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Adriamycin (ADR) is widely used against breast cancer, but subsequent resistance always occurs. YAP, a downstream protein of angiomotin (AMOT), importantly contributes to ADR resistance, whereas the mechanism is largely unknown. MCF‐7 cells and MDA‐MB‐231 cells were used to establish ADR‐resistant cell. Then, mRNA and protein expressions of AMOT and YAP expressions were determined. After AMOT transfection alone or in combination with YAP, the sensitivity of the cells to ADR were evaluated in vitro by examining cell proliferation, apoptosis, and cell cycle, as well as in vivo by examining tumor growth. Additionally, the expressions of proteins in YAP pathway were determined in AMOT‐overexpressing cells. In the ADR‐resistant cells, the expression of AMOT was decreased while YAP was increased, respectively, and the nucleus localization of YAP was increased at the same time. After AMOT overexpression, these were inhibited, whereas the cell sensitivity to ADR was enhanced. However, the AMOT‐induced changes were significantly suppressed by YAP knockdown. The consistent results in vivo showed that AMOT enhanced the inhibition of ADR on tumor growth, and inhibited YAP signaling, evidenced by decreased levels of YAP, CycD1, and p‐ERK. Our data revealed that decreased AMOT contributed to ADR resistance in breast cancer cells, which was importantly negatively mediated YAP. These observations provide a potential therapy against breast cancer with ADR resistance. [ABSTRACT FROM AUTHOR]

Adriamycin (ADR) is a frequently employed chemotherapeutic agent for the management of breast cancer. Nevertheless, multidrug resistance (MDR) can impair its therapeutic efficacy in breast cancer. MDR is characterized by increased expression of the P‐glycoprotein (P‐gp) efflux pump, up‐regulation of anti‐apoptotic proteins, and downregulation of pro‐apoptotic proteins. Consequently, inhibition of ATP‐binding cassette (ABC) transporter proteins has been deemed the most efficacious approach to overcome MDR. In this study, we used MTT (3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5 diphenyl tetrazolium bromide), Western blots, flow cytometry, immunofluorescence, and constructed xenograft tumors to investigate whether ginsenoside Rg3‐near‐infrared photothermal (Rg3‐NIR) combination reversed multidrug resistance in MCF‐7/ADR breast cancer. In vivo and in vitro experiments, the results showed that Rg3‐NIR co‐treatment was effective in inducing the apoptosis of MCF‐7/ADR breast cancer cells. This was achieved by reversing the expression of drug resistance‐associated proteins, while also inhibiting cell proliferation, migration, and epithelial–mesenchymal transition (EMT) processes via attenuation of the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT) signaling pathway transduction. Ginsenoside Rg3 combined with near‐infrared photothermal therapy (NIR) effectively reverses multidrug resistance in breast cancer MCF‐7/ADR cells, providing a new therapeutic strategy for breast cancer drug resistance. [ABSTRACT FROM AUTHOR]

Novel strategies for treating triple-negative breast cancer (TNBC) are ongoing because of the lack of standard-of-care treatment. Nanoframed materials with a protein pillar are considered a valuable tool for designing multigoals of energy-absorbing/medication cargo and are a bridge to cross-conventional treatment strategies. Nanobioconjugates of gold nanoclusters–bovine serum albumin (AuNCs–BSA) and doxorubicin–AuNCs–BSA (Dox–AuNCs–BSA) were prepared and employed as a simultaneous double photosensitizer/sonosensitizer and triple chemotherapeutic/photosensitizer/sonosensitizer, respectively. The highly stable AuNCs–BSA and Dox–AuNCs–BSA have ζ potentials of –29 and –18 mV, respectively, and represent valuable photothermal and sonodynamic activities for the combination of photothermal therapy and sonodynamic therapy (PTT/SDT) and synchronized chemotherapy/photothermal therapy/sonodynamic therapy (CTX/PTT/SDT) of human TNBC cells, respectively. The efficiency of photothermal conversion of AuNCs–BSA was calculated to be a promising value of 32.9%. AuNCs–BSA and Dox–AuNCs–BSA were activated on either laser light irradiation or ultrasound exposure with the highest efficiency on the combination of both types of radiation. CTX/PTT/SDT of MCF-7 and MDA-MB-231 breast cancer cell lines by Dox–AuNCs–BSA were evaluated with the MTT cell proliferation assay and found to progress synergistically. Results of the MTT assay, detection of the generation of intracellular reactive oxygen species and occurrence of apoptosis in the cells confirmed that CTX/PTT/SDT by Dox–AuNCs–BSA was attained with lower needed doses of the drug and improved tumor cell ablation, which would result in the enhancement of therapeutic efficacy and overcoming of therapeutic resistance. [ABSTRACT FROM AUTHOR]

Breast cancer is the most prevalent malignant tumor in women. Adriamycin (ADR) is a primary chemotherapy drug, but resistance limits its effectiveness. Ferroptosis, a newly identified cell death mechanism, involves the transferrin receptor (TFRC), closely linked with tumor cells. This study aimed to explore TFRC and ferroptosis's role in breast cancer drug resistance. Bioinformatics analysis showed that TFRC was significantly downregulated in drug-resistant cell lines, and patients with low TFRC expression might demonstrate a poor chemotherapeutic response to standard treatment. High expression of TFRC was positively correlated with most of the ferroptosis-related driver genes. The research findings indicate that ferroptosis markers were higher in breast cancer tissues than in normal ones. In chemotherapy-sensitive cases, Ferrous ion (Fe2+) and malondialdehyde (MDA) levels were higher than in resistant cases (all p < .05). TFRC expression was higher in breast cancer than in normal tissue, especially in the sensitive group (all p < .05). Cytological experiments showed increased hydrogen peroxide (H2O2) after ADR treatment in both sensitive and resistant cells, with varying MDA changes (all p < .05). Elevating TFRC increased Fe2+ and MDA in ADR-resistant cells, enhancing their sensitivity to ADR. However, TFRC upregulation combined with ADR increased proliferation and invasiveness in resistant cell lines (all p < .05). In conclusion, ADR resistance to breast cancer is related to the regulation of iron ion-mediated ferroptosis by TFRC. Upregulation of TFRC in ADR-resistant breast cancer cells activates ferroptosis and reverses ADR chemotherapy resistance of breast cancer. [ABSTRACT FROM AUTHOR]

