18F-FMISO PET imaging and ex vivo immunofluorescence staining results exhibited that the tumor hypoxia was significantly improved at 24 h post-injection of the CCm-HSA-ICG-PFTBA. For in vivo PDT treatment, the tumor volume and weight of the CCm-HSA-ICG-PFTBA with NIR group were both the smallest among all the groups and significantly decreased compared to the untreated group (P < 0.01). No obvious biotoxicity was observed by the injection of CCm-HSA-ICG-PFTBA till 14 days. Conclusions By using the high oxygen solubility of perfluorocarbon (PFC) and the homologous targeting ability of cancer cell membranes, CCm-HSA-ICG-PFTBA can target tumor tissues, mitigate the hypoxia of the tumor microenvironment, and enhance the PDT efficacy in TNBC xenografts. Furthermore, the HSA, ICG, and PFC are all FDA-approved materials, which render the nanoparticles highly biocompatible and enhance the potential for clinical translation in the treatment of TNBC patients.

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