Publications by authors named "Leila Farahmand"

43 Publications

Potential role of interferons in treating COVID-19 patients.

Int Immunopharmacol 2021 Jan 3;90:107171. Epub 2020 Nov 3.

Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran 1517964311, Iran. Electronic address:

The recently public health crises in the world is emerged by spreading the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) also named COVID-19. The virus is originated in bats and transported to humans via undefined intermediate animals. This virus can produce from weak to severe respiratory diseases including acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), pneumonia and even death in patients. The COVID-19 disease is distributed by inhalation via contaminated droplets or contact with infected environment. The incubation time is from 2 to 14 day and the symptoms are typically fever, sore throat, cough, malaise, fatigue, breathlessness among others. It needs to be considered that many infected people are asymptomatic. Developing various immunological and virological methods to diagnose this disease is supported by several laboratories. Treatment is principally supportive; however, there are several agents that are using in treating of COVID-19 patients. Interferons (IFNs) have shown to be crucial in fighting with COVID-19 disease and can be a suitable candidate in treatment of these patients. Combination therapy can be more effective than monotherapy to cure this disease. Prevention necessitates to be performed by isolation of suspected people and home quarantine as well as taking care to infected people with mild or strict disease at hospitals. As the outbreak of SARS-CoV-2 has accelerated, developing effective therapy is an urgent requirement to battle the virus and prevent further pandemic. In this manuscript we reviewed available information about SARS-CoV-2 and probable therapies for COVID-19 patients.
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http://dx.doi.org/10.1016/j.intimp.2020.107171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608019PMC
January 2021

Enhancement of extracellular bispecific anti-MUC1 nanobody expression in BL21 (DE3) by optimization of temperature and carbon sources through an autoinduction condition.

Eng Life Sci 2020 Aug 25;20(8):338-349. Epub 2020 May 25.

Recombinant Proteins Department Breast Cancer Research Center Motamed Cancer Institute Tehran Iran.

is one of the most suitable hosts for production of antibodies and antibody fragments. Antibody fragment secretion to the culture medium improves product purity in cell culture and diminishes downstream costs. In this study, strain BL21 (DE3) harboring gene encoding bispecific anti-MUC1 nanobody was selected, and the autoinduction methodology for expression of bispecific anti-MUC1 nanobody was investigated. Due to the replacement of IPTG by lactose as inducer, less impurity and toxicity in the final product were observed. To increase both intracellular and extracellular nanobody production, initially, the experiments were performed for the key factors including temperature and duration of protein expression. The highest amount of nanobody was produced after 21 h at 33°C. The effect of different carbon sources, glycerol, glucose, lactose, and glycine as a medium additive at optimum temperature and time were also assessed by using response surface methodology. The optimized concentrations of carbon sources were obtained as 0.75% (w/v), 0.03% (w/v), 0.1% (w/v), and 0.75% (w/v) for glycerol, glucose, lactose, and glycine, respectively. Finally, the production of nanobody in 2 L fermenter under the optimized autoinduction conditions was evaluated. The results show that the total titer of 87.66 µg/mL anti-MUC1 nanobody, which is approximately seven times more than the total titer of nanobody produced in LB culture medium, is 12.23 µg/L .
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http://dx.doi.org/10.1002/elsc.201900158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401236PMC
August 2020

Interferons: role in cancer therapy.

Immunotherapy 2020 Aug 7;12(11):833-855. Epub 2020 Jul 7.

Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran 1517964311, Iran.

Interferons (IFNs) are a group of signaling cytokines, secreted by host cells to induce protection against various disorders. IFNs can directly impact on tumor cells or indirectly induce the immune system to protect host cells. The expression levels of IFNs and its functions of are excellently modulated in a way to protect host cells from probable toxicities caused by extreme responses. The efficacy of anticancer therapies is correlated to IFNs signaling. Although IFN signaling is involved in induction of antitumor responses, chronic stimulation of the IFN signaling pathway can induce resistance to various antineoplasm therapies. Hence, IFNs are expressed by both cancer and immune cells, and modulate their biological function. Understanding this mechanism of action might be a key target of combination therapies.
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http://dx.doi.org/10.2217/imt-2019-0217DOI Listing
August 2020

Anticancer potentiality and mode of action of low-carbohydrate proteins and peptides from mushrooms.

Appl Microbiol Biotechnol 2020 Aug 15;104(16):6855-6871. Epub 2020 Jun 15.

Recombinant Proteins Department, Breast Cancer Research Center, Moatamed Cancer Institute, ACECR, Tehran, Iran.

Severe side effects of chemotherapy as well as drug resistance highlight the ongoing need to discover novel natural bioactive compounds with anticancer potentiality. Mushroom-derived proteins are among the naturally occurring compounds that have been the subject of a body of research on their potentiality in cancer therapy. The greatest attention in relevant review articles has been paid to well-known mushroom-derived glycoproteins such as lectins and protein-bound polysaccharide complexes such as polysaccharide-K (PSK) or krestin and polysaccharopeptide (PSP), which contain substantial amounts of carbohydrates (50-90%). These complex compounds exert their anticancer activity mainly by binding to cell membranes leading to extrinsic (death receptor) apoptosis or intrinsic (mitochondrial) apoptotic pathways. However, several other research studies have reported pure, well-characterized, proteins or peptides from mushrooms, which are carbohydrate-free or have very low amounts of carbohydrate. These proteins may fall into four categories including fungal immunomodulatory proteins, ubiquitin-like proteins, enzymes, and unclassified proteins. Well-defined chemical structure, elucidated full amino acid or N-terminal sequences, purity, and having some distinct and specific pathways compared to glycoproteins have made these low-carbohydrate proteins attractive for cancer research. The aim of this review was therefore to improve the current understanding of mushroom-derived low-carbohydrate proteins and to consolidate the existing knowledge of the most promising mushroom species from which low-carbohydrate proteins have been derived, characterized, and examined for their anticancer activity. In addition, molecular targets and mechanisms of action of these proteins have been discussed. Key points • Mushroom-derived low-carbohydrate proteins lack or have low carbohydrate. • Low-carbohydrate proteins show potent anticancer activities in vitro and in vivo. • There are specific pathways for low-carbohydrate proteins to inhibit cancer cells.
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http://dx.doi.org/10.1007/s00253-020-10707-8DOI Listing
August 2020

The role of activated leukocyte cell adhesion molecule (ALCAM) in cancer progression, invasion, metastasis and recurrence: A novel cancer stem cell marker and tumor-specific prognostic marker.

