scholarly journals A Biomimetic Drug Delivery System Targeting Tumor Hypoxia in Triple-Negative Breast Cancers

2020 ◽  
Vol 10 (3) ◽  
pp. 1075 ◽  
Author(s):  
Katyayani Tatiparti ◽  
Mohd Ahmar Rauf ◽  
Samaresh Sau ◽  
Arun K. Iyer
Keyword(s):  
Triple Negative ◽  
Apoptotic Cell ◽  
Tumor Hypoxia ◽  
Chemical Properties ◽  
Treatment Resistance ◽  
Cell Killing ◽  
Cell Uptake ◽  
Cancer Drug ◽  
Breast Cancers

Triple-negative breast cancer (TNBC) is amongst the most challenging tumor subtypes because it presents itself without the estrogen, progesterone, and HER2 receptors. Hence, assessing new markers is an essential requirement for enhancing its targeted treatment. The survival of TNBC relies upon the advancement of hypoxia that contributes to treatment resistance, immune response resistance, and tumor stroma arrangement. Here, we explored bovine serum albumin (BSA) nanoparticle encapsulating the anti-cancer drug Paclitaxel (PTX) for cell-killing mediated by tumor hypoxia. For targeting hypoxia, we conjugated Acetazolamide (ATZ) with BSA nanoparticle that encapsulated PTX (referred hereon as BSA-PTX-ATZ) utilizing copper-free click chemistry, specifically the Strain-Promoted Alkyne Azide Cycloaddition (SPAAC). The in-vitro cell killing study uncovered that BSA-PTX-ATZ is more productive contrasted with free PTX. The evaluations of the physio-chemical properties of BSA-PTX-ATZ proves that the shelf-life is approximately two months when stored either at room or freezing temperatures or under refrigerated conditions. There is no leakage of PTX from the formulation during that period, while their nanoparticulate nature remained undisturbed. The BSA-PTX-ATZ nanoparticles indicated altogether higher cell killing in hypoxic conditions contrasted with normoxia proposing the hypoxia-mediated delivery mechanism of the activity of the formulation. Higher cell uptake found with fluorescent-marked BSA-PTX-ATZ shows CA-IX mediated cell uptake, substantiated by the prominent apoptotic cell death contrasted with free PTX.

scholarly journals Carbonic Anhydrase-IX Guided Albumin Nanoparticles for Hypoxia-mediated Triple-Negative Breast Cancer Cell Killing and Imaging of Patient-derived Tumor

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2362
Author(s):  
Katyayani Tatiparti ◽  
Mohd Ahmar Rauf ◽  
Samaresh Sau ◽  
Arun K. Iyer
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Tumor Targeting ◽  
Triple Negative ◽  
Unmet Need ◽  
Cell Killing ◽  
Cell Uptake ◽  
High Rate ◽  
Tumor Xenograft

Triple-Negative Breast Cancer (TNBC) is considered as the most onerous cancer subtype, lacking the estrogen, progesterone, and HER2 receptors. Evaluating new markers is an unmet need for improving targeted therapy against TNBC. TNBC depends on several factors, including hypoxia development, which contributes to therapy resistance, immune evasion, and tumor stroma formation. In this study, we studied the curcumin analogue (3,4-Difluorobenzylidene Curcumin; CDF) encapsulated bovine serum albumin (BSA) nanoparticle for tumor targeting. For tumor targeting, we conjugated Acetazolamide (ATZ) with CDF and encapsulated it in the BSA to form a nanoparticle (namely BSA-CDF-ATZ). The in vitro cytotoxicity study suggested that BSA-CDF-ATZ is more efficient when compared to free CDF. The BSA-CDF-ATZ nanoparticles showed significantly higher cell killing in hypoxic conditions compared to normoxic conditions, suggesting better internalization of the nanoparticles into cancer cells under hypoxia. Fluorescent-dye labeled BSA-CDF-ATZ revealed higher cell uptake of the nanoparticle compared to free dye indicative of better delivery, substantiated by a high rate of apoptosis-mediated cell death compared to free CDF. The significantly higher tumor accumulation and low liver and spleen uptake in TNBC patient-derived tumor xenograft models confirm the significant potential of BSA-CDF-ATZ for targeted TNBC imaging and therapy.

scholarly journals Influence of Germline BRCA Genotype on the Survival of Patients with Triple-Negative Breast Cancer

