[10]-Gingerol improves doxorubicin anticancer activity and decreases its side effects in triple negative breast cancer models

Background and objective:Bevacizumab (BVZ) is a recombinant humanized antibody that inhibits the vascular endothelial growth factor A (VEGFA) and is used for the treatment of various types of cancer. BVZ is primarily given by the intravenous drip (I.V.), which often leads to low efficacy and various side effects. Therefore, the present study was to evaluate the effect of local delivery of BVZ against triple-negative breast cancer (TNBC) xenograft tumors.Methods:Mice 4T1 TNBC cells were engrafted in female BALB/c mice. After the tumors reached about 5 mm (diameter), animals were treated with BVZ through the local injection from four directions around the tumors. The tumor growth, survival and potential mechanisms of action were evaluated.Results:The growth and microvessel density of engrafted tumors were dramatically reduced with the tumor inhibition rate of 32.8 ± 3%. No obvious side effects were observed. The expression of VEGFA, VEGF receptor (VEGFR), matrix metalloproteinase (MMP)-2, MMP-9, Delta-like ligand 4 (DLL4) and Integrin-5 was significantly reduced in TNBC tumor tissues. In contrast, tissue inhibitor of matrix metalloproteinase (TIMP)-2 was significantly upregulated in xenograft tumors. Additionally, local delivery of BVZ led to the reduction of VEGFA and tumor necrosis factor (TNF)-alpha in the serum. Protein-protein interaction (PPI) analysis revealed that the proteins altered by the local delivery of BVZ were associated with angiogenesis and regulation of cell migration.Conclusion:This study provided evidence associated with local delivery of BVZ against TNBC tumors supporting the use of BVZ local injections to overcome some of the disadvantages associated with I.V. therapy with BVZ.

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Mechanistic Study on Thymoquinone Conjugated ZnO Nanoparticles Mediated Cytotoxicity and Anticancer Activity in Triple Negative Breast Cancer Cells

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210412104731 ◽

2021 ◽

Vol 21 ◽

Author(s):

Sampath K. Banupriya ◽

Krishnamoorthy Kavithaa ◽

Arumugam Poornima ◽

Sundaravadivelu Sumathi

Keyword(s):

Breast Cancer ◽

Anticancer Activity ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Zno Nanoparticles ◽

Breast Cancer Cells ◽

Triple Negative ◽

Molecular Techniques ◽

Mechanistic Study ◽

Spectroscopic Techniques

Background: In the current era, development of molecular techniques involves nanotechniques and the synthesis of nanoparticles is considered as the preferred field in nanotechnology. Objective: The aim of the present work is to analyze the anticancer activity of the thymoquinone conjugated ZnO nanoparticles and to understand its mechanism of action in triple negative breast cancer cell line MDA-MB-231. Methods: Zinc Oxide (ZnO) nanoparticles have extensive applications and it was synthesized using a chemical precipitation method. Thymoquinone (TQ) is the major bioactive component of the seeds of Nigella sativa. Synthesized nanoparticles were characterized using various spectroscopic techniques. Thymoquinone coated nanoparticles were checked for its efficiency. The cytotoxicity of ZnO, TQ and TQ conjugated ZnO nanoparticles against MDA-MB-231. Colony forming and cell migration assay were performed to measure the proliferative competence of the breast cancer cells on exposure to nanoparticles. The mechanism of apoptosis was probed by assessing MMP, interplay between ER stress and ROS. Results: The results of the characterization techniques confirmed the particles synthesized were ZnO and TQ-ZnO nanoparticles. pH dependent release of the compound was observed. Anti-proliferative effect that impairs the formation of colony was found to be enhanced in cells exposed to combined treatment with the nanoconjugate. Conclusion: Hence, the TQ conjugated ZnO nanoparticles can act as an efficient carrier for drug delivery at the target site in TNBC cells.

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Enhanced Anticancer Activity of Nanoformulation of Dasatinib against Triple-Negative Breast Cancer by Reduced Metabolic Degradation

10.20944/preprints202104.0724.v1 ◽

2021 ◽

Author(s):

Fatemah Bahman ◽

Valeria Pittalà ◽

Mohamed Haider ◽

Khaled Greish

Keyword(s):

