Agent For Treatment Of Breast Cancer Research Articles

α-Mangostin and apigenin induced the necrotic death of BT474 breast cancer cells with autophagy and inflammation

Objective: To find new compounds in order to overcome the mainstay of metastatic breast cancer due to the adverse side effects from, and increasing resistance to, current chemotherapeutic agents. Methods: α-Mangostin and apigenin were reported in comparison to doxorubicin, a chemotherapeutic drug. Ductal carcinoma (BT474) cell line and non-tumorigenic epithelial tissue from mammary gland (MCF-10A) were used. Cell viability assessment was calculated by the standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Cell morphology was investigated by light microscopy. By flow cytometry analysis, programmed cell death was observed using annexin V and propidium iodide staining while cell-cycle arrest was observed using propidium iodide staining. Change in transcriptional expression was evaluated by real-time quantitative reverse transcription PCR. Results: In 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, the result revealed α-mangostin and apigenin were more cytotoxic to BT474 cells. Longer exposure times to α-mangostin and apigenin caused more floating cells and a lower density of adhered cells with more vacuoles present in the colonies in BT474 only. α-Mangostin and apigenin caused necrosis in BT474 cells in a 24 h exposure, but a small amount of early apoptotic cells could also be detected at 24, 48 and 72 h exposure, whereas doxorubicin caused early apoptosis to BT474 cells at 24 h. Transcript expression and activity analysis supported caspase-3 was involved in the death of BT474 cells treated by all compounds. Moreover, α-mangostin and apigenin arrested the cell-cycle at the G1-phase, but at the G2/M-phase by doxorubicin. All three compounds induced a change in transcript expression levels of inflammation-associated, proto-oncogene, autophagy-associated and apoptosis-associated genes. Conclusions: α-Mangostin and apigenin are worth investigating as potential new sources of chemotherapeutic agents for breast cancer treatment.

Analgesic, anti-inflammatory and anticancer activities of Combretin A and Combretin B isolated from Combretum fragrans F. HOFFM (Combretaceae) leaves.

Previous pharmacological and phytochemical studies showed that, Combretum fragrans F. HOFFM (Combretaceae) is a Cameroonian medicinal plant possessing numerous therapeutic virtues and rich in various active secondary metabolites. In this study, we investigate in vivo anti-nociceptive and anti-inflammatory activity and, in vitro anticancer, anti-TNFα, ROS and NO-inhibitory activities of Combretum A and Combretin B, two triterpenes cycloartane-type isolated from the leaves of Combretum fragrans. The effect on ROS, TNF-α and NO production, anticancer activity and cytotoxicity assay were done using chemiluminescence technique, ELISA kit, colorimetric method, MCF-7 cells and MTT assay, respectively. Antinociceptive and anti-inflammatory activities were estimated using a model of acetic acid, formalin and carrageenan. Combretin A and Combretin B significantly (p<0.001) inhibited extracellular ROS production. These compounds also significantly (p<0.001) reduced TNF-α and NO production. Moreover, these compounds decreased cell viability of MCF-7 cell lines. For acetic acid- or formalin-induced pain, as well as carrageenan-induced acute inflammation, Combretin A and Combretin B exhibited significant (p<0.001) anti-nociceptive and anti-inflammatory activities. Anti-nociceptive, anti-inflammatory and anticancer potential associated with inhibitory effects on ROS, TNFα and NO production in this study show that, Combretin A and Combretin B could be considered as the promising chemotherapeutic agents in breast cancer treatment and inflammatory disease.