2021 ◽  
Vol 1 (3) ◽  
pp. 140-147
Author(s):  
Cynthia Villarreal-Garza ◽  
Ana S. Ferrigno ◽  
Alejandro Aranda-Gutierrez ◽  
Paul H. Frankel ◽  
Nora H. Ruel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Point Mutations ◽  
Treatment Resistance ◽  
Cancer Center ◽  
Breast Cancers ◽  
Entire Cohort ◽  
Pathogenic Variants ◽  
Mutational Status

The presence of BRCA pathogenic variants (PV) in triple-negative breast cancer (TNBC) is associated with a distinctive genomic profile that makes the tumor particularly susceptible to DNA-damaging treatments. However, patients with BRCA PVs can develop treatment resistance through the appearance of reversion mutations and restored BRCA expression. As copy-number variants (CNV) could be less susceptible to reversion mutations than point mutations, we hypothesize that carriers of BRCA CNVs may have improved survival after treatment compared with carriers of other BRCA PVs or BRCA wild-type. Women diagnosed with stage I–III TNBC at ≤50 years at a cancer center in Mexico City were screened for BRCA PVs using a recurrent PV assay (HISPANEL; 77% sensitivity). Recurrence-free survival (RFS) and overall survival (OS) were compared according to the mutational status. Among 180 women, 17 (9%) were carriers of BRCA1 ex9–12del CNVs and 26 (14%) of other BRCA PVs. RFS at ten years for the whole cohort was 79.2% [95% confidence interval (CI), 72.3–84.6], with no significant differences according to mutational status. 10-year OS for the entire cohort was 85.3% (95% CI, 78.7–90.0), with BRCA CNV carriers demonstrating numerically superior OS rates other PV carriers and noncarriers (100% vs. 78.6% and 84.7%; log-rank P = 0.037 and P = 0.051, respectively). This study suggests that BRCA1 ex9–12del CNV carriers with TNBC may have a better OS, and supports the hypothesis that the genotype of BRCA PVs may influence survival by limiting treatment resistance mediated by reversion mutations among CNV carriers. Significance: Large CNV BRCA carriers in a cohort of young Mexican patients with TNBC had superior OS rates than carriers of other BRCA pathogenic variants (i.e., small indels or point mutations). We hypothesize that this is due to the resistance of CNVs to reversion mutations mediating resistance to therapy. If validated, these findings have important prognostic and clinical treatment implications for BRCA-associated breast cancers.

Co-loading of an anthracycline analogue Pirarubicin and Salinomycin in a 1:3 ratio into Quatramerbiodegradable polymeric nanoparticles synergistically inhibit growth of triple-negative breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15047-e15047
Author(s):  
Surender Kharbanda ◽  
Anees Mohammad ◽  
Sachchidanand Tiwari ◽  
Neha Mehrotra ◽  
Sireesh Appajosyula ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancers ◽  
Mice Model ◽  
Single Drug ◽  
Tnbc Cell ◽  
Dual Drug

e15047 Background: Triple negative breast cancer (TNBC) accounts for about 10-15% of all breast cancers and differ from other types of invasive breast cancers in that they grow and spread faster. TNBCs have limited treatment options and a worse prognosis. Therapy with anthracyclines considered to be one of the most effective agents in the treatment. Unfortunately, resistance to anthracycline therapy is very common due to drug efflux mediated by overexpression of ABC transporter. Pirarubicin (PIRA), an analogue of doxorubicin (DOX), is approved in Japan, Korea and China and is shown to be less cardiotoxic than DOX. Recent studies suggest that cancer stem cells (CSCs) play an important role in tumorigenesis and biology of TNBC. Targeting CSCs may be a promising, novel strategy for the treatment of this aggressive disease. Recent studies have shown that salinomycin (SAL) preferentially targets the viability of CSCs. Methods: SAL and PIRA were co-encapsulated in polylactic acid (PLA)-based block copolymeric nanoparticles (NPs) to efficiently co-deliver these agents to treat TNBC cells. Results: Generated SAL-PIRA co-encapsulated dual drug-loaded NPs showed an average diameter of 110 ± 7 nm, zeta potential of -12.5 mV and PDI of less than 0.25. Both of these anti-cancer agents showed slow and sustained release profile in non-physiological buffer (PBS, pH 7.4) from these dual drug-encapsulated NPs. Additionally, multiple ratios (PIRA:SAL = 3:1, 1:1, 1:3) were encapsulated to generate diverse dual drug-loaded NPs. The results demonstrate that, in contrast to 1:1 and 3:1, treatment of TNBC cells with 1:3 ratio of PIRA:SAL dual drug-loaded NPs, was associated with significant inhibition of growth in vitro in multiple TNBC cell lines. Interestingly, PIRA:SAL (1:3) was synergistic as compared to either SAL- or PIRA single drug-loaded NPs. The IC50 of PIRA and SAL in single drug-encapsulated NPs is 150 nM and 700 nM respectively in MDA-MB-468. Importantly, the IC50 of PIRA in dual drug-encapsulated NPs dropped down to 30 nM (5-fold). Similar results were obtained in SUM-149 TNBC cell line. Studies are underway to evaluate in vivo biological activity of PIRA:SAL (1:3) on tumor growth in a TNBC xenograft mice model. Conclusions: These results demonstrate that a novel dual drug-loaded NP formulation of PIRA and SAL in a unique ratio of 1:3 represents an approach for successful targeting of CSCs and bulk tumor cells in TNBC and potentially other cancer types.

