Targeting intracellular B2 receptors using novel cell-penetrating antagonists to arrest growth and induce apoptosis in human triple-negative breast cancer

Dubuc, Céléna; Savard, Martin; Bovenzi, Veronica; Lessard, Andrée; Fortier, Audrey; Côté, Jérôme; Neugebauer, Witold; Rizzolio, Flavio; Geha, Sameh; Giordano, Antonio; Chemtob, Sylvain; Gobeil, Fernand

doi:10.18632/oncotarget.24009

Cited by 21 publications

(21 citation statements)

References 80 publications

(108 reference statements)

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“…From a clinical standpoint, these tumours are frequently resistant to treatment, have quick progression, low 5‐year survival rate, increased local recurrence and are highly metastatic. This kind of tumours can be observed at any age; however, they mostly occur accompanied by BRCA1 mutations in younger women (>40 years of age) . Chemotherapy is the treatment of choice for triple‐negative breast cancer patients, of which Doxorubicin and Taxol are the standard chemotherapeutic agents used as anticancer therapy in combination with α‐HER2/neu receptor targeted therapy.…”

Section: Introductionmentioning

confidence: 99%

The toxic effect of cytostatics on primary cilia frequency and multiciliation

Filipová

Díaz-García

Bezrouk

et al. 2019

J Cellular Molecular Medi

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The primary cilium is considered as a key component of morphological cellular stability. However, cancer cells are notorious for lacking primary cilia in most cases, depending upon the tumour type. Previous reports have shown the effect of starvation and cytostatics on ciliogenesis in normal and cancer cells although with limited success, especially when concerning the latter. In this study, we evaluated the presence and frequency of primary cilia in breast fibroblasts and in triple‐negative breast cancer cells after treatment with cytostatics finding that, in the case of breast fibroblasts, primary cilia were detected at their highest incidence 72 hours after treatment with 120 nM doxorubicin. Further, multiciliated cells were also detected after treatment with 80 nM doxorubicin. On the other hand, treatment with taxol increased the number of ciliated cells only at low concentrations (1.25 and 3.25 nM) and did not induce multiciliation. Interestingly, triple‐negative breast cancer cells did not present primary cilia after treatment with either doxorubicin or taxol. This is the first study reporting the presence of multiple primary cilia in breast fibroblasts induced by doxorubicin. However, the null effect of these cytostatics on primary cilia incidence in the evaluated triple negative breast carcinomas cell lines requires further research.

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Section: Introductionmentioning

confidence: 99%

The toxic effect of cytostatics on primary cilia frequency and multiciliation

Filipová

Díaz-García

Bezrouk

et al. 2019

J Cellular Molecular Medi

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“…B2R is considered to be widely expressed in human cancer and in experimental murine tumors (27). Targeting B2R using cell-penetrating antagonists has been shown to arrest the growth and induce the apoptosis of human triple-negative breast cancer (28). The BK antagonist dimer, CU201, has been shown to inhibit the growth of small cell lung cancer (SCLC) and non-small cell lung cancers (NSCLC) cell lines but to have no effect on the growth of normal lung cells (29).…”

Section: Discussionmentioning

confidence: 99%

Serum bradykinin levels as a diagnostic marker in cervical cancer with a potential mechanism to promote VEGF expression via BDKRB2

et al. 2019

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Bradykinin (BK) is one of the kinin peptides and preferentially binds to bradykinin B2 receptor (BDKRB2). A recent study indicated that BK played an important role in the occurrence and progression of cancer. In this study, we evaluated the serum BK levels in 130 cervical cancer (CC) cases (including 65 cases with pre- and post-surgery paired samples, another 65 cases with only pre-surgery samples), 35 cervical intraepithelial neoplasia (CIN) cases (pre- and post-surgery paired) and 35 control cases. We found that BK was overexpressed in patients with CC compared to patients with CIN and the control group. When combined with squamous cell carcinoma-related antigen (SCCA), the diagnostic efficacy of BK was prominently enhanced. Moreover, we detected the expression level of the BK receptor BDKRB2 in CC, CIN and normal cervical tissues and observed a higher expression in the CC and CIN tissues than in the normal cervix. We then explored the possible mechanisms of action of BK in promoting the progression of CC. When BK was added to the cell culture medium, human umbilical vein endothelial cell (HUVEC) angiogenesis increased and vascular endothelial growth factor (VEGF) expression in CC cell lines was also elevated. The BK antagonist, HOE140, exerted an opposite effect. The knockdown or the overexpression of BDKRB2 in CC cell lines further confirmed its oncogenic role in angiogenesis. Taken together, the findings of this study suggest that BK may be a diagnostic biomarker for CC and may notably improve the diagnostic efficacy when combined with SCCA. BK promotes the progression of CC by upregulating the expression of VEGF via BDKRB2 and subsequently facilitating angiogenesis.

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“…IHC staining of B2R was performed with an automated system (Dako Autostainer plus) using the Envision Flex High pH visualization system (Dako, Agilent Technologies, Mississauga, ON, CA) [ 19 ]. To this end, sections were stained with the rabbit polyclonal anti-B2R antisera AS277-83 (1:2000; kindly given by Dr. W. Müller-Esterl, University of Frankfurt Medical School, Germany) whose target specificity has been described elsewhere [ 66 , 67 , 68 , 69 ]. Negative controls (sections with isotype control antibody—normal goat IgG, AB-108-C, R&D Systems or normal rabbit IgG, 2729S, CST) were included to verify the specificity of immunostaining.…”

Section: Methodsmentioning

confidence: 99%

Pharmacological Modulation of Blood–Brain Barrier Permeability by Kinin Analogs in Normal and Pathologic Conditions

et al. 2020

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The blood–brain barrier (BBB) is a major obstacle to the development of effective diagnostics and therapeutics for brain cancers and other central nervous system diseases. Peptide agonist analogs of kinin B1 and B2 receptors, acting as BBB permeabilizers, have been utilized to overcome this barrier. The purpose of the study was to provide new insights for the potential utility of kinin analogs as brain drug delivery adjuvants. In vivo imaging studies were conducted in various animal models (primary/secondary brain cancers, late radiation-induced brain injury) to quantify BBB permeability in response to kinin agonist administrations. Results showed that kinin B1 (B1R) and B2 receptors (B2R) agonists increase the BBB penetration of chemotherapeutic doxorubicin to glioma sites, with additive effects when applied in combination. B2R agonist also enabled extravasation of high-molecular-weight fluorescent dextrans (155 kDa and 2 MDa) in brains of normal mice. Moreover, a systemic single dose of B2R agonist did not increase the incidence of metastatic brain tumors originating from circulating breast cancer cells. Lastly, B2R agonist promoted the selective delivery of co-injected diagnostic MRI agent Magnevist in irradiated brain areas, depicting increased vascular B2R expression. Altogether, our findings suggest additional evidence for using kinin analogs to facilitate specific access of drugs to the brain.

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Targeting intracellular B2 receptors using novel cell-penetrating antagonists to arrest growth and induce apoptosis in human triple-negative breast cancer

Cited by 21 publications

References 80 publications

The toxic effect of cytostatics on primary cilia frequency and multiciliation

The toxic effect of cytostatics on primary cilia frequency and multiciliation

Serum bradykinin levels as a diagnostic marker in cervical cancer with a potential mechanism to promote VEGF expression via BDKRB2

Pharmacological Modulation of Blood–Brain Barrier Permeability by Kinin Analogs in Normal and Pathologic Conditions

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