Background: Recently the carcinogenic and toxic effects of some heavy metals such as chromium (Cr), and lead (Pb) through the mechanism of oxidative stress have been reported. Due to the various consequences of chemotherapeutic treatments on body hemostasis, the present study aimed to evaluate the effect of Adriamycin 60 mg/m2 and Cytoxan 600 mg/m2 (AC) chemotherapy on the serum levels of Cr, Pb, and the percent α-diphenyl-β-picrylhydrazyl (DPPH) inhibition. Methods: This study was performed on 50 patients with breast cancer at two separate sampling times, the first at the initiation of chemotherapy and the last at the end of three courses of the AC chemotherapy treatment. Serum levels of Cr and Pb were measured using atomic absorption spectrophotometry. The percent DPPH inhibition (% I) and also the effect of age and stage of the disease on the mentioned variables were evaluated. Statistical comparison of the obtained results before and after chemotherapy was performed using paired sample t-test. Intra-group evaluation of age and disease stages was done using an independent sample t-test. Results: A significant decrease was observed in the percent DPPH inhibition after 3 courses of chemotherapy (p

Pyrotinib (PYR) is a pan-HER kinase inhibitor that inhibits signaling via the RAS/RAF/MEK/MAPK and PI3K/AKT pathways. In this study, we aimed to investigate the antitumor efficacy of pyrotinib combined with adriamycin (ADM) and explore its mechanisms on HER2+ breast cancer. We investigated the effects of PYR and ADM on breast cancer in vitro and in vivo. MTT assay, Wound-healing, and transwell invasion assays were used to determine the effects of PYR, ADM or PYR combined with ADM on cell proliferation, migration, and invasion of SK-BR-3 and AU565 cells in vitro. Cell apoptosis and cycle were detected through flow cytometry. In vivo, xenograft models were established to test the effect of PYR, ADM, or the combined therapy on the nude mice. Western blotting was performed to assess the expression of Akt, p-Akt, p-65, p-p65, and FOXC1. The results indicated that PYR and ADM significantly inhibited the proliferation, migration, and invasion of SK-BR-3 and AU565 cells, and the inhibitory rate of the combination group was higher than each monotherapy group. PYR induced G1 phase cell-cycle arrest, while ADM induced G2 phase arrest, while the combination group induced G2 phase arrest. The combined treatment showed synergistic anticancer activities. Moreover, PYR significantly downregulated the expression of p-Akt, p-p65, and FOXC1. In clinical settings, PYR also exerts satisfactory efficacy against breast cancer. These findings suggest that the combination of PYR and ADM shows synergistic effects both in vitro and in vivo. PYR suppresses the proliferation, migration, and invasion of breast cancers through down-regulation of the Akt/p65/FOXC1 pathway.

Abstract Purpose Adriamycin is a novel chemotherapeutic agent of great benefit for treating breast cancer. However, adriamycin ‐resistance remains a major obstacle. The vital Glutathione transferase P1 (GSTPi) inhibitor 6‐(7‐nitro‐2,1,3‐benzoxadiazol‐4‐ylthio) hexanol (NBDHEX) has recently shown antitumor activity in various cancers. In this study, we analyzed the effect of NBDHEX and adriamycin combination against breast cancer in vitro and in vivo. Methods CCK‐8 assay was performed to test cell viability. The location and expression level of GSTpi was determined by immunofluorescence and Western blot in cells and immunohistochemistry staining in tissues. The enzyme activity test was applied to detect the effect of NBDHEX on the activity of GSTpi. The apoptosis related proteins' expression was tested using Western blot. The phosphorylation sites of GSTpi were detected by mass spectrometry. Antitumor effects of single treatment or co‐administration of adriamycin and NBDHEX were evaluated in nude mice. Results NBDHEX treatment inhibited GSTpi enzyme activity and co‐administration of adriamycin and NBDHEX promoted apoptosis of adriamycin‐resistance breast cancer cell. Moreover, drug combination of NBDHEX and adriamycin significantly enhanced tumor growth inhibition compared with single agent. Conclusion NBDHEX serves as a good candidate for combination with adriamycin, offering new insights for breast cancer treatment.

Background: Recently the carcinogenic and toxic effects of some heavy metals such as chromium (Cr), and lead (Pb) through the mechanism of oxidative stress have been reported. Due to the various consequences of chemotherapeutic treatments on body hemostasis, the present study aimed to evaluate the effect of Adriamycin 60 mg/m2 and Cytoxan 600 mg/m2 (AC) chemotherapy on the serum levels of Cr, Pb, and the percent a-diphenyl-ß-picrylhydrazyl (DPPH) inhibition. Methods: This study was performed on 50 patients with breast cancer at two separate sampling times, the first at the initiation of chemotherapy and the last at the end of three courses of the AC chemotherapy treatment. Serum levels of Cr and Pb were measured using atomic absorption spectrophotometry. The percent DPPH inhibition (% I) and also the effect of age and stage of the disease on the mentioned variables were evaluated. Statistical comparison of the obtained results before and after chemotherapy was performed using paired sample t-test. Intra-group evaluation of age and disease stages was done using an independent sample t-test. Results: A significant decrease was observed in the percent DPPH inhibition after 3 courses of chemotherapy (p<0.001). Cr and also Pb were significantly higher in patients with breast cancer after AC chemotherapy (p<0.001). Conclusion: According to the results, AC chemotherapy in patients with breast cancer is associated with higher levels of Cr and Pb, which can eventually lead to worsened oxidative stress status in affected patients. However, it seems that these changes do not necessarily depend on age and the stage of the disease. [ABSTRACT FROM AUTHOR]