Synergetic effects of Docetaxel and ionizing radiation reduced cell viability on MCF-7 breast cancer cell

BackgroundIn recent decades neoadjuvant therapies such as combined chemotherapy and radiotherapy have been introduced for cancer management. Compared with monotherapy modalities, neoadjuvant therapy is associated with greater effectiveness while having minor side effects. Docetaxel is a chemotherapy agent for breast cancer treatment which can blocks the cell cycle at the G2/M phase which has shown special sensitivity to the ionizing radiation and hence causes cell death. To the best of our knowledge, there are currently no reports that explore the synergistic effects of Docetaxel and ionizing radiation on MCF-7 cancer cell death.MethodsWe divided cells into four different groups; control, cells which got in touch with Docetaxel, cells that with exposure to radiotherapy and cells which were influenced with combination of Docetaxel and radiotherapy. In vitro cell viability tests were done at different concentration of Docetaxel and different dose of radiation for 24, 48 and 72 h after the experiment.ResultsResults showed that the cytotoxicity was depending on the doses of radiation and Docetaxel. Radiation at 2 Gy dose was unable to produce significant effects neither in the radiation-only nor in the neoadjuvant therapy groups. However, the synergistic effects of neoadjuvant therapy were apparent at 4 and 6 Gy doses of radiation which could exert more significant cytotoxic effects on MCF-7 cells.ConclusionsStudy findings suggest that neoadjuvant therapy by using Docetaxel and 4 and 6 Gy ionizing radiation has synergistic effects on MCF-7 cell death and produces more significant results compared with monotherapy modalities.

Ginkgetin induces cell death in breast cancer cells via downregulation of the estrogen receptor.

Ginkgetin is a natural biflavonoid isolated from the leaves of Ginkgo biloba, and is characterized by its anti-inflammatory and anti-viral activities. Although numerous studies state that it has also antitumor activity, the anti-proliferative effect of ginkgetin and the underlying mechanism in breast cancer cells have not yet been investigated. In the present study, ginkgetin inhibited the cell viability of MCF-7 and T-47D cells dose-dependently, and suppressed the expression of the estrogen receptor (ER) at the mRNA and protein levels. Among the targets of the ER, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), cyclin D1 and survivin were also downregulated by ginkgetin treatment. The anti-proliferative effects of ginkgetin were sufficient to suppress the growth by estradiol stimulation. However, ginkgetin did not significantly affect the viability of MDA-MB-231 cells, which are ER-negative cells. Furthermore, the knockdown of the ER and an inhibitor of PFKFB3 significantly sensitized MCF-7 and T-47D cells to ginkgetin. These findings suggest that ginkgetin induces cell death in ER-positive breast cancer cells via the inhibition of ER expression and that it is a promising agent for breast cancer treatment.

PH and NIR-light-responsive magnetic iron oxide nanoparticles for mitochondria-mediated apoptotic cell death induced by chemo-photothermal therapy

Recently, various therapeutic strategies in anticancer drug development are focused to reduce adverse side effects and to enhance the therapeutic efficacy. Mostly, the iron oxide (Fe3O4) nanoparticles have widely been utilized as an efficient drug delivery system towing to their unique properties such as excellent magnetic behavior, considerably low toxicity, easy surface modification and high drug-loading efficacy. In the present study, we synthesized a multifunctional, DMSA coated, water soluble Fe3O4 nanoparticles (Fe3O4@DMSA/DOX) for an effective pH and NIR-light triggered delivery of anticancer drug (DOX) in cancer therapy. The combination of photothermal therapy combined with chemotherapy results demonstrated that the synthesized Fe3O4@DMSA/DOX is an excellent candidate for pH- and NIR-light induced phothothermal agent for an effective delivery of anticancer drug (DOX) into the target sub-cellular level into the human breast cancer (MDA-MB-231) cells. Furthermore, the Fe3O4@DMSA/DOX nanoparticles induced an excellent temperature elevation upon NIR light irradiation and controlled DOX release in vitro. The Fe3O4@DMSA/DOX nanoparticles exhibited synergistic effect when combining chemotherapy with photothermal therapy and showed an excellent cell toxicity to MDA-MB-231 cells. In addition, the combined chemo-photothermal therapy of Fe3O4@DMSA/DOX nanoparticles promoted an effective cell death by mitochondrial disruption mediated by ROS generation. Thus, the synthesized Fe3O4@DMSA/DOX nanoparticles could be utilized as potential anticancer agents for breast cancer treatment.