scholarly journals MiR-302b as a Combinatorial Therapeutic Approach to Improve Cisplatin Chemotherapy Efficacy in Human Triple-Negative Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2261 ◽  
Author(s):  
Alessandra Cataldo ◽  
Sandra Romero-Cordoba ◽  
Ilaria Plantamura ◽  
Giulia Cosentino ◽  
Alfredo Hidalgo-Miranda ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Triple Negative ◽  
Standard Of Care ◽  
Integrin Subunit ◽  
Breast Cancers ◽  
Therapeutic Tool ◽  
Response To Chemotherapy ◽  
Cisplatin Sensitivity

Introduction: Chemotherapy is still the standard of care for triple-negative breast cancers (TNBCs). Here, we investigated miR-302b as a therapeutic tool to enhance cisplatin sensitivity in vivo and unraveled the molecular mechanism. Materials and Methods: TNBC-xenografted mice were treated with miR-302b or control, alone or with cisplatin. Genome-wide transcriptome analysis and independent-validation of Integrin Subunit Alpha 6 (ITGA6) expression was assessed on mice tumor samples. Silencing of ITGA6 was performed to evaluate cisplatin response in vitro. Further, potential transcription factors of ITGA6 (E2F transcription facor 1 (E2F1), E2F transcription factor 2 (E2F2), and Yin Yang 1 (YY1)) were explored to define the miRNA molecular mechanism. The miR-302b expression was also assessed in TNBC patients treated with chemotherapy. Results: The miR–302b-cisplatin combination significantly impaired tumor growth versus the control through indirect ITGA6 downregulation. Indeed, ITGA6 was downmodulated in mice treated with miR-302b–cisplatin, and ITGA6 silencing increased drug sensitivity in TNBC cells. In silico analyses and preclinical assays pointed out the regulatory role of the E2F family and YY1 on ITGA6 expression under miR-302b–cisplatin treatment. Finally, miR-302b enrichment correlated with better overall survival in 118 TNBC patients. Conclusion: MiR-302b can be exploited as a new therapeutic tool to improve the response to chemotherapy, modulating the E2F family, YY1, and ITGA6 expression. Moreover, miR-302b could be defined as a new prognostic factor in TNBC patients.

Defective fetal liver erythropoiesis and T lymphopoiesis in mice lacking the phosphatidylserine receptor

Blood ◽  
2004 ◽  
Vol 103 (9) ◽  
pp. 3362-3364 ◽  
Author(s):  
Yuya Kunisaki ◽  
Sadahiko Masuko ◽  
Mayuko Noda ◽  
Ayumi Inayoshi ◽  
Terukazu Sanui ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Apoptotic Cell ◽  
Fetal Liver ◽  
Lymphoid Cells ◽  
Cell Uptake ◽  
Developmental Defect ◽  
Apoptotic Cells ◽  
Phosphatidylserine Receptor ◽  
T Lymphopoiesis