Numerous clinical studies have established the debilitating neurocognitive side effects of chemotherapy in the treatment of breast cancer, often referred as chemobrain. We hypothesize that cognitive impairments are associated with elevated microglial inflammation in the brain. Thus, either elimination of microglia or restoration of microglial function could ameliorate cognitive dysfunction. Using a rodent model of chronic Adriamycin (ADR) treatment, a commonly used breast cancer chemotherapy, we evaluated two strategies to ameliorate chemobrain: 1) microglia depletion using the colony stimulating factor-1 receptor (CSF1R) inhibitor PLX5622 and 2) human induced pluripotent stem cell-derived microglia (iMG)-derived extracellular vesicle (EV) treatment. In strategy 1 mice received ADR once weekly for 4 weeks and were then administered CSF1R inhibitor (PLX5622) starting 72 h post-ADR treatment. ADR-treated animals given a normal diet exhibited significant behavioral deficits and increased microglial activation 4-6 weeks later. PLX5622-treated mice exhibited no ADR-related cognitive deficits and near complete depletion of IBA-1 and CD68+ microglia in the brain. Cytokine and RNA sequencing analysis for inflammation pathways validated these findings. In strategy 2, 1 week after the last ADR treatment, mice received retro-orbital vein injections of iMG-EV (once weekly for 4 weeks) and 1 week later, mice underwent behavior testing. ADR-treated mice receiving EV showed nearly complete restoration of cognitive function and significant reductions in microglial activation as compared to untreated ADR mice. Our data demonstrate that ADR treatment elevates CNS inflammation that is linked to cognitive dysfunction and that attenuation of neuroinflammation reverses the adverse neurocognitive effects of chemotherapy.

Purpose: Adriamycin is a novel chemotherapeutic agent of great benefit for treating breast cancer. However, adriamycin ‐resistance remains a major obstacle. The vital Glutathione transferase P1 (GSTPi) inhibitor 6‐(7‐nitro‐2,1,3‐benzoxadiazol‐4‐ylthio) hexanol (NBDHEX) has recently shown antitumor activity in various cancers. In this study, we analyzed the effect of NBDHEX and adriamycin combination against breast cancer in vitro and in vivo. Methods: CCK‐8 assay was performed to test cell viability. The location and expression level of GSTpi was determined by immunofluorescence and Western blot in cells and immunohistochemistry staining in tissues. The enzyme activity test was applied to detect the effect of NBDHEX on the activity of GSTpi. The apoptosis related proteins' expression was tested using Western blot. The phosphorylation sites of GSTpi were detected by mass spectrometry. Antitumor effects of single treatment or co‐administration of adriamycin and NBDHEX were evaluated in nude mice. Results: NBDHEX treatment inhibited GSTpi enzyme activity and co‐administration of adriamycin and NBDHEX promoted apoptosis of adriamycin‐resistance breast cancer cell. Moreover, drug combination of NBDHEX and adriamycin significantly enhanced tumor growth inhibition compared with single agent. Conclusion: NBDHEX serves as a good candidate for combination with adriamycin, offering new insights for breast cancer treatment. [ABSTRACT FROM AUTHOR]

Metaplastic breast cancer (MPBC) is a rare variant of breast cancer and most treatment protocols are based on the guidelines for triple negative breast cancer. However, response to standard anthracycline and taxane based chemotherapy is poor. Published literature on use of ifosfamide based chemotherapy in the first line setting for MPBC is scarce. We carried out this record based analysis on MPBC patients treated at our institute with the combination of ifosfamide and Adriamycin (IA) as first line therapy. Patients were analysed for the clinical and demographic profile; pathology and treatment details; and treatment outcomes. Four patients who received IA chemotherapy were evaluated. Three of the four patients were postmenopausal. The median size of the tumor was 7.5 cm, only one patient had a heavy nodal burden and lung was the most common site of metastases seen in all three patients with metastatic disease. Pathology showed heterogenous, mixed histology with high grade tumors. All patients had triple negative tumors. All four patients underwent mastectomy and received IA chemotherapy as per standard doses. One patient had complete response, one had partial response and one patient progressed after 4 cycles of chemotherapy. The patient with localized disease continues to be disease free till date. Grade 3,4 neutropenia and grade 2 anemia was the most common chemotherapy related toxicity. The response rates in MPBC with IA regimen appear to be similar to the currently used anthracycline-taxane combinations, with slightly more haematological toxicity. Ifosfamide and adriamycin regimen may be considered in MPBC patients as primary or salvage systemic therapy. [ABSTRACT FROM AUTHOR]

3D organoid model technologies have led to the development of innovative tools for cancer precision medicine. Yet, the gold standard culture system (Matrigel®) lacks the ability for extensive biophysical manipulation needed to model various cancer microenvironments and has inherent batch-to-batch variability. Tunable hydrogel matrices provide enhanced capability for drug testing in breast cancer (BCa), by better mimicking key physicochemical characteristics of this disease's extracellular matrix. Here, we encapsulated patient-derived breast cancer cells in bioprinted polyethylene glycol-derived hydrogels (PEG), functionalized with adhesion peptides (RGD, GFOGER and DYIGSR) and gelatin-derived hydrogels (gelatin methacryloyl; GelMA and thiolated-gelatin crosslinked with PEG-4MAL; GelSH). Within ranges of BCa stiffnesses (1–6 kPa), GelMA, GelSH and PEG-based hydrogels successfully supported the growth and organoid formation of HR+,−/HER2+,− primary cancer cells for at least 2–3 weeks, with superior organoid formation within the GelSH biomaterial (up to 268% growth after 15 days). BCa organoids responded to doxorubicin, EP31670 and paclitaxel treatments with increased IC50 concentrations on organoids compared to 2D cultures, and highest IC50 for organoids in GelSH. Cell viability after doxorubicin treatment (1 µM) remained >2-fold higher in the 3D gels compared to 2D and doxorubicin/paclitaxel (both 5 µM) were ~2.75–3-fold less potent in GelSH compared to PEG hydrogels. The data demonstrate the potential of hydrogel matrices as easy-to-use and effective preclinical tools for therapy assessment in patient-derived breast cancer organoids. [ABSTRACT FROM AUTHOR]