Exp Mol Pathol 2020 08 5;115:104443. Epub 2020 May 5.

Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran. Electronic address:

Activated leukocyte cell adhesion molecule (ALCAM) or CD166 is a 100 to 105 KDa transmembrane immunoglobulin which is involved in activation of T-cells, hematopoiesis, neutrophils trans-endothelial migration, angiogenesis, inflammation and tumor propagation and invasiveness through formation of homophilic and heterophilic interactions. Recently, many studies have proposed that the expression pattern of ALCAM is highly associated with the grade, stage and invasiveness of tumors. Although ALCAM is a valuable prognostic marker in different carcinomas, similar expression patterns in different tumor types may be associated with completely different prognostic states, making it to be a tumor-type-dependent prognostic marker. In addition, ALCAM isoforms provide ways for primary detection of tumor cells with metastatic potential. More importantly, this prognostic marker has shown to be considerably dependent on the cytoplasmic and membranous expression, indirect and direct regulation of post-transcriptional molecules, pro-apoptotic proteins functionalities and several other oncogenic proteins or signalling pathways. This review mainly focuses on the pathways involved in expression of ALCAM and its prognostic value of in different types of cancers and the way in which it is regulated.
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http://dx.doi.org/10.1016/j.yexmp.2020.104443DOI Listing
August 2020

Breast cancer: Biology, biomarkers, and treatments.

Int Immunopharmacol 2020 Jul 29;84:106535. Epub 2020 Apr 29.

Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran. Electronic address:

During the past recent years, various therapies emerged in the era of breast cancer. Breast cancer is a heterogeneous disease in which genetic and environmental factors are involved. Breast cancer stem cells (BCSCs) are the main player in the aggressiveness of different tumors and also, these cells are the main challenge in cancer treatment. Moreover, the major obstacle to achieve an effective treatment is resistance to therapies. There are various types of treatment for breast cancer (BC) patients. Therefore, in this review, we present the current treatments, novel approaches such as antibody-drug conjugation systems (ADCs), nanoparticles (albumin-, metal-, lipid-, polymer-, micelle-based nanoparticles), and BCSCs-based therapies. Furthermore, prognostic and predictive biomarkers will be discussed also biomarkers that have been applied by some tests such as Oncotype DX, Mamm αPrint, and uPA/PAI-1 are regarded as suitable prognostic and predictive factors in breast cancer.
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http://dx.doi.org/10.1016/j.intimp.2020.106535DOI Listing
July 2020

Dual in vitro invasion/migration suppressing and tamoxifen response modulating effects of a recombinant anti-ALCAM scFv on breast cancer cells.

Cell Biochem Funct 2020 Jul 20;38(5):651-659. Epub 2020 Mar 20.

Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.

It has been shown that overexpression of activated leukocyte cell adhesion molecule (ALCAM) is involved in development of resistance to tamoxifen therapy and promotion of cell invasion, migration and metastasis in ER+ breast cancer cells. Thus, we hypothesized that blockade of ALCAM interconnections with antibodies could be an effective approach for reversing mentioned negative events associated with ALCAM overexpression in breast cancer cells. Here, an anti-ALCAM scFv was recombinantly expressed and used throughout study for examination of the putative anticancer effects of ALCAM blockade. The anti-ALCAM scFv coding sequence was obtained from GenBank database and after addition of a 6× His-tag moiety, signal peptide and flanking sequences, the whole construct was expressed in Escherichia coli. Tamoxifen resistant MCF7 cells were then pretreat for 24 hours with purified recombinant anti-ALCAM scFv prior to administration of tamoxifen. In parallel, the cytotoxicity profile of anti-ALCAM scFv and tamoxifen co-treatments against tamoxifen resistant and sensitive MCF7 cell lines was also evaluated using CompuSyn software. The invasion/migration inhibitory effects of anti-ALCAM scFv on MDA-MB-231 cells were also evaluated. Pretreatment with anti-ALCAM scFv could successfully enhance anti-proliferative effects of tamoxifen against resistant MCF-7 cell lines. Furthermore, the combination of 19.2:1 of tamoxifen to anti-ALCAM scFv demonstrated synergistic cell inhibitory effect against tamoxifen resistant MCF7 cell lines. Also, incubating MDA-MB-231 cell lines with anti-ALCAM scFv resulted in a 30% and 25% reduction in number of invaded and migrated cells respectively. Overall, application of anti-ALCAM scFv could significantly suppress cancer cells metastasis in vitro and modulate tamoxifen resistant ER+ MCF7 cell line's sensitivity to tamoxifen. SIGNIFICANCE OF THE STUDY: Acquisition of resistance to tamoxifen therapy is one of the major challenges associated with cancer chemotherapy, gradually turning a responsive tumour into a refractory more invasive one which ultimately ends in disease progression and relapse. Here, we reported expression of an anti-ALCAM scFv, capable of increasing the sensitivity of tamoxifen resistant ER+ MCF-7 cells to tamoxifen therapy following a 24-hour pretreatment period. In addition, we demonstrated that the anti-ALCAM scFv monotherapy was also capable of suppressing invasion and migration of MDA-MB-231 cells in Boyden chamber assays.
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http://dx.doi.org/10.1002/cbf.3525DOI Listing
July 2020

Functional investigation of the Val1714Gly and Asp1733Gly variants by computational tools and yeast transcription activation assay.