Breast Cancer ◽

Anticancer Activity ◽

Triple Negative Breast Cancer ◽

Tyrosine Kinases ◽

Triple Negative ◽

Growth Factor Receptor ◽

Initial Response ◽

Response To Chemotherapy

Triple negative breast cancer (TNBC) is the most aggressive breast cancer accounting for around 15% of identified breast cancer cases. TNBC, by lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is unresponsive to current targeted therapies. Existing treatment relies on chemotherapeutic treatment but, despite an initial response to chemotherapy, the inception of resistance and relapse is unfortunately common. Dasatinib is an approved second-generation inhibitor of multiple tyrosine kinases and literature data strongly support its use in the management of TNBC. However, dasatinib binds to plasma proteins and undergoes extensive metabolism through oxidation and conjugation. To protect dasatinib from fast pharmacokinetic degradation and to prolong its activity, it was encapsulated on poly(styrene-co-maleic acid) (SMA) micelles. The obtained SMA-dasatinib nanoparticles (NPs) were evaluated for their physicochemical properties, in vitro antiproliferative activity in different TNBC cell lines, and in vivo anticancer activity in a syngeneic model of breast cancer. Obtained results showed that SMA-dasatinib is more potent against 4T1 TNBC tumor growth in vivo compared to free drug. This enhanced effect was ascribed to the encapsulation of the drug protecting it from a rapid metabolism. Our finding highlights the often-overlooked value of nanoformulations in protecting its cargo from degradation. Overall, results may provide an alternative therapeutic strategy for TNBC management.

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Triple Negative Breast Cancer: A review of common therapeutic Targets and Current Treatment options.

University of Ottawa Journal of Medicine ◽

10.18192/uojm.v7i1.1563 ◽

2017 ◽

Vol 7 (1) ◽

Author(s):

Daud Akhtar ◽

Ahsen Chaudhry

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Side Effects ◽

Triple Negative Breast Cancer ◽

Cancer Du Sein ◽

Triple Negative ◽

Treatment Options ◽

Cell Signalling ◽

Effets Secondaires ◽

Breast Cancer Chemotherapy

Triple negative breast cancer (TNBC) is a subtype of breast cancer which lacks ER, PR, and HER2 expression. It is characterized by poor prognosis and resistance to standard treatment forms for breast cancer. Chemotherapy is still currently the core neo-adjuvant treatment option for patients with TNBC, although it has mixed levels of efficacy on overall survival and many serious side effects. Platinum- based therapies have been used to treat TNBC in conjunction with chemotherapy, but they are not a widely effective treatment due to the heterogeneity of TNBC. For this reason, other novel approaches, particularly those which target molecular components involved in TNBC pathogenesis, are being investigated. Angiogenesis inhibitors, which include monoclonal antibodies or small molecules that inhibit VEGF, have been shown to improve progression-free survival, but have not demonstrated an impact on overall survival. PARP enzyme inhibitors, when combined with chemotherapy and carboplatin for the treatment of TNBC, have demonstrated a significant reduction in risk progression and mortality. However, the majority of PARP inhibitors are still in trials and their effectiveness in clini- cal settings has yet to be determined. Additional proposed targets for directed therapy against TNBC include cell signalling pathways involving EGFR or PI3K. Overall, issues such as treatment resistance and side effects are important challenges that must be overcome in order to enable improvements in patient prognosis and clinical impact. RÉSUMÉ Le cancer du sein triple négatif (CSTN) est un sous-type de cancer du sein auquel il manque les récepteurs d’œstrogènes (ER), les récepteurs de progestérone (PR) et l’expression de HER2. Il est caractérisé par un pronostic défavorable et une résistance aux traite- ments standards du cancer du sein. À l’heure actuelle, la chimiothérapie est encore l’option principale de traitement néoadjuvant pour les patients ayant le CSTN, bien qu’elle ait des niveaux variés d’efficacité sur la survie globale, ainsi que de nombreux effets secondaires sérieux. Les thérapies à base de platine ont été utilisées pour traiter le CSTN en conjonction avec la chimiothérapie, mais elles ne sont pas très efficaces étant donné l’hétérogénéité du CSTN. En raison de cela, d’autres approches novatrices, particulièrement celles qui ciblent les composantes moléculaires impliquées dans la pathogenèse du CSTN, font actuellement l’objet d’enquêtes. Les inhibiteurs de l’angiogenèse, dont les anticorps monoclonaux ou les petites molécules inhibant le VEGF, ont démontré la capacité d’améliorer la survie sans progression de la maladie, mais n’ont pas démontré d’impact sur la survie globale. Les inhibiteurs d’enzymes PARP, lorsque combinés avec la chimiothérapie et le carboplatine pour le traitement du CSTN, ont démontré une réduction significative du risque de progression et de la mortalité. Toutefois, la majorité des inhibiteurs PARP subissent encore des essais et leur efficacité clinique reste à être déterminée. D’autres cibles suggérées pour la thérapie dirigée contre le CSTN incluent les voies de signalisation impliquant le EGFR ou le PI3K. Dans l’ensemble, des problèmes tels la résistance au traitement et les effets secondaires sont des défis importants qui doivent être surmontés afin de permettre des améliorations au niveau du pronostic du patient et de l’impact clinique.

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