Introduction: Thromboembolic conditions in cancer patients undergoing chemotherapy are 4 to 7 times higher than in control patients. The aim of this study is to evaluate the procoagulant activity of microparticles (MPs) expressing phosphatidylserine (PS) derived from breast cancer cell line MDA-MB-231 treated with Adriamycin. Methods & Materials: In this experimental study, MDA-MB-231 breast cancer cells were treated with concentrations of 0.5, 1, and 2 μM adriamycin for 24 and 48 hours. Using centrifugation technique, the MPs in the cell culture medium were separated from other contents and flow cytometry was used to count and determine the MPs phenotype. At the end, the statistical analysis of the data was done SPSS software version 23 (IBM, USA). Results: The total number of MPs increased by 11.3 and 11.8 times in 24 and 48 hours treated and 2 μM dose respectively (p<0.001). Almost 49% of all MPs were positive in terms of Annexin V marker, which is an indicator of procoagulant MPs. In the culture medium treated with a dose of 2 μM, the procoagulant activity of MPs at 24 and 48 hours was 42 ± 5.9 nM and 58 ± 6.8 nM PS, respectively, which was more than 14 compared to the control groups. They had an increase (p<0.001). Conclusion: Adriamycin increases the procoagulant activity of tumor-derived MPs, which can be one of the important and effective reasons for causing thromboembolic conditions in patients undergoing chemotherapy. [ABSTRACT FROM AUTHOR]

A 34-year-old woman with a rapidly growing right breast mass visited our hospital. The mass was diagnosed as a right breast cancer (cT3N1M0 stage ⦀A). Her serum leucocyte count and C-reactive protein levels were high, and she had persistent fever. However, serum procalcitonin and β-D-glucan levels were normal, and no apparent infection focus was detected, although her serum granulocyte colony-stimulating factor (G-CSF) level was markedly elevated to 42.7 pg/mL. Therefore, a G-CSF-producing breast cancer was suspected. A pathological analysis of the surgical specimen revealed a squamous cell carcinoma of the breast (pT2N0 [i+] M0 stage ∥A). Right mastectomy (with the resection of the pectoralis major muscle), axillary lymph node dissection, and split layer grafting were performed. The leucocyte count and serum G-CSF level decreased on postoperative day (POD) 1 and normalized on POD 6. As adjuvant chemotherapy, 4 cycles of a combination chemotherapy with adriamycin and cyclophosphamide and 12 cycles of weekly paclitaxel were administered. After chemotherapy, the patient also underwent postmastectomy radiotherapy. Currently, 30 months after surgery, the patient is alive and well with neither progression nor distant metastasis. G-CSF-producing breast cancers tend to rapidly grow such as in the current case; thus, surgery should be performed immediately, followed by appropriate adjuvant treatment.

Abstract To achieve better antitumour efficacy, it is urgent to improve anticancer drug delivery efficiency in targeting cancer cells. In this work, chitosan-functionalized graphene oxide (ChrGO) nanosheets were fabricated via microwave-assisted reduction, which were employed to the intracellular delivery nanosystem for anticancer drug agent in breast cancer cells. Drug loading and release research indicated that adriamycin can be efficiently loaded on and released from the ChrGO nanosheets. Less drug release during delivery and better biocompatibility of ChrGO/adriamycin significantly improve its safety and therapeutic efficacy in HER2-overexpressing BT-474 cells. Furthermore, ChrGO/adriamycin in combination with trastuzumab exhibited synergistic antitumour activity in BT-474 cells, which demonstrated superior therapeutic efficacy compared with each drug alone. Cells treated with trastuzumab (5 μg/mL) or equivalent ChrGO/adriamycin (5 μg/mL) each elicited 54.5% and 59.5% cell death, respectively, while the combination treatment with trastuzumab and ChrGO/adriamycin resulted in a dramatic 88.5% cell death. The dual-targeted therapy displayed higher apoptosis, indicating superior therapeutic efficacy due to the presence of different mechanisms of action. The combined treatment of ChrGO/adriamycin and trastuzumab in BT-474 cells induced cell cycle arrest and apoptosis, which ultimately led to the death of augmented cancer cells. This work has provided a facile microwave-assisted fabrication of ChrGO as a controlled and targeted intracellular drug delivery nanosystem, which is expected to be a novel promising therapy for treating HER2-overexpressing breast cancer cells.