Mol Biol Res Commun 2019 Sep;8(3):113-118

Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.

Mutations in the gene are known to be a major cause of hereditary breast cancer. However, characterizing the point associated with cancer in is challenging because the functional impact of most of them is still unknown. Nowadays, a variety of methods are employed to identify cancer-associated mutations in . This study is aimed to assess the functional effects of two mutations, Asp1733Gly and Val1714Gly, using a combination of tools and yeast functional transcription activator assay. Our computational analysis showed that theVal1714Gly mutation was deleterious, while the other one, Asp1733Gly, predicted as neutral. yeast functional transcription activator assay, displayed similar ability with positive controls. In contrast, the Val1714Gly mutation completely abrogated transcriptional activity in the yeast. These results that Val1714Gly and Asp1733Gly can be classified as pathogenic and benign mutations for the BRCA1, respectively.
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http://dx.doi.org/10.22099/mbrc.2019.33971.1414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802689PMC
September 2019

Evaluation the potential of recombinant anti-CD3 nanobody on immunomodulatory function.

Mol Immunol 2020 02 26;118:174-181. Epub 2019 Dec 26.

Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran. Electronic address:

T cells are the most predominant effector cells in immune-mediated elimination of cancer and circumventing tumor progression. Among various approaches, T cells activation by specific antibodies independently of their TCR specificity, is considered as an effective approach to circumvent tumor progression. The most common surface marker for all T cells which is crucial for T cell activation is regarded as CD3. Therefore, the goal of our study was to evaluate the preclinical efficacy of recombinant anti-CD3 nanobody. To this end, anti-CD3 sequence, was PCR amplified, following cloning and expression in E.coli and purification, the purified nanobody with a molecular weight of ∼17 kDa was confirmed by western blot. Furthermore, flow cytometry analysis demonstrated that purified nanobody could bind to CD3 on Jurkat cell line. Subsequently, results from inoculation of 3 μg/g of nanobody to tumor bearing balb/c mice indicate inhibition of tumor growth. Furthermore, circulating levels of tumoricidal cytokines such as IL-2 and IFNγ were raised whereas tolerogenic cytokines such as IL-4, 6 and 10 were decreased at the end of the treatment. Moreover, IHC analysis confirmed the presence and also the percentage of TILs in tumor sites in response to anti-CD3 therapy. Hence, our results suggest that the purified anti-CD3 nanobody may become a promising candidate for targeting and activating CTLs to induce anti-tumor responses and may provide groundwork for future studies involving other kind of cancers.
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http://dx.doi.org/10.1016/j.molimm.2019.12.017DOI Listing
February 2020

tumor-suppressing and anti-angiogenic activities of a recombinant anti-CD3ε nanobody in breast cancer mice model.

Immunotherapy 2019 12 9;11(18):1555-1567. Epub 2019 Dec 9.

Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.

Achievements in cancer immunotherapy require augmentation of a host's anti-tumor immune response for anti-cancer modality. Different concentrations of recombinant anti-CD3 nanobody were administered at predetermined time intervals during a 24-day treatment period and then expression of angiogenic biomarkers including VEGFR2, MMP9 and CD31, as well as tumor cell proliferation marker ki67, was determined in tumor sections by immunohistochemistry. Furthermore, expression of cytokines was examined in peripheral blood of mice. Based on our results, administration of nanobody could reduce biomarker expression in tumor sections. Tumor growth was also delayed and survival rate was increased in response to nanobody treatment. Moreover, expression of pro-inflammatory cytokines was reduced. In conclusion, we demonstrated that administration of nanobody could effectively suppress angiogenesis as well as tumor growth.
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http://dx.doi.org/10.2217/imt-2019-0068DOI Listing
December 2019

Development of an anti-CD45RA-quantum dots conjugated scFv to detect leukemic cancer stem cells.

Mol Biol Rep 2020 Jan 22;47(1):225-234. Epub 2019 Oct 22.

Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.

Leukemic cancer stem cells (LSCs), aberrantly overexpressing CD45RA are among the major causes of relapse following chemotherapy in patients with acute myeloid leukemia and serve as a highly sensitive marker for predicting relapse occurrence following chemotherapy. The main purpose of current study was to develop a sensitive approach for detecting LSCs based on a conjugate of an anti-CD45 scFv and quantum dot. The variable light and heavy chain sequences of a recently developed anti-CD45RA monoclonal antibody were derived from hybridoma cells and PCR amplified to construct scFv. Following insertion of scFv gene into a pET32a-lic vector and expression in Escherichia coli and purification, the purified scFv, was conjugated with carbon dots (C dots) and used for the detection of CD45RA cells while CD45RA-cells served as negative control. Subsequently, Functional activity of the conjugate was analyzed by flow cytometry and ICC to detect the cell surface antigen binding and detection ability. Based on results, purified CD45RA scFv conjugated C dots could specifically recognize CD45RA positive cells, but not any CD45RA negative ones. In conclusion, here we developed a low-cost but very efficient approach for detection of CD45RA positive cells including LSCs.
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http://dx.doi.org/10.1007/s11033-019-05122-wDOI Listing
January 2020

Morphological Changes Induced By Extremely Low-Frequency Electric Fields.

Bioelectromagnetics 2019 Sep 3;40(6):375-390. Epub 2019 Jun 3.

INSF Chair of Computational Electromagnetics and Bio-electromagnetics, School of Electrical and Computer Engineering, University of Tehran, Tehran, Iran.