Abstract Clearance of apoptotic cells by macrophages is considered important for prevention of inflammatory responses leading to tissue damage. The phosphatidylserine receptor (PSR), which specifically binds to phosphatidylserine (PS) exposed on the surface of apoptotic cells, mediates uptake of apoptotic cells in vitro, yet the physiologic relevance of PSR remains unknown. This issue was addressed by generating PSR-deficient (PSR-/-) mice. PSR-/- mice exhibited severe anemia and died during the perinatal period. In the PSR-/- fetal livers, erythroid differentiation was blocked at an early erythroblast stage. In addition, PSR-/- embryos exhibited thymus atrophy owing to a developmental defect of T-lymphoid cells. Clearance of apoptotic cells by macrophages was impaired in both liver and thymus of PSR-/- embryos. However, this did not induce up-regulation of inflammatory cytokines. These results indicate that during embryonic development, PSR-mediated apoptotic cell uptake is required for definitive erythropoiesis and T lymphopoiesis, independently of the prevention of inflammatory responses. (Blood. 2004;103:3362-3364)

Using epigenetic reprogramming to target triple-negative breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14565-e14565
Author(s):  
D. Sharma ◽  
B. B. Knight ◽  
R. Yacoub ◽  
T. Liu ◽  
L. Taliaferro-Smith ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Combined Treatment ◽  
Brdu Incorporation ◽  
Breast Cancers

e14565 Background: The outcome for patients with breast cancer has been significantly improved by the use of targeted agents. The prognosis of triple negative (TN) breast cancers, which do not express hormone receptors (ER, PR) or Her2, is poor, because of an aggressive clinical course and lack of targeted therapeutic agents. Epigenetic silencing of specific genes has been observed in breast cancer and some of these genes are more important due to available targeted therapies such as ER. Since all endocrine therapies are designed to block ER function in some way, the identification of new therapies or strategies that could sensitize TN breast cancers to existing endocrine therapy could provide a revolutionary means of treating this aggressive subtype of cancer Methods: We examined the efficacy of combined treatment of HDAC inhibitor LBH589 and DNMT inhibitor decitabine to regenerate ER and PR in TN breast cancer cells using RT-PCR and immunoblotting. Changes in growth and proliferation of TN breast cancer cells in response to LBH589 and decitabine treatment were determined by XTT, BrdU incorporation and colony formation assay. Changes in apoptotic proteins were determined by western blotting. Athymic nude mice were used to establish pre-clinical models for TN breast cancer cells and effectiveness of combined treatment of LBH589 and decitabine was determined. Tumors biopsies were analyzed for ER and PR re-expression by western blot analysis and immunohistochemistry at the end of the treatment. Results: Combined treatment of LBH589 and decitabine resulted in re-expression of ER and PR in TN breast cancers in vitro and in vivo. Although re-expression of ER and PR were noted following LBH589 treatment alone, re-expression was more robust with the combination. TN breast cancer cells showing re-expressed ER can be targeted with tamoxifen. Tamoxifen inhibits growth of TN breast cancer cells re- expressing ER by triggering apoptosis. Conclusions: The importance of epigenetic events such as DNA methylation and HDAC inhibition in tumor progression is becoming increasingly evident. A trial evaluating the ability of LBH589 and decitabine to re- express ER, which can then be targeted by tamoxifen, is planned in patients with metastatic TN breast cancer. No significant financial relationships to disclose.

Effects of lobaplatin as a single agent and in combination with TRAIL on the growth of triple-negative p53-mutated breast cancers in vitro

2012 ◽  
Vol 23 (4) ◽  
pp. 426-436 ◽  
Author(s):  
Jörg B. Engel ◽  
Theresa Martens ◽  
Jens C. Hahne ◽  
Sebastian F.M. Häusler ◽  
Mathias Krockenberger ◽  
...  
Keyword(s):  
Triple Negative ◽  
Single Agent ◽  
Breast Cancers

scholarly journals Simultaneous Multi-Organ Metastases from Chemo-Resistant Triple-Negative Breast Cancer Are Prevented by Interfering with WNT-Signaling

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2039 ◽  
Author(s):  
Iram Fatima ◽  
Ikbale El-Ayachi ◽  
Hilaire C. Playa ◽  
Jackelyn A. Alva-Ornelas ◽  
Aysha B. Khalid ◽  
...  
Keyword(s):  
Cell Lines ◽  
Triple Negative ◽  
De Novo ◽  
Tumor Model ◽  
Model Systems ◽  
Breast Cancers ◽  
Primary Tumors ◽  
Multiple Organs