Accumulating evidence suggests that developmental chemoresistance in cancers is closely associated with the dysregulation of circular RNA transcriptions. The objective of this study is to disclose the role of circ_0001667 and provide a potential functional mechanism in breast cancer. Quantitative real‐time PCR was applied for the analysis of circ_0001667, microRNA‐4458 (miR‐4458) and nuclear receptor coactivator 3 (NCOA3) expression. In adriamycin (ADM)‐resistant cell lines, we investigated cell proliferation using 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5 diphenyl tetrazolium bromide (MTT) assay and colony formation assay. Cell migration and cell invasion were determined by transwell assay. The protein levels of multi‐drug resistance‐1, matrix metalloproteinases‐9, cleaved‐caspase3, cleaved‐caspase9 and NCOA3 were detected by western blot. ADM resistance was ascertained by IC50 value using MTT assay. Cell apoptosis was checked by flow cytometry assay. The putative relationship between miR‐4458 and circ_0001667 and NCOA3 was validated by pull‐down assay, dual‐luciferase reporter assay or RNA Immunoprecipitation assay. Circ_0001667 knockdown inhibited MCF‐7/ADM and MDA‐MB‐231/ADM cell proliferation, migration, invasion and ADM resistance. MiR‐4458 was a target of circ_0001667, and its expression was decreased in ADM‐resistant tumor tissues and cells. MiR‐4458 inhibition reversed the effects of circ_0001667 knockdown. In depth, NCOA3 was a target of circ_0001667, and circ_0001667 knockdown weakened NCOA3 expression by releasing miR‐4458. MCF‐7/ADM and MDA‐MB‐231/ADM cell proliferation, migration, invasion, and ADM resistance inhibited by miR‐4458 restoration were recovered by NCOA3 overexpression. Circ_0001667 knockdown also repressed tumor growth and ADM resistance in vivo. Circ_0001667 knockdown blocks cancer progression and attenuates ADM resistance by depleting NCOA3 via releasing miR‐4458 in breast cancer. [ABSTRACT FROM AUTHOR]

Objective: We aimed to evaluate the therapeutic effects of paclitaxel in combination with mTOR inhibitor everolimus on adriamycin-resistant breast cancer cell line MDA-MB-231 (MDA-MB-231/ADR). Materials and methods: MDA-MB-231/ADR cells were treated with different concentrations of paclitaxel and everolimus. The IC50 values after 48 h of treatment were measured by the MTT assay. The apoptosis rate and cell cycle were detected by flow cytometry. The protein expressions of Akt, PI3K, mTOR, p-pI3K, p-AKT and p-mTOR were detected by Western blot. Results: When paclitaxel at ≥1.56 μg/ml was used, the growth of MDA-MB-231/ADR cells was inhibited more significantly than that of control group (P

Purpose: Emerging evidence suggests that cytotoxic therapy may promote drug resistance and metastasis while inhibiting the growth of primary tumors. As yet, however, the underlying mechanisms remain unclear. Here, we aimed to investigate the pro-metastatic effects of adriamycin (ADR) therapy on breast cancer cells and to investigate the mechanisms underlying these effects. Methods: Differentially expressed genes between MCF-7 and ADR-resistant MCF-7 breast cancer cells were identified using high-throughput RNA-seq and differential gene expression analyses. In vitro transwell and scratch wound-healing assays, and an in vivo spontaneous metastasis model were used to study the metastatic potential of the breast cancer cells. The relationship between SIRT7 and TEK expression was studied using promoter activity, electrophoretic mobility shift (EMSA), CHIP-qPCR and Co-IP assays. Results: Using transcriptome sequencing, we identified two key genes (SIRT7 and TEK) that might contribute to the pro-metastatic effect of ADR on breast cancer cells. SIRT7 acted as a negative regulator for TEK by inducing deacetylation of H3K18 at the TEK promoter. Through transcription factor prediction and double fluorescence experiments, we found that EST-1 could bind to the TEK promoter. Knockdown of EST-1 removed the transcriptional inhibition of TEK that was mediated by up-regulation of SIRT7. Co-IP showed that SIRT7 interacts directly with EST-1 in breast cancer cells, indicating that SIRT7 may induce H3K18 deacetylation at the TEK promoter region by directly binding to EST-1. In vitro and in vivo results showed that overexpression of SIRT7 or inhibition of TIE2 significantly reduced ADR-dependent breast cancer cell invasion/metastasis. Conclusion: Our findings suggest that ADR therapy may accelerate breast cancer metastasis in a SIRT7/TEK(TIE2) dependent manner. [ABSTRACT FROM AUTHOR]

The present study was conducted on 75 women with breast cancer and 20 women as control in Baghdad teaching hospital for tumors at medicine city. Breast cancer women were treated by Adriamycin (Doxorubicin), sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi’s sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used together with other chemotherapy agents. Doxorubicin is given by injection into a vein. Their ages ranged (38.06 ±3.01) years among the control group and (50.88 ±2.85) for before treatment (31.09 ±0.95) and treated with Doxorubicin (28.26 ±1.19) groups. The BMI (kg/m2) shows a nonsignificant increase (P £ 0.05) in before (31.09 ±0.95) in comparison with the control group (29.10 ±0.70). While before group shows a significant increase (31.09 ±0.95) when compared with the treated group (28.26 ±1.19). In the premenopausal cancer breast women, the levels of estrogen pg/ml were non-significant in before treated breast cancer group (68.84 ± 22.37) and (37.76 ± 6.97) in the treated breast cancer group in comparison with the control group (65.07 ± 26.25 ). In post-menopausal, the values decreased in before and treated cancer groups (12.07 ± 2.71; 22.28 ± 2.51) respectively in comparison with the control group (59.67 ± 31.46). The values were non-significant in before and treated groups. The estrogen levels were decreased significantly (P £ 0.01) in the post-menopausal (12.07 ± 2.71) group in comparison with before the pre-menopausal ( 68.84 ± 22.37) group. Also the levels were decreased significantly (P £ 0.01) in post-menopausal group (22.28±2.51) in comparison with treated pre -menopausal groups (37.76 ± 6.97). The pre and post-menopausal control groups showed non-significant difference (65.07 ± 26.25; 59.67 ± 31.46), respectively. The premenopausal of breast cancer in our study were 16/75 (21.33%) and 59/75 (78.66%) were menopausal. [ABSTRACT FROM AUTHOR]