Combining doxorubicin with a phenolic extract from flaxseed oil: Evaluation of the effect on two breast cancer cell lines.

Breast cancer is one of the most frequently diagnosed forms of cancer and different treatments are used to block its progression. However, it still represents a very common cause of death in women. Doxorubicin(Dox) is reported as an effective agent in breast cancer treatment nonetheless it induces many side‑effects. For this reason, many laboratories are engaged in understanding how it is possible to decrease the drug concentration, considering that one of the possible solutions is to use drug synergy, combining it with natural substances. Recently we showed that a phenolic extract from flaxseed(FS) oil, named PEFSO, induced on MCF‑7 cell line an increase of apoptosis with related modification of G0/G1 phase cell cycle, and the activation of signaling and pro‑oxidant pathways. In this study we present data on the combined effect of Dox and PEFSO on two different breast cancer cell lines to define the conditions to use lower doses of this chemotherapeutic agent. We report the data relating to the ability of this mixture to induce cytotoxicity and apoptosis, cell cycle modification, mitochondrial membrane depolarization and activation of extrinsic and/or intrinsic apoptotic pathway.

Nab-paclitaxel after docetaxel hypersensitivity reaction: case report and literature review

Taxanes, including paclitaxel and docetaxel, are one of the most active cytotoxic agents in breast cancer treatment including Her-2 positive subtype characterized by aggressive clinical and pathological features since the early stage. However, their use is sometimes limited by the occurrence of hypersensivity reactions (HSRs) characterized by erythematous rashes, bronchospasm, respiratory distress, hypotension, and pulmonary edema. Cross-reactions between paclitaxel and docetaxel are described in literature with a rate ranging from 49% to 90%. Abraxane (nab-paclitaxel), an albumin-bound form of paclitaxel, has a different toxicity profile from solvent-based paclitaxel and a lower rate of HSRs. Interestingly, several authors have recently reported cases of patients who developed HSRs to taxanes, principally paclitaxel, and were then safety treated with Abraxane, suggesting the absence of cross-reactivity between these drugs. Based on these considerations, we report our clinical experience and perform a literature review on this topic with the aim to investigate the cross-reactivity between nab-paclitaxel and other taxanes, in particular with docetaxel. (www.actabiomedica.it)

FT-IR characterization of a theranostic nanoprobe for photodynamic therapy and epidermal growth factor receptor targets

Photodynamic Therapy (PDT) is an effective cancer treatment method based on light-activation of a photosensitizer in the presence of cellular oxygen. In an effort to develop a novel PDT agent for breast cancer treatment we report on the synthesis and characterization of a bifunctional theranostic nanoprobe; possessing both a photosensitizer agent (Chlorin e6) and tumor targeting agent – an Epidermal Growth Factor (EGF) complex which targets the EGF receptor. It’s effectiveness in arresting cancer cell growth was tested using the breast cancer cell line MDA-MB-468. FT-IR analysis confirms that carbodiimide chemistry was effective in creating covalent bonded complexes between the photosensitizer Chlorin e6 (Ce6) and cysteamine, and the EGF and α-lipoic acid, which exhibit excellent affinity for gold nanoparticles (AuNPs). In particular, for the Ce6-cysteamine complex FT-IR analysis shows peaks with significant increase in intensity at 1713, 1542, 2227cm−1 and a decrease at 941cm−1 and for the EGF-α-lipoic acid complex there are significant decreases in intensity at 1708, 1073, 947cm−1 and increases at 1542, 1680, 1108cm−1. These changes are consistent with the creation of amide bonds, loss of carboxylic acid, and modification of the NH and CO bonds. Conjugation of these complexes to AuNPs was confirmed by UV–vis and Dynamic Light Scattering experiments. MDA-MB-468 cells treated with the bifunctional nanoprobe exhibited similar cell death and mitochondrial activity at 10-fold smaller Ce6 concentrations when bound to AuNPs compared with free Ce6. In addition only half the exposure time was needed to achieve these effects compared with unbound Ce6.