In this paper, morphological effects of electric fields on avian erythrocytes (nucleated red blood cells) have been studied in detail. Morphological changes include rounding and cytoplasm transparency. It has been shown that the effect is non-thermal. Careful imaging and image analyses have been carried out to show that the degree of this effect is frequency-dependent, and has a higher conversion rate at higher temperatures. Furthermore, to better understand the mechanisms behind the morphological changes, we investigated the dedifferentiation hypothesis and performed a series of tests on avian erythrocytes including fluorescence spectroscopy for hemoglobin, and tests on human umbilical cord blood, mesenchymal stem cells, and bone marrow mesenchymal stem cells including flow-cytometry analysis for expression of certain markers and calcium staining. Bioelectromagnetics. 2019;40:375-390. © 2019 Bioelectromagnetics Society.
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http://dx.doi.org/10.1002/bem.22195DOI Listing
September 2019

The Prognostic Value of Circulating Tumor Cells in Primary Breast Cancer Prior to any Systematic Therapy: A Systematic Review.

Curr Stem Cell Res Ther 2019 ;14(6):519-529

Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.

Background: Numerous studies have defined the outstanding role of circulating tumor cells (CTC) in the management of cancer, particularly the ones in association with primary tumor metastases.

Objective: The overall aim of the present study was to investigate whether CTCs may serve as a clinical prognostic marker for survival in primary breast cancer.

Methods: Articles Published from June 2011 to July 2017 in PubMed, EMBase, and Cochrane library databases were thoroughly screened for selecting the ones meeting the inclusion criteria.

Result: Studies applying CellSearch® method demonstrated the risk ratios (RR) of 2.51 (95% CI: 1.78- 3.54), 3.98 (95% CI: 2.28- 6.95), 5.59 (95% CI: 3.29- 9.51), and 3.38 (95% CI: 1.88- 6.06) for death rate and relapse rates of 2.48 (95% CI: 1.89 - 3.26), 3.62 (95% CI: 2.37 - 5.51), 4.45 (95% CI: 2.94 - 6.73), and 2.88 (95 % CI: 1.99 - 4.17) at four CTC positive cut points (≥ 1, ≥ 2, ≥ 3, and ≥ 5 CTCs/7.5 ml). Two studies applying the AdnaTest® also documented increased death (RR: 1.38, 95 % CI: 0.42- 4.49) and relapse rates (RR: 2.97, 95 % CI: 1.23 - 7.18)).

Conclusion: Results of this meta-analysis allude CTCs as potent prognostic markers in primary breast cancers prior to any systemic therapy especially when it is studied via CellSearch® administration, considering that the more the CTCs, the greater the death and relapse rates.
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http://dx.doi.org/10.2174/1574888X14666190306103759DOI Listing
February 2020

Challenges facing antiangiogenesis therapy: The significant role of hypoxia-inducible factor and MET in development of resistance to anti-vascular endothelial growth factor-targeted therapies.

J Cell Physiol 2019 05 4;234(5):5655-5663. Epub 2018 Dec 4.

Department of Recombinant Proteins, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.

It is now fully recognized that along with multiple physiological functions, angiogenesis is also involved in the fundamental process and pathobiology of several disorders including cancer. Recent studies have fully established the role of angiogenesis in cancer progression as well as invasion and metastasis. Consequently, many therapeutic agents such as monoclonal antibodies targeting angiogenesis pathway have been introduced in clinic with the hope for improving the outcomes of cancer therapy. Bevacizumab (Avastin®) was the first anti-vascular endothelial growth factor (VEGF) targeting monoclonal antibody developed with this purpose and soon received its accelerated US Food and Drug Administration (FDA) approval for treatment of patients with metastatic breast cancer in 2008. However, the failure to meet expecting results in different follow-up studies, forced FDA to remove bevacizumab approval for metastatic breast cancer. Investigations have now revealed that while suppressing VEGF pathway initially decreases tumor progression rate and vasculature density, activation of several interrelated pathways and signaling molecules following VEGF blockade compensate the insufficiency of VEGF and initially blocked angiogenesis, explaining in part the failure observed with bevacizumab single therapy. In present review, we introduce some of the main pathways and signaling molecules involved in angiogenesis and then propose how their interconnection may result in development of resistance to bevacizumab.
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http://dx.doi.org/10.1002/jcp.27414DOI Listing
May 2019

Recruited bone marrow derived cells, local stromal cells and IL-17 at the front line of resistance development to anti-VEGF targeted therapies.

Life Sci 2019 Jan 22;217:34-40. Epub 2018 Nov 22.

Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran. Electronic address:

Although anti-angiogenic agents targeting VEGF have shown affordable beneficial outcomes in several human cancer types, in most pre-clinical and clinical studies, these effects are transient and followed by rapid relapse and tumor regrowth. Recently, it has been suggested that recruited bone marrow derived cells (BMDCs) to the tumor-microenvironment together with stromal cells play an important role in development of resistance to anti-VEGF therapies. Additionally, acquired resistance to anti-VEGF therapies has shown to be mediated partly through overexpression of different pro-angiogenic cytokines and growth factors including G-CSF, IL-6, IL-8, VEGF and FGF by these cells. Alongside, IL-17, a pro-inflammatory cytokine, mostly secreted by infiltrated CD4 T helper cells, has shown to mediate resistance to anti-VEGF therapies, through recruiting BMDCs and modulating stromal cells activities including endothelial cells, tumor associated macrophages and cancer associated fibroblasts. Here, we examined the role of BMDCs, tumor stromal cells, IL-17 and their negotiation in development of resistance to anti-VEGF targeted therapies.
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http://dx.doi.org/10.1016/j.lfs.2018.11.033DOI Listing
January 2019

The antiproliferative effects of cold atmospheric plasma-activated media on different cancer cell lines, the implication of ozone as a possible underlying mechanism.

J Cell Physiol 2019 05 1;234(5):6778-6782. Epub 2018 Nov 1.

Tasnim Biotechnology Research Center, Faculty of Medicine, AJA University of Medical Sciences, Etemadzadeh Ave., West Fatemi, Tehran, Iran.