Introduction: Longitudinal melanonychia presents with pigmented longitudinal streaks of the nail plate. It results from an increased activity of melanocytes or melanocytic hyperplasia in the nail matrix or nail bed and is associated with increased melanin deposition in the nail plate. Distal onycholysis is characterized by separation of the distal part of the nail plate from the nail bed. Objective: To present a case of longitudinal melanonychia and distal onycholysis associated with 5-fluorouracil/adriamycin/cyclophosphamide chemotherapy. Case report: A 66-year-old woman, who received 5-fluorouracil/adriamycin/cyclophosphamide for breast cancer developed longitudinal melanonychia and distal onycholysis. After discontinuation of chemotherapy, nail changes improved significantly. Conclusions: Drug-induced longitudinal melanonychia and distal onycholysis are common adverse effects of breast cancer chemotherapy. This case shows that lesions may resolve after discontinuation of therapy. [ABSTRACT FROM AUTHOR]

A 34-year-old woman with a rapidly growing right breast mass visited our hospital. The mass was diagnosed as a right breast cancer (cT3N1M0 stage ⦀A). Her serum leucocyte count and C-reactive protein levels were high, and she had persistent fever. However, serum procalcitonin and β-D-glucan levels were normal, and no apparent infection focus was detected, although her serum granulocyte colony-stimulating factor (G-CSF) level was markedly elevated to 42.7 pg/mL. Therefore, a G-CSF-producing breast cancer was suspected. A pathological analysis of the surgical specimen revealed a squamous cell carcinoma of the breast (pT2N0 [i+] M0 stage ∥A). Right mastectomy (with the resection of the pectoralis major muscle), axillary lymph node dissection, and split layer grafting were performed. The leucocyte count and serum G-CSF level decreased on postoperative day (POD) 1 and normalized on POD 6. As adjuvant chemotherapy, 4 cycles of a combination chemotherapy with adriamycin and cyclophosphamide and 12 cycles of weekly paclitaxel were administered. After chemotherapy, the patient also underwent postmastectomy radiotherapy. Currently, 30 months after surgery, the patient is alive and well with neither progression nor distant metastasis. G-CSF-producing breast cancers tend to rapidly grow such as in the current case; thus, surgery should be performed immediately, followed by appropriate adjuvant treatment. [ABSTRACT FROM AUTHOR]

To achieve better antitumour efficacy, it is urgent to improve anticancer drug delivery efficiency in targeting cancer cells. In this work, chitosan-functionalized graphene oxide (ChrGO) nanosheets were fabricated via microwave-assisted reduction, which were employed to the intracellular delivery nanosystem for anticancer drug agent in breast cancer cells. Drug loading and release research indicated that adriamycin can be efficiently loaded on and released from the ChrGO nanosheets. Less drug release during delivery and better biocompatibility of ChrGO/adriamycin significantly improve its safety and therapeutic efficacy in HER2-overexpressing BT-474 cells. Furthermore, ChrGO/adriamycin in combination with trastuzumab exhibited synergistic antitumour activity in BT-474 cells, which demonstrated superior therapeutic efficacy compared with each drug alone. Cells treated with trastuzumab (5 μg/mL) or equivalent ChrGO/adriamycin (5 μg/mL) each elicited 54.5% and 59.5% cell death, respectively, while the combination treatment with trastuzumab and ChrGO/adriamycin resulted in a dramatic 88.5% cell death. The dual-targeted therapy displayed higher apoptosis, indicating superior therapeutic efficacy due to the presence of different mechanisms of action. The combined treatment of ChrGO/adriamycin and trastuzumab in BT-474 cells induced cell cycle arrest and apoptosis, which ultimately led to the death of augmented cancer cells. This work has provided a facile microwave-assisted fabrication of ChrGO as a controlled and targeted intracellular drug delivery nanosystem, which is expected to be a novel promising therapy for treating HER2-overexpressing breast cancer cells. [ABSTRACT FROM AUTHOR]

Adriamycin (ADM) is one of the postoperative chemotherapy drugs for breast cancer (BCa) patients. Circular RNAs have been shown to modulate ADM resistance in many cancers. However, it is unclear whether circ_0006528 can modulate the ADM chemoresistance in BCa. Levels of circ_0006528, microRNA-1236-3p (miR-1236-3p), and chromodomain helicase DNA-binding protein 4 (CHD4) were detected by quantitative real-time polymerase chain reaction or western blot. Cell proliferation, the half maximal inhibitory concentration (IC50) value of ADM, and cell migration and invasion were evaluated by cell counting kit-8 and transwell assays, respectively. The interaction among circ_0006528, miR-1236-3p, and CHD4 was confirmed using dual-luciferase reporter assays. Tumor formation in nude mice was performed to explore the effect of circ_0006528 in vivo. Higher levels of circ_0006528 and CHD4 and lower level of miR-1236-3p were found in ADM-resistant BCa tissues and cells, and patients with high circ_0006528 had a shorter overall survival. Circ_0006528 could directly bind to miR-1236-3p, and circ_0006528 knockdown or miR-1236-3p overexpression could suppress cell proliferation, migration, invasion, and ADM resistance in ADM-resistant BCa cells. Moreover, circ_0006528-regulated CHD4 expression by sponging miR-1236-3p, and CHD4 elevation reversed the inhibitory effect of circ_0006528 knockdown on ADM-resistant BCa cells. Consistently, circ_0006528 inhibition retarded ADM-resistant BCa tumor growth in vivo by decreasing CHD4 and increasing miR-1236-3p. Downregulation of circ_0006528 restrained cell proliferation, migration, invasion, and drug resistance of ADM-resistant BCa cells through inhibiting CHD4 and inducing miR-1236-3p. [ABSTRACT FROM AUTHOR]