Targeting cancer stem cells and signaling pathways by phytochemicals: Novel approach for breast cancer therapy.

Breast cancer is the most common form of cancer diagnosed in women worldwide and the second leading cause of cancer-related deaths in the USA. Despite the development of newer diagnostic methods, selective as well as targeted chemotherapies and their combinations, surgery, hormonal therapy, radiotherapy, breast cancer recurrence, metastasis and drug resistance are still the major problems for breast cancer. Emerging evidence suggest the existence of cancer stem cells (CSCs), a population of cells with the capacity to self-renew, differentiate and be capable of initiating and sustaining tumor growth. In addition, CSCs are believed to be responsible for cancer recurrence, anticancer drug resistance, and metastasis. Hence, compounds targeting breast CSCs may be better therapeutic agents for treating breast cancer and control recurrence and metastasis. Naturally occurring compounds, mainly phytochemicals have gained immense attention in recent times because of their wide safety profile, ability to target heterogeneous populations of cancer cells as well as CSCs, and their key signaling pathways. Therefore, in the present review article, we summarize our current understanding of breast CSCs and their signaling pathways, and the phytochemicals that affect these cells including curcumin, resveratrol, tea polyphenols (epigallocatechin-3-gallate, epigallocatechin), sulforaphane, genistein, indole-3-carbinol, 3, 3'-di-indolylmethane, vitamin E, retinoic acid, quercetin, parthenolide, triptolide, 6-shogaol, pterostilbene, isoliquiritigenin, celastrol, and koenimbin. These phytochemicals may serve as novel therapeutic agents for breast cancer treatment and future leads for drug development.

Abstract 318: Trigonella foenum (fenugreek) inhibited cancer stem cell properties and increased sensitivity to Doxorubicin resistant ZR-75-1 human breast cancer cell line by targeting mutant p53 and Notch-4

Abstract Despite advances in detection and therapies, breast cancer is the most common malignant disease in women worldwide. Doxorubicin is one of the effective agent for breast cancer treatment, but the resistance to it is representing a major obstacle for breast cancer treatment. Herein, we established a breast cancer cell line that showed a significant resistance to doxorubicin at clinically relevant concentrations. The epithelial breast cancer cell line ZR-75-1 was sequentially treated with doxorubicin for several treatment cycles. In consequence, we obtained chemoresistant cells displaying a mesenchymal-like phenotype, ZR-75-1-DR. The ZR-75-1-DR cells showed an increase in breast cancer stem cells (BCSC) activity, mutant p53 but not wild type, NOTCH-4 and microRNAs, small noncoding RNAs, expression compared to parental cells, suggesting their expression may contribute to the evolvement of BCSCs. Understanding the early molecular mechanisms of cross talk among mutant p53, Notch-4 and microRNAs in resistant to doxorubicin is crucial to provide better therapeutic strategies for breast cancer progression. Recently, we showed that Trigonella foenum (Fenugreek) extract (FCE), a traditional herbal plant with anti-tumor activity, induced apoptosis in HepG2 cells mediated by up-regulation of wild P53. To investigate the possible effect of FCE in the expression levels of mutant p53, Notch-4 and miRNAs in ZR-75-1-DR and parental cell lines, cells were pre-treated with or without FCE and/or doxorubicin for different time intervals. miRNAs were quantified using qRT-PCR and p53, Notch-4 expression and BCSC phenotype were evaluated by western blot analysis and immunohistochemistry. Our results revealed that FCE treatment showed a significant decrease in cell viability, clonogenicity and invasion capacity with a decrease in expression of mutant p53 and Notch-4 in ZR-75-1-DR compared to untreated cells. Furthermore, the inhibition of mutant p53 and Notch-4 expression was associated with a significant decrease in miR-21 and miR-142 with an increase in expression of let-7a and miR-34a. Furthermore, ZR-75-1-DR pre-treated with FCE showed an increase in chemosensitivity to doxorubicin at low doses with reduction in expression of stemness factor, ALDH1, compared to the parental and doxorubicin treated cells. In vivo, knockdown both mutant p53 and NOTCH-4 showed a significant regression in tumor size of ZR-75-1-DR xenografts compared to those of parental cells and control lentivirus after combined treatment with FCE and doxorubicin, but not with doxorubicin alone. All in all, our data introduced FCE as a promising non-toxic herbal, which has fourteen bioactive compounds and therapeutic potential to reduced cancer stem cell properties and increased sensitivity to doxorubicin treatment, by directly targeting mutant p53, NOTCH4 and microRNAs. Citation Format: Ahmed S. Sultan, Amira S. Fayala, Marwa Elkamel, Reem Bakir, Fatma Foad. Trigonella foenum (fenugreek) inhibited cancer stem cell properties and increased sensitivity to Doxorubicin resistant ZR-75-1 human breast cancer cell line by targeting mutant p53 and Notch-4. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 318.