Recent studies have proven several promising anticancer activities for cold atmospheric plasma (CAP) against a wide range of cancer cells in vitro. Recently, media treated with CAP have also found to effectively eradicate cancer cells similar to the CAP. Based on advantages, many researchers prefer to apply CAP-activated media (PAM) as an alternative to cap in the treatment of cancer. However, less has been achieved regarding the anticancer effects and anticancer mechanisms of PAM. Investigating the selective anticancerous activities of PAM, the viability of SKBR3, MCF7, ASPC-1, A-549, G-292, and SW742 cancer cell lines, as well as normal human skin fibroblasts (FMGB-1) and MCF10A cells in relation to the media activation time, and the length of exposure was studied. Also, we examined the concentration of ozone in media as a function to CAP activation time since recent studies have proposed ozone as a pivotal reactive species in the induction of cell death. Based on the result, both increasing the duration of media activation time and the length of exposure to PAM could significantly increase the anticancer activity. Nevertheless, the cytotoxicity on normal cells was either not affected or slightly increased. Among the six tested cancer cell lines, SW742 was the most resistant and SKBR3 the most susceptible cancer cell lines to PAM. Also, increasing duration of treatment with CAP resulted in a significant rise in O concentration levels in media. Overall, these results suggest PAM, as a promising tool in the treatment of different cancers and O formation as a probable underlying mechanism.
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http://dx.doi.org/10.1002/jcp.27428DOI Listing
May 2019

Self-filling microwell arrays (SFMAs) for tumor spheroid formation.

Lab Chip 2018 11;18(22):3516-3528

Biomaterials and Tissue Engineering Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.

Tumor spheroid formation in microwell arrays is a promising approach for high-throughput screening of chemotherapeutic agents. This method offers the advantage of better mimicking the complexities of tumors as compared to conventional monolayer culture systems. However, using these technologies to their full potential is hindered by the inability to seed the cells within the wells uniformly and with high yield and reproducibility. Moreover, standard manufacturing approaches for fabrication of microwell arrays rely on lithography and etching techniques, which are costly, labor-intensive, and time-consuming. Herein, we report on the development of self-filling microwell arrays (SFMAs) in which cells are directed from a loading chamber to microwells using inclined guiding channels. The SFMAs are fabricated by replica molding of three-dimensionally (3D) printed molds in agarose. We characterize the fabrication process, demonstrate the ability to culture breast adenocarcinoma MCF-7 and glioma U87 in SFMAs and perform drug toxicity studies. We envision that the proposed innovative approach opens avenues of opportunities for high-throughput three-dimensional cell culture for drug screening and disease modeling.
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http://dx.doi.org/10.1039/c8lc00708jDOI Listing
November 2018

A Review on The Role of VEGF in Tamoxifen Resistance.

Anticancer Agents Med Chem 2018 ;18(14):2006-2009

Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.

Background: Certain molecular deviations can lead to the development of breast cancer. For instance, estrogen and estrogen receptors play a significant role in inducing tumor proliferation. However, the efficacy of endocrine therapy through the administration of anti-estrogen drugs, such as Tamoxifen, is challenged by acquired resistance.

Methods: Relevant articles were retrieved from Medline and google scholar. All were screened to select the ones discussing the molecular mechanisms of angiogenesis and Tamoxifen resistance. The molecular interactions contributing in the resistant network were studied from the eligible articles.

Results: Tamoxifen resistance occurs as a consequence of over-activated signal transduction pathways such as RTK s dependent cascades. It has been shown that microvessel count was greater in Tamoxifen resistant tissues than in responsive ones.

Conclusion: In this review, the interaction between estrogen, Tamoxifen, VEGF, and VEGF receptors (VEGFRs) in Tamoxifen resistant cells has been discussed. VEGF and estrogen-independent growth cascades, especially MAPK have a positive feedback loop in Tamoxifen resistant cells. It has been proposed that over-activated pathways in Tamoxifen resistant cells induce pin1 mediated VEGF over-expression, which in turn result in enhanced activation of MAPK.
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http://dx.doi.org/10.2174/1871520618666180911142259DOI Listing
July 2019

Monoclonal antibody-based therapeutics, targeting the epidermal growth factor receptor family: from herceptin to Pan HER.

J Pharm Pharmacol 2018 Jul 25;70(7):841-854. Epub 2018 Mar 25.

Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.

Objectives: Monoclonal antibody-based of cancer therapy has been considered as one of the most successful therapeutic strategies for both haematologic malignancies and solid tumours in the last two decades. Epidermal growth factor receptor (EGFR) family signalling pathways play a key role in the regulation of cell proliferation, survival and differentiation. Hence, anti-EGFR family mAbs is one of the most promising approaches in cancer therapy.

Key Findings: Here, recent advances in anti-EGFR mAb including approved or successfully tested in preclinical and clinical studies have been reviewed. Although we focus on monoclonal antibodies against the EGF receptor, but the mechanisms underlying the effects of EGFR-specific mAb in cancer therapy, to some extend the resistance to existing anti-EGFR therapies and some therapeutic strategies to overcome resistance such as combination of mAbs on different pathways are briefly discussed as well.

Summary: The EGFR family receptors, is considered as an attractive target for mAb development to inhibit their consecutive activities in tumour growth and resistance. However, due to resistance mechanisms, the combination therapies may become a good candidate for targeting EGFR family receptors.
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http://dx.doi.org/10.1111/jphp.12911DOI Listing
July 2018

The effect of mesenchymal stem cell-conditioned medium on proliferation and apoptosis of breast cancer cell line.

J Cancer Res Ther 2018 Jan-Mar;14(2):341-344

Cancer Genetics Department, Breast Cancer Research Center, Academic Center for Education Culture and Research; Tasnim Biotechnology Research Center, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran.