Drug resistance in breast cancer (BC) cells continues to be a stern obstacle hindering BC treatment. Adriamycin (ADR) is a frequently employed chemotherapy agent used to treat BC. The exosomal transfer of microRNAs (miRNAs) has been reported to enhance the drug-resistance of BC cells. Herein, we first sought to elucidate the possible role of the exosomal transfer of miR-221-3p in the drug resistance of MCF-7 cells to ADR. Differentially expressed genes (DEGs) were initially screened through microarray analysis in BC drug resistance-related datasets. Next, the expression of miR-221-3p and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) was quantified in ADR-resistant MCF-7 (MCF-7/ADR) and ADR-sensitive MCF-7 (MCF-7/S) cell lines, after which exosomes were separated and identified in each cell line. Target relationship between miR-221-3p and PIK3R1 was validated by a dual-luciferase reporter assay. Next, the expression of miR-221-3p and PIK3R1 was altered to clarify their effects on the resistance of MCF-7 cells to ADR in vitro and in vivo. PIK3R1 was identified as a BC drug resistance-related DEG, with the regulatory miR-221-3p subsequently obtained. Moreover, the MCF-7/ADR cells exhibited a low expression of PIK3R1 and a high expression of miR-221-3p. Notably, PIK3R1 was identified as a target gene of miR-221-3p. The overexpression of miR-221-3p in MCF-7/ADR cell-derived exosomes promoted ADR resistance in MCF-7/S cells via the PI3K/AKT signaling pathway. The in vitro results were reproducible in in vivo assays. Taken together, drug-resistant BC cell-derived exosomal miR-221-3p can promote the resistance of BC cells to ADR by targeting PIK3R1 via the PI3K/AKT signaling pathway in vitro and in vivo. These findings provide encouraging insights and provide perspectives for further investigation into the BC drug resistance mechanism.

Aim: This study aimed to explore the regulative mechanisms of miR-27a-3p in chemo-resistance of breast cancer cells. Materials and Methods: qRT-PCR was employed to determine miR-27a-3p expression in two breast cancer cell lines, MCF-7 and MCF-7/adriamycin-resistant cell line (MCF-7/ADR). The two cell lines were treated with miR-27a-3p mimics or inhibitors or corresponding negative control (NC), respectively. The changes were investigated by qRT-PCR, CCK-8 assay, Western blot (WB), colony formation assay, and flow cytometry assay. Moreover, luciferase reporter assay was analyzed to verify the downstream target gene of miR-27a-3p. Further investigation in the correlation between miR-27a-3p and BTG2 was launched by WB, flow cytometry assay, and CCK-8 assay. The expression of Akt and p-Akt was detected by WB. Key Findings: Significantly higher miR-27a-3p expression was confirmed in MCF-7/ADR as compared with sensitive cell line MCF-7 (P< 0.05). The down-regulation of miR-27a-3p in MCF-7/ADR enhanced the sensitivity of cancer cells to adriamycin treatment, decreased multidrug resistance gene 1/P-glycoprotein (MDR1/P-gp) expression, enhanced the apoptosis-related proteins expression, increased adriamycin-induced apoptosis, and inhibited cell proliferation as compared to NC groups (P< 0.05). The up-regulation of miR-27a-3p in MCF-7 showed the opposite results. BTG2 is identified as a direct target of miR-27a-3p and its down-regulation reversed ADR-resistance. BTG2 treatment exhibited inhibitory effect on PI3K/Akt pathway in MCF-7/ADR cells. Significance: miR-27a-3p might be associated with resistance of breast cancer cells to adriamycin treatments, modulating cell proliferation and apoptosis by targeting BTG2 and promoting the PI3K/Akt pathway in breast cancer cells. miR-27a-3p/BTG2 axis might be a potential therapeutic target for clinical BC resistance. [ABSTRACT FROM AUTHOR]

Drug resistance in breast cancer (BC) cells continues to be a stern obstacle hindering BC treatment. Adriamycin (ADR) is a frequently employed chemotherapy agent used to treat BC. The exosomal transfer of microRNAs (miRNAs) has been reported to enhance the drug-resistance of BC cells. Herein, we first sought to elucidate the possible role of the exosomal transfer of miR-221-3p in the drug resistance of MCF-7 cells to ADR. Differentially expressed genes (DEGs) were initially screened through microarray analysis in BC drug resistance-related datasets. Next, the expression of miR-221-3p and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) was quantified in ADR-resistant MCF-7 (MCF-7/ADR) and ADR-sensitive MCF-7 (MCF-7/S) cell lines, after which exosomes were separated and identified in each cell line. Target relationship between miR-221-3p and PIK3R1 was validated by a dual-luciferase reporter assay. Next, the expression of miR-221-3p and PIK3R1 was altered to clarify their effects on the resistance of MCF-7 cells to ADR in vitro and in vivo. PIK3R1 was identified as a BC drug resistance-related DEG, with the regulatory miR-221-3p subsequently obtained. Moreover, the MCF-7/ADR cells exhibited a low expression of PIK3R1 and a high expression of miR-221-3p. Notably, PIK3R1 was identified as a target gene of miR-221-3p. The overexpression of miR-221-3p in MCF-7/ADR cell-derived exosomes promoted ADR resistance in MCF-7/S cells via the PI3K/AKT signaling pathway. The in vitro results were reproducible in in vivo assays. Taken together, drug-resistant BC cell-derived exosomal miR-221-3p can promote the resistance of BC cells to ADR by targeting PIK3R1 via the PI3K/AKT signaling pathway in vitro and in vivo. These findings provide encouraging insights and provide perspectives for further investigation into the BC drug resistance mechanism. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the most common serious disease around the world. The trace elements have a vital role in the metabolism and chemotherapy may change the level of metal ions. Due to the ambiguity of the existence in this regard, the study examined the trace element serum levels in women with breast cancer before and after chemotherapy . Methods: Sixty patients were studied undergoing specialist. First sampling was taken before chemotherapy (after 4 weeks of surgery) and second sampling was taken after the completion of 3 courses of chemotherapy, approximately 9 weeks after the first chemotherapy. The patients took Adriamycin 60mg/m2 Cytoxan 600mg/m2. Serum zinc and iron levels were measured using standard spectrophotometric method. Measurement of serum copper was done by atomic absorption spectroscopy. Results: Serum zinc and iron levels in women after chemotherapy significantly decreased (p