Triple-negative breast cancers (TNBCs), which lack specific targeted therapy options, evolve into highly chemo-resistant tumors that metastasize to multiple organs simultaneously. We have previously shown that TNBCs maintain an activated WNT10B-driven network that drives metastasis. Pharmacologic inhibition by ICG-001 decreases β-catenin-mediated proliferation of multiple TNBC cell lines and TNBC patient-derived xenograft (PDX)-derived cell lines. In vitro, ICG-001 was effective in combination with the conventional cytotoxic chemotherapeutics, cisplatin and doxorubicin, to decrease the proliferation of MDA-MB-231 cells. In contrast, in TNBC PDX-derived cells doxorubicin plus ICG-001 was synergistic, while pairing with cisplatin was not as effective. Mechanistically, cytotoxicity induced by doxorubicin, but not cisplatin, with ICG-001 was associated with increased cleavage of PARP-1 in the PDX cells only. In vivo, MDA-MB-231 and TNBC PDX orthotopic primary tumors initiated de novo simultaneous multi-organ metastases, including bone metastases. WNT monotherapy blocked multi-organ metastases as measured by luciferase imaging and histology. The loss of expression of the WNT10B/β-catenin direct targets HMGA2, EZH2, AXIN2, MYC, PCNA, CCND1, transcriptionally active β-catenin, SNAIL and vimentin both in vitro and in vivo in the primary tumors mechanistically explains loss of multi-organ metastases. WNT monotherapy induced VEGFA expression in both tumor model systems, whereas increased CD31 was observed only in the MDA-MB-231 tumors. Moreover, WNT-inhibition sensitized the anticancer response of the TNBC PDX model to doxorubicin, preventing simultaneous metastases to the liver and ovaries, as well as to bone. Our data demonstrate that WNT-inhibition sensitizes TNBC to anthracyclines and treats multi-organ metastases of TNBC.

[10]-Gingerol Affects Multiple Metastatic Processes and Induces Apoptosis in MDAMB- 231 Breast Tumor Cells

2019 ◽  
Vol 19 (5) ◽  
pp. 645-654 ◽  
Author(s):  
Angelina M. Fuzer ◽  
Ana C.B.M. Martin ◽  
Amanda B. Becceneri ◽  
James A. da Silva ◽  
Paulo C. Vieira ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Antitumor Agents ◽  
Apoptotic Cell ◽  
3D Culture ◽  
Primary Concern ◽  
Breast Cancers ◽  
Her2 Gene

Background: Triple Negative Breast Cancer (TNBC) represents the approximately 15% of breast cancers that lack expression of Estrogen (ER) and Progesterone Receptors (PR) and do not exhibit amplification of the human epidermal growth factor receptor 2 (HER2) gene, imposing difficulties to treatment. Interactions between tumor cells and their microenvironment facilitate tumor cell invasion in the surrounding tissues, intravasation through newly formed vessels, and dissemination to form metastasis. To treat metastasis from breast and many other cancer types, chemotherapy is one of the most extensively used methods. However, its efficacy and safety remain a primary concern, as well as its toxicity and other side effects. Thus, there is increasing interest in natural antitumor agents. In a previous work, we have demonstrated that [10]-gingerol is able to revert malignant phenotype in breast cancer cells in 3D culture and, moreover, to inhibit the dissemination of TNBC to multiple organs including lung, bone and brain, in spontaneous and experimental in vivo metastasis assays in mouse model. Objective: This work aims to investigate the in vitro effects of [10]-gingerol, using human MDA-MB-231TNBC cells, in comparison to non-tumor MCF-10A breast cells, in order to understand the antitumor and antimetastatic effects found in vivo and in a 3D environment. Methods: We investigated different steps of the metastatic process in vitro, such as cell migration, invasion, adhesion and MMP activity. In addition, we analyzed the anti-apoptotic and genotoxic effects of [10]-gingerol using PEAnnexin, DNA fragmentation, TUNEL and comet assays, respectively. Results: [10]-gingerol was able to inhibit cell adhesion, migration, invasion and to induce apoptosis more effectively in TNBC cells, when compared to non-tumor cells, demonstrating that these mechanisms can be involved in the antitumor and antimetastatic effects of [10]-gingerol, found both in 3D culture and in vivo. Conclusion: Taken together, results found here are complementary to previous studies of our group and others and demonstrate that additional mechanisms, besides apoptotic cell death, is used by [10]-gingerol to accomplish its antitumor and antimetastatic effects. Our results indicate a potential for this natural compound as an antitumor molecule or as an adjuvant for chemotherapeutics already used in the clinic.

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