Low doses of paclitaxel enhance liver metastasis of breast cancer cells in the mouse model.

Paclitaxel is the most commonly used chemotherapeutic agent in breast cancer treatment. In addition to its well-known cytotoxic effects, recent studies have shown that paclitaxel has tumor-supportive activities. Importantly, paclitaxel levels are not maintained at the effective concentration through one treatment cycle; rather, the concentration decreases during the cycle as a result of drug metabolism. Therefore, a comprehensive understanding of paclitaxel's effects requires insight into the dose-specific activities of paclitaxel and their influence on cancer cells and the host microenvironment. Here we report that a low dose of paclitaxel enhances metastasis of breast cancer cells to the liver in mouse models. We used microarray analysis to investigate gene expression patterns in invasive breast cancer cells treated with low or clinically relevant high doses of paclitaxel. We also investigated the effects of low doses of paclitaxel on cell migration, invasion and metastasis in vitro and in vivo. The results showed that low doses of paclitaxel promoted inflammation and initiated the epithelial-mesenchymal transition, which enhanced tumor cell migration and invasion in vitro. These effects could be reversed by inhibiting NF-κB. Furthermore, low doses of paclitaxel promoted liver metastasis in mouse xenografts, which correlated with changes in estrogen metabolism in the host liver. Collectively, these findings reveal the paradoxical and dose-dependent effects of paclitaxel on breast cancer cell activity, and suggest that increased consideration be given to potential adverse effects associated with low concentrations of paclitaxel during treatment. Gene expression microarray data are available in the GEO database under accession number GSE82048.

IR-780 Dye as a Sonosensitizer for Sonodynamic Therapy of Breast Tumor.

Sonodynamic therapy (SDT) has become a new modality for cancer therapy through activating certain chemical sensitizers by ultrasound (US). Discovery and development of novel sonosensitizers are attracting extensive attentions. Here, we introduce IR-780 iodide, a lipophilic heptamethine dye with a peak optical absorption of 780 nm wavelength, which can function as SDT agents for breast cancer treatment. The in vitro cellular uptake, cell viability, and the generation levels of reactive oxygen species (ROS) were examined by using 4T1 breast cancer cells incubated with various concentrations of IR-780 followed by US irradiation. Our results showed a dose- and time-dependent cellular uptake of IR-780 iodide in 4T1 cancer cells. Significant lower viabilities and more necrotic/apoptotic cells were found when these cancer cells were treated with IR-780 iodide with US irradiation. Further analyzing the generation of ROS demonstrated significant increase of 1O2 level and H2O2, but not ⋅OH in the SDT-treated cells. The in vivo anti-tumor efficacy of SDT with IR-780 revealed significant tumor growth inhibition of xenografts of 4T1 cancer cells; it was further confirmed by histological analysis and TUNEL staining. Our results strongly suggest that SDT combined with IR-780 may provide a promising strategy for tumor treatment with minimal side effects.