Purpose: Bone marrow-derived mesenchymal stem cells (MSCs) have the potential ability to differentiate into bone, muscle, fat, and cartilage lineage cells. Furthermore, MSCs are known to migrate into tumor-associated stroma of cancer. This tumor microenvironment consists of a dynamic network of growth factors, immune cells, fibroblasts, extracellular matrix, and MSCs. MSCs as nonhematopoietic stem cells affect tumor, epithelial cells by alteration proliferative capacity, morphology, and aggregation pattern of tumor cells.

Materials And Methods: This research aimed to further elucidate the MSCs effects in the progress of proliferation, cell cycle, and apoptosis in breast cancer by gene expression analysis in human breast cancer cell lines exposed to MSCs conditioned media (CM). Expression pattern of two genes, including survivin (Birc5) as anti-apoptotic gene and serine threonine kinase 15 as proliferative gene, were studied.

Results: Anti-apoptotic and proliferative genes were up-regulated in co-cultured breast tumor cells with MSCs-CM that correlate with tumor progression and poor prognosis.

Conclusion: Our results and other findings indicate the interaction of breast tumor cells with MSCs through paracrine factors. Also, the applications of MSCs as therapeutic tools are facing controversial concerns.
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http://dx.doi.org/10.4103/0973-1482.177213DOI Listing
August 2018

Stemness Phenotype in Tamoxifen Resistant Breast Cancer Cells May be Induced by Interactions Between Receptor Tyrosine Kinases and ERα-66.

Recent Pat Anticancer Drug Discov 2018 ;13(3):302-307

Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.

Background: Tamoxifen is widely administered for patients with estrogen receptor-positive breast cancer. Despite many patients benefiting from Tamoxifen as an effective anti-hormonal agent in adjuvant therapy, a noticeable number of patients tend to develop resistance.

Objective: The aim of this study was to shed light upon the molecular mechanisms associated with Tamoxifen resistance which can help improve current treatment strategies available for stimulating responsiveness and combating resistance.

Methods: Relevant articles were obtained from PubMed and google scholar, nearly all dated from 2010 to 2017. Articles were screened to select the ones meeting the objective. The molecular interactions in the resistant network were extracted from the appropriate articles.

Results: The mechanisms of developing Tamoxifen resistance were briefly outlined. Overactivation of Receptor Tyrosine Kinases (RTKs) pathways, commonly known as alternative growth cascades, is one of the main players in acquired cancer cell stemness, which can induce unrestricted proliferation in the presence of Tamoxifen. There are seven recent patents including 6291496B1 as an anti-HER2, 8143226B2 as an inhibitor of RTK phosphorylation, 9062308B2 as an anti-HOXB7, Lapatinib functioning as an anti-EGFR/HER2, Everolimus as an inhibitor of mTOR, Exemestane as an aromatase inhibitor and Perifosine as an AKT inhibitor.

Conclusion: Altogether, it seems that tumor cells express a stemness phenotype which tends to override anti-hormonal adjuvant therapies. Since RTKs are overactivated and overexpressed in such cells, specialized targeted therapies suppressing RTKs would be a novel and effective way in restoring Tamoxifen sensitivity in resistant breast cancer tumor cells.
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http://dx.doi.org/10.2174/1574892813666180305164634DOI Listing
November 2018

Unique CD44 intronic SNP is associated with tumor grade in breast cancer: a case control study and in silico analysis.

Cancer Cell Int 2018 23;18:28. Epub 2018 Feb 23.

1Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, No 146, South Gandhi Ave, Vanak Sq., Tehran, Iran.

Background: CD44 encoded by a single gene is a cell surface transmembrane glycoprotein. Exon 2 is one of the important exons to bind CD44 protein to hyaluronan. Experimental evidences show that hyaluronan-CD44 interaction intensifies the proliferation, migration, and invasion of breast cancer cells. Therefore, the current study aimed at investigating the association between specific polymorphisms in exon 2 and its flanking region of CD44 with predisposition to breast cancer.

Methods: In the current study, 175 Iranian female patients with breast cancer and 175 age-matched healthy controls were recruited in biobank, Breast Cancer Research Center, Tehran, Iran. Single nucleotide polymorphisms of CD44 exon 2 and its flanking were analyzed via polymerase chain reaction and gene sequencing techniques. Association between the observed variation with breast cancer risk and clinico-pathological characteristics were studied. Subsequently, bioinformatics analysis was conducted to predict potential exonic splicing enhancer (ESE) motifs changed as the result of a mutation.

Results: A unique polymorphism of the gene encoding CD44 was identified at position 14 nucleotide upstream of exon 2 (A37692→G) by the sequencing method. The A > G polymorphism exhibited a significant association with higher-grades of breast cancer, although no significant relation was found between this polymorphism and breast cancer risk. Finally, computational analysis revealed that the intronic mutation generated a new consensus-binding motif for the splicing factor, SC35, within intron 1.

Conclusions: The current study results indicated that A > G polymorphism was associated with breast cancer development; in addition, in silico analysis with ESE finder prediction software showed that the change created a new SC35 binding site.
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http://dx.doi.org/10.1186/s12935-018-0522-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824488PMC
February 2018

Metas-Chip precisely identifies presence of micrometastasis in live biopsy samples by label free approach.

Nat Commun 2017 12 19;8(1):2175. Epub 2017 Dec 19.

Nano Bio Electronic Devices Lab, School of Electrical and Computer Engineering, College of Engineering, University of Tehran, P.O. Box 14395/515, Tehran, Iran.

Detecting the micrometastasis is a major challenge in patients' survival. The small volume of the biopsied tissue results in limited number of histopathological samples and might reduce the rate of accurate diagnosis even by molecular technologies. We introduce a microelectronic biochip (named Metas-Chip) to detect the micrometastasis in unprocessed liquid or solid samples. It works based on the tendency of malignant cells to track single human umbilical vein endothelial cell (HUVEC)-sensing traps. Such cells detach themselves from the biopsied sample and invade the sensing traps by inducing membrane retraction and blebbing, which result in sharp changes in electrical response of the sensing elements. Metas-Chip identified the metastasis in more than 70 breast cancer patients, in less than 5 h. Moreover it detected the metastasis in lymph nodes of nine patients whom were missed by conventional pathological procedure. Multilevel IHC and real-time polymerase chain reaction (RT-PCR) tests confirmed the diagnosis.
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http://dx.doi.org/10.1038/s41467-017-02184-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736647PMC
December 2017

Functionalised nanomaterials for eradication of CSCs, a promising approach for overcoming tumour heterogeneity.