Discovery of a novel inhibitor of kinesin-like protein KIFC1.

Historically, drugs used in the treatment of cancers also tend to cause damage to healthy cells while affecting cancer cells. Therefore, the identification of novel agents that act specifically against cancer cells remains a high priority in the search for new therapies. In contrast with normal cells, most cancer cells contain multiple centrosomes which are associated with genome instability and tumorigenesis. Cancer cells can avoid multipolar mitosis, which can cause cell death, by clustering the extra centrosomes into two spindle poles, thereby enabling bipolar division. Kinesin-like protein KIFC1 plays a critical role in centrosome clustering in cancer cells, but is not essential for normal cells. Therefore, targeting KIFC1 may provide novel insight into selective killing of cancer cells. In the present study, we identified a small-molecule KIFC1 inhibitor, SR31527, which inhibited microtubule (MT)-stimulated KIFC1 ATPase activity with an IC50 value of 6.6 μM. By using bio layer interferometry technology, we further demonstrated that SR31527 bound directly to KIFC1 with high affinity (Kd=25.4 nM). Our results from computational modelling and saturation-transfer difference (STD)-NMR experiments suggest that SR31527 bound to a novel allosteric site of KIFC1 that appears suitable for developing selective inhibitors of KIFC1. Importantly, SR31527 prevented bipolar clustering of extra centrosomes in triple negative breast cancer (TNBC) cells and significantly reduced TNBC cell colony formation and viability, but was less toxic to normal fibroblasts. Therefore, SR31527 provides a valuable tool for studying the biological function of KIFC1 and serves as a potential lead for the development of novel therapeutic agents for breast cancer treatment.

Resveratrol and Its Analogs As Antitumoral Agents For Breast Cancer Treatment.

Resveratrol (3,5,4'-tri-hydroxystilbene) (RSV), a naturally occurring phytoalexin, readily available in the diet, has gained interest as a non-toxic agent capable of displaying cancer-preventing and anti-cancer properties. Several studies, using both in vitro and in vivo models, have illustrated RSV capacity to modulate a multitude of signaling pathways associated with cellular growth and division, apoptosis, angiogenesis, invasion and metastasis. However, its clinical application is limited because of a low oral bioavailability with high adsorption but rapid metabolism and low tissue concentrations. Several chemical modifications to the backbone structure have been made for the purpose of improving pharmacokinetic parameters. One promising strategy involves the introduction of methoxylic or hydroxylic groups on the phenylic rings of RSV. Moreover, by replacing the alkene linker between the two aromatic rings with a heterocyclic system rigid analogs such as 2,3- thiazolidin-4-ones and 3-chloro-azetidin-2-ones that displayed higher cytotoxic activity and hence higher ability to inhibit in vitro breast cancer cell growth have been synthesized. In vitro studies have demonstrated, for some of these compounds, a greater bioaccessibility than RSV and more selective inhibitory effects on breast cancer cell growth. Further investigations, particularly in vivo, are required as next step to implicate these analogs as pharmacologic agents for a possible clinical anticancer application.

PCP4/PEP19 promotes migration, invasion and adhesion in human breast cancer MCF-7 and T47D cells.

Purkinje cell protein (PCP) 4/peptide (PEP) 19 is expressed in Purkinje cells where it has a calmodulin-binding, anti-apoptotic function. We recently demonstrated that PCP4/PEP19 is expressed and inhibit apoptosis in human breast cancer cell lines. In the present study we investigated the role of PCP4/PEP19 in cell morphology, adhesion, migration, and invasion in MCF-7 and T47D human breast cancer cell lines. Knockdown of PCP4/PEP19 reduced the formation of filopodia-like cytoplasmic structures and vinculin expression, and enhanced E-cadherin expression. Activities of migration, invasion, and cell adhesion were also decreased after the knockdown of PCP4/PEP19 in MCF-7 and T47D cells. These results suggested that PCP4/PEP19 promotes cancer cell adhesion, migration, and invasion and that PCP4/PEP19 may be a potential target for therapeutic agents in breast cancer treatment which act by inhibiting epithelial-mesenchymal transition and enhancing apoptotic cell death.

Cordycepin, a Natural Antineoplastic Agent, Induces Apoptosis of Breast Cancer Cells via Caspase-dependent Pathways

Cordycepin, a major compound separated from Cordyceps sinensis, is known as a potential novel candidate for cancer therapy. Breast cancer, the most typical cancer diagnosed among women, remains a global health problem. In this study, the anti-breast cancer property of cordycepin and its underlying mechanisms was investigated. The direct effects of cordycepin on breast cancer cells both in in vitro and in vivo experiments were evaluated. Cordycepin exerted cytotoxicity in MCF-7 and MDA-MB-231 cells confirmed by reduced cell viability, inhibition of cell proliferation, enhanced lactate dehydrogenase release and reactive oxygen species accumulation, induced mitochondrial dysfunction and nuclear apoptosis in human breast cancer cells. Cordycepin increased the activation of pro-apoptotic proteins, including caspase-8, caspase-9, caspase-3 and Bax, and suppressed the expression of the anti-apoptotic protein, B-cell lymphoma 2 (Bcl-2). The inhibition on MCF-7-xenografted tumor growth in nude mice further confirmed cordycepin's anti-breast cancer effect. These aforementioned results reveal that cordycepin induces apoptosis in human breast cancer cells via caspase-dependent pathways. The data shed light on the possibility of cordycepin being a safe agent for breast cancer treatment.

Inhibitory Effect of Ginseng on Breast Cancer Cell Line Growth Via Up-Regulation of Cyclin Dependent Kinase Inhibitor, p21 and p53

Objective:Breast cancer is global female health problem worldwide. Most of the currently used agents for breast cancer treatment have toxic side-effects. Ginseng root, an oriental medicine, has many health benefits and may exhibit direct anti-cancer properties. This study was performed to assess the effects of ginseng on breast cancer cell lines.Materials and Methods:Cytotoxicity of ginseng extract was measured by MTT assay after exposure of MDA-MB-231, MCF-10A and MCF-7 breast cancer cells to concentrations of 0.25, 0.5, 1, 1.5, 2 and 2.5 mg/well. Expression levels of p21WAF, p16INK4A, Bcl-2, Bax and P53 genes were analyzed by quantitative real time PCR.Results:The treatment resulted in inhibition of cell proliferation in a dose-and time-dependent manner. p53, p21WAF1and p16INK4A expression levels were up-regulated in ginseng treated MDA-MB-231 and MCF-7 cancer cells compared to untreated controls and in MCF-10A cells. The expression levels of Bcl2 in the MDA-MB-231 and MCF-7 cells were down-regulated. In contrast, that of Bax was significantly up-regulated.Conclusion:The results of this study revealed that ginseng may inhibit breast cancer cell growth by activation of the apoptotic pathway.

Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors That Also Modulate Estrogen Receptors.