J Drug Target 2018 09 23;26(8):649-657. Epub 2017 Nov 23.

a Recombinant Proteins Department, Breast Cancer Research Center , Motamed Cancer Institute, ACECR , Tehran , Iran.

Today, intratumoural heterogeneity has been recognised as one of the main causes of cancer treatment failure and drug resistance development through which multiple mechanisms are simultaneously involved. From the broad diversity of cells presented in tumour microenvironment, owing to their proliferative potential and longevity, cancer stem cells (CSCs), are the main cell subpopulation involved in tumour development, propagation, metastatic dissemination and induction of intratumoural heterogeneity. Accordingly, selective targeting and eradication of CSCs may represent a promising approach for cancer therapy and evading drug resistance development. Nanotechnology is an attractive outgrowing field in medicine due to its promising capabilities in solving several obstacles associated with conventional chemotherapy agents including poor solubility, lack of selectivity and high systemic toxicity. Accordingly, multiple types of nanocarriers have been successfully developed for improving selective delivery and reducing non-selective toxicities of CSC-specific chemotherapy agents. In Current review, we mostly focus on examining the role of CSCs in development of intratumoral heterogeneity and introducing recently developed nano delivery systems for more efficient targeting and eradication of them.
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http://dx.doi.org/10.1080/1061186X.2017.1405426DOI Listing
September 2018

Suppression of chronic inflammation with engineered nanomaterials delivering nuclear factor κB transcription factor decoy oligodeoxynucleotides.

Drug Deliv 2017 Nov;24(1):1249-1261

b Genetics Department , Motamed Breast Cancer Research Center, ACECR , Tehran , Iran.

As a prototypical pro-inflammatory transcription factor, constitutive activation of NF-κB signaling pathway has been reported in several chronic inflammatory disorders including inflammatory bowel disease, cystic fibrosis, rheumatoid arthritis and cancer. Application of decoy oligodeoxynucleotides (ODNs) against NF-κB, as an effective molecular therapy approach, has brought about several promising outcomes in treatment of chronic inflammatory disorders. However, systematic administration of these genetic constructs is mostly hampered due to their instability, rapid degradation by nucleases and poor cellular uptake. Both chemical modification and application of delivery systems have shown to effectively overcome some of these limitations. Among different administered delivery systems, nanomaterials have gained much attention for delivering NF-κB decoy ODNs owing to their high loading capacity, targeted delivery and ease of synthesis. In this review, we highlight some of the most recently developed nanomaterial-based delivery systems for overcoming limitations associated with clinical application of these genetic constructs.
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http://dx.doi.org/10.1080/10717544.2017.1370511DOI Listing
November 2017

Clinical Evidence on the Magnitude of Change in Growth Pathway Activity in Relation to Tamoxifen Resistance is Required.

Curr Cancer Drug Targets 2018 ;18(7):668-676

Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.

Background: Despite prolonged disease-free survival and overall survival rates in Estrogen Receptor (ER)-positive patients undergoing adjuvant treatment, Tamoxifen therapy tends to fail due to eventual acquisition of resistance.

Objective: Although numerous studies have emphasized the Role of Receptor Tyrosine Kinases (RTKs) in the development of Tamoxifen resistance, inadequate clinical evidence is available regarding the alteration of biomarker expression during acquired resistance, thus undermining the validity of the findings.

Results: Results of two meta-analyses investigating the effect of HER2 status on the prognosis of Tamoxifen-receiving patients have demonstrated that despite HER2-negative patients having longer disease-free survival; there is no difference in overhaul survival between the two groups. Furthermore, due to the intricate molecular interactions among estrogen receptors including ERα36, ERα66, and also RTKs, it is not surprising that RTK suppression does not restore Tamoxifen sensitivity. In considering such a complex network, we speculate that by the time HER2/EGFR is suppressed via targeted therapies, activation of ERα66 and ERα36 initiate molecular signaling pathways downstream of RTKs, thereby enhancing cell proliferation even in the presence of both Tamoxifen and RTK inhibitors.

Conclusion: Although clinical findings regarding the molecular pathways downstream of RTKs have been thoroughly discussed in this review, further clinical studies are required in determining a consistency between preclinical and clinical findings. Discovering the best targets in preventing tumor progression requires thorough comprehension of estrogen-dependent and estrogen-independent pathways during Tamoxifen resistance development. Indeed, exploring additional clinically-proven targets would allow for better characterized treatments being available for breast cancer patients.
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http://dx.doi.org/10.2174/1568009617666170808110820DOI Listing
October 2019

Estrogen can restore Tamoxifen sensitivity in breast cancer cells amidst the complex network of resistance.

Biomed Pharmacother 2017 Sep 23;93:1320-1325. Epub 2017 Jul 23.

Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran. Electronic address:

Breast cancer-related deaths have been on the decline ever since the application of systemic therapies. Chiefly, endocrine therapy, such as Tamoxifen, enhances the survival of estrogen receptor (ER)-positive patients. More than a decade has passed since the introduction of Tamoxifen, however, drug resistance, particularly to Tamoxifen, still remains a major challenge. It has been shown that not only does chronic Tamoxifen exposures induce resistance, but estrogen deprivation can as well. There are two Tamoxifen resistant cell lines, long term estrogen deprived (LTED) cells and cells that have acquired resistance due to long-term exposure to Tamoxifen (Tam-R). Despite having similar cytosolic pathways over-activated in Tam-R and LTED-R cells during the development of resistance, the administration of receptor tyrosine kinases (RTKs) inhibitors fail to restore Tamoxifen sensitivity in LTED-Rs. This alludes to existing differences in the underlying molecular mechanisms of resistance. Surprisingly, despite estrogen being recognized as a breast cancer stimulator; it has recently been introduced as an apoptotic inducer in unresponsive cells. Furthermore, the addition of estrogen to the media of LTED and Tam-R cells triggers cell death, perhaps is functioning as an anti-proliferative agent. In this review, we outline the molecular pathways potentially facilitating estrogen-induced apoptosis in resistant cells.
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http://dx.doi.org/10.1016/j.biopha.2017.07.057DOI Listing
September 2017

Significant Role of MUC1 in Development of Resistance to Currently Existing Anti-cancer Therapeutic Agents.

Curr Cancer Drug Targets 2018 ;18(8):737-748

Recombinant Proteins Department, Breast Cancer Research Centre, Motamed Cancer Institute, ACECR, Tehran, Iran.

As an extensively glycosylated transmembrane protein of epithelium, Mucin1 (MUC1) mostly protects cells from tensions induced by external milieu. Physiologically, during stress condition, MUC1 separates into MUC1-N and MUC1-C moieties, resulting in transduction of inward survival signals, essential for maintaining cell's functionality. Recent studies have proposed a significant correlation between MUC1 overexpression and amplification of cancer cell's proliferation and metastasis through modulation of multiple signaling pathways and cell-cell and cell-matrix interactions. It has been shown that MUC1- Cytoplasmic Domain (MUC1-CD) accelerates development of resistance to several anti-cancer therapeutic agents including bortezomib, trastuzumab and tamoxifen. Furthermore, MUC1-CD is also involved in promoting expression of multi drug resistance (MDR) genes and finally, silencing MUC1 expression was together with resensitization of human epidermal growth factor receptor 2 positive (HER2+) and/or estrogen receptor (ER+) positive breast cancer cells to bortezomib, trastuzumab and tamoxifen respectively. In this review, we briefly describe the role of MUC1 proto-oncogene in cancer cell's survival, tumor progression and metastasis and then continue with mentioning the mechanisms through which MUC1 induce resistance to various currently existing therapeutic agents in market including bortezomib, trastuzumab and tamoxifen.
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http://dx.doi.org/10.2174/1568009617666170623113520DOI Listing
October 2019

NF-κB as the main node of resistance to receptor tyrosine kinase inhibitors in triple-negative breast cancer.

Tumour Biol 2017 Jun;39(6):1010428317706919

2 Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, 1517964311 Tehran, Iran.

Graphical abstract Although accounting for merely a minute portion of diagnosed breast cancers, disproportionate number of deaths and associated low survival rate of patients have made triple-negative breast cancer to be considered as the most lethal breast cancer subtype. More importantly, intrinsic or developed resistance to chemotherapeutic regimens and disappointing outcomes of trials associated with many newly developed agents are other obstacles in establishment of a durable response in these patients. Interestingly, these happen despite the outstanding preclinical outcomes observed by these agents, most importantly among them, targeted receptor tyrosine kinase inhibitors. Pursuing these disappointing outcomes, especially in the case of targeted receptor tyrosine kinase inhibitors, many researches have focused on identification of the hidden factors involved. Highly inflammatory, rich in reactive oxygen species, and hypoxic microenvironment of triple-negative breast cancer tumors and the involving mediators were the first suggestions for observed resistance and poor clinical outcomes of targeted receptor tyrosine kinase inhibitors. Interestingly, for all aberrantly expressed mediators observed in microenvironment, downstream pathways converge in a common node, nothing but the nuclear factor-κB, the insidious factor proposed to be the cause of many events opposing achievement of a desired outcome. In first section of current review, we describe the signaling pathways underlying activation of receptor tyrosine kinases and their convergence at the nuclear factor-κB node, and in next section, we demonstrate how unique hypoxic, inflammatory, rich in free-radical microenvironment of triple-negative breast cancer exacerbate pathways in which otherwise could become mostly suppressed by receptor tyrosine kinase inhibitors.
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http://dx.doi.org/10.1177/1010428317706919DOI Listing
June 2017

Stimuli-Responsive Mesoporous Silica NPs as Non-viral Dual siRNA/Chemotherapy Carriers for Triple Negative Breast Cancer.

Mol Ther Nucleic Acids 2017 Jun 29;7:164-180. Epub 2017 Mar 29.

Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, 1517964311 Tehran, Iran. Electronic address:

Triple negative breast cancer (TNBC) is the most aggressive and lethal subtype of breast cancer. It is associated with a very poor prognosis and intrinsically resistant to several conventional and targeted chemotherapy agents and has a 5-year survival rate of less than 25%. Because the treatment options for TNBC are very limited and not efficient enough for achieving minimum desired goals, shifting toward a new generation of anti-cancer agents appears to be very critical. Among recent alternative approaches being proposed, small interfering RNA (siRNA) gene therapy can potently suppress Bcl-2 proto-oncogene and p-glycoprotein gene expression, the most important chemotherapy resistance inducers in TNBC. When resensitized, primarily ineffective chemotherapy drugs turn back into valuable sources for further intensive chemotherapy. Regrettably, siRNA's poor stability, rapid clearance in the circulatory system, and poor cellular uptake mostly hampers the beneficial outcomes of siRNA therapy. Considering these drawbacks, dual siRNA/chemotherapy drug encapsulation in targeted delivery vehicles, especially mesoporous silica nanoparticles (MSNs) appears to be the most reasonable solution. The literature is full of reports of successful treatments of multi-drug-resistant cancer cells by administration of dual drug/siRNA-loaded MSNs. Here we tried to answer the question of whether application of a similar approach with identical delivery devices in TNBC is rational.
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http://dx.doi.org/10.1016/j.omtn.2017.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5415966PMC
June 2017