A series of triphenylethylene bisphenol analogues of the selective estrogen receptor modulator (SERM) tamoxifen were synthesized and evaluated for their abilities to inhibit aromatase, bind to estrogen receptor α (ER-α) and estrogen receptor β (ER-β), and antagonize the activity of β-estradiol in MCF-7 human breast cancer cells. The long-range goal has been to create dual aromatase inhibitor (AI)/selective estrogen receptor modulators (SERMs). The hypothesis is that in normal tissue the estrogenic SERM activity of a dual AI/SERM could attenuate the undesired effects stemming from global estrogen depletion caused by the AI activity of a dual AI/SERM, while in breast cancer tissue the antiestrogenic SERM activity of a dual AI/SERM could act synergistically with AI activity to enhance the antiproliferative effect. The potent aromatase inhibitory activities and high ER-α and ER-β binding affinities of several of the resulting analogues, together with the facts that they antagonize β-estradiol in a functional assay in MCF-7 human breast cancer cells and they have no E/Z isomers, support their further development in order to obtain dual AI/SERM agents for breast cancer treatment.

MiR-129-3p promotes docetaxel resistance of breast cancer cells via CP110 inhibition

Docetaxel is commonly used as an effective chemotherapeutic agent in breast cancer treatment, but the underlying mechanisms of drug resistance are not fully understood. The purpose of this study was to investigate the possible role of miR-129-3p in breast cancer cell resistance to docetaxel. MiR-129 and miR-129-3p inhibitor were transfected into breast cancer cells to investigate their effects on chemoresistance to docetaxel. The function of miR-129-3p was evaluated by apoptosis, cell proliferation, and cell cycle assays. We found that miR-129-3p was up-regulated in MDA-MB-231/Doc cells, concurrent with CP110 down-regulation, compared to the parental MDA-MB-231 cells. In vitro drug sensitivity assays demonstrated that miR-129-3p inhibition sensitized MDA-MB-231/Doc and MCF-7 cells to docetaxel, whereas miR-129 overexpression enhanced MDA-MB-231 and MCF-7 cell resistance to docetaxel. Ectopic miR-129 expression reduced CP110 expression and the luciferase activity of a CP110 3′ untranslated region-based reporter construct in MDA-MB-231 cells, suggesting that CP110 is a direct miR-129-3p target. We demonstrated that restoration of CP110 expression in MDA-MB-231 and MCF-7 cells by miR-129 overexpression rendered the cells sensitive to docetaxel. In a nude xenograft model, miR-129 up-regulation significantly decreased MDA-MB-231 cells’ response to docetaxel. Our findings suggest that miR-129-3p down-regulation potentially sensitizes breast cancer cells to docetaxel treatment.

In vitro effects of tamoxifen on adipose-derived stem cells.

In breast reconstructive procedures, adipose-derived stem cells (ASCs) that are present in clinical fat grafting isolates are considered to play the main role in improving wound healing. In patients following chemotherapy for breast cancer, poor soft tissue wound healing is a major problem. However, it is unclear if tamoxifen (TAM) as the most widely used hormonal therapeutic agent for breast cancer treatment, affects the ASCs and ultimately wound healing. This study evaluated whether TAM exposure to in vitro human ASCs modulate cellular functions. Human ASCs were isolated and treated with TAM at various concentrations. The effects of TAM on cell cycle, cell viability and proliferation rates of ASCs were examined by growth curves, MTT assay and BrdU incorporation, respectively. Annexin V and JC-1 Mitochondrial Membrane Potential assays were used to analyze ASC apoptosis rates. ASCs were cultured in derivative-specific differentiation media with or without TAM (5 uM) for 3 weeks. Adipogenic and osteogenic differentiation levels were measured by quantitative RT-PCR and histological staining. TAM has cytotoxic effects on human ASCs through apoptosis and inhibition of proliferation in dose- and time-dependent manners. TAM treatment significantly down-regulates the capacity of ASCs for adipogenic and osteogenic differentiation (p<0.05 vs. control), and inhibit the ability of the ASCs to subsequently formed cords in Matrigel. This study is the first findings to our knowledge that demonstrated that TAM inhibited ASC proliferation and multi-lineage ASC differentiation rates. These results may provide insight into the role of TAM with associated poor soft tissue wound healing and decreased fat graft survival in cancer patients receiving TAM.