The first-line chemotherapy drug adriamycin (ADM) is widely used for the treatment of breast cancer, but the acquired drug resistance and the normal tissue toxicity remain clinical challenges. Alteronol has been reported to exert wide-ranging anti-tumor activity. In this study, we firstly examined the synergistic anti-tumor effects and the underlying mechanisms of alteronol combined with ADM in breast cancer. We have found that the combination of alteronol and ADM significantly suppressed the expression levels of the cell cycle-related proteins (CDC2 and Cyclin B1) and induced cell cycle arrest at the G2/M phase, leading to cell proliferation inhibition in breast cancer 4T1 cells. Moreover, co-treatment of alteronol and ADM (i) remarkably activated p38 and JNK kinases, (ii) elevated ROS levels, (iii) triggered mitochondrial dysfunction, (iv) released cytochrome c into the cytoplasm, (v) upregulated apoptosis-related proteins, e.g., cleaved PARP, Bax, and cleaved caspase-3/9, and (vi) downregulated the expression of Bcl-2, followed by apoptosis. Furthermore, our in vivo studies showed that the low-dose combination of alteronol (2 mg/kg) and ADM (1 mg/kg) significantly inhibited tumor growth in tumor bearing mice, and the anti-tumor effect of the combination was the same as that of high-dose ADM (8 mg/kg). In addition, the low-dose combination group showed lower toxicities to major organs than the high-dose ADM group. Taken together, these data demonstrate that the low-dose combination of alteronol and ADM could notably improve the anti-tumor activity and have lower toxicities to major organs than those in high-dose ADM group.

The first-line chemotherapy drug adriamycin (ADM) is widely used for the treatment of breast cancer, but the acquired drug resistance and the normal tissue toxicity remain clinical challenges. Alteronol has been reported to exert wide-ranging anti-tumor activity. In this study, we firstly examined the synergistic anti-tumor effects and the underlying mechanisms of alteronol combined with ADM in breast cancer. We have found that the combination of alteronol and ADM significantly suppressed the expression levels of the cell cycle-related proteins (CDC2 and Cyclin B1) and induced cell cycle arrest at the G2/M phase, leading to cell proliferation inhibition in breast cancer 4T1 cells. Moreover, co-treatment of alteronol and ADM (i) remarkably activated p38 and JNK kinases, (ii) elevated ROS levels, (iii) triggered mitochondrial dysfunction, (iv) released cytochrome c into the cytoplasm, (v) upregulated apoptosis-related proteins, e.g., cleaved PARP, Bax, and cleaved caspase-3/9, and (vi) downregulated the expression of Bcl-2, followed by apoptosis. Furthermore, our in vivo studies showed that the low-dose combination of alteronol (2 mg/kg) and ADM (1 mg/kg) significantly inhibited tumor growth in tumor bearing mice, and the anti-tumor effect of the combination was the same as that of high-dose ADM (8 mg/kg). In addition, the low-dose combination group showed lower toxicities to major organs than the high-dose ADM group. Taken together, these data demonstrate that the low-dose combination of alteronol and ADM could notably improve the anti-tumor activity and have lower toxicities to major organs than those in high-dose ADM group. [ABSTRACT FROM AUTHOR]

Aims: Increasing evidence links the abnormal expression of microRNAs and ATP-binding cassette subfamily C member 4 (ABCC4) with tumor development and progression, as well as with chemoresistance. Our aims were to determine the therapeutic potential of targeting both miR-124-3p and ABCC4 in breast cancer cells and to determine if duel targeting increased their sensitivity to chemotherapeutic drugs, in vitro. Materials and Methods: The expression of the ABCC4 protein and miR-124-3p were detected, respectively, by immunohistochemical staining and quantitative real-time polymerase chain reaction in breast cancer tumor tissue, MCF-7 and MCF-7-ADR cell lines. Suppression of ABCC4 expression and miR-124-3p overexpression were performed in MCF-7-ADR cell lines. Western blot assays were used to detect expression of ABCC4 and permeability glycoprotein 1/multi-drug resistance protein 1 (P-gp) in cells. Cell Counting Kit-8, flow cytometry, transwell, and scratch assays were conducted to detect cell proliferation, cell cycle, invasion, and migration of cells. Results: We found that ABCC4 protein expression was significantly increased, while the miR-124-3p level was significantly decreased in breast cancer tissue and cell lines. Tumor size and clinical tumor node metastasis stage were significantly correlated with elevated expression of ABCC4 and decreased expression of miR-124-3p. Interestingly, ABCC4 expression was significantly increased in MCF-7-ADR cells, while miR-124-3p level was significantly decreased compared with MCF-7 cells. The inhibition of ABCC4 and miR-124-3p overexpression both led to a significant decrease in cell proliferation, invasion, and migration of MCF-7-ADR cells, and combination of suppression of ABCC4 with miR-124-3p overexpression had a synergistic inhibitory effect. Our results further demonstrated that inhibition of ABCC4 expression and overexpression of miR-124-3p significantly enhanced the sensitivity to adriamycin (ADR) in MCF-7-ADR cells, and that simultaneous dual-targeting of miR-124-3p and ABCC4 had a stronger promotive effect on the sensitivity to ADR in MCF-7-ADR cells. Moreover, western blot analysis showed that miR-124-3p overexpression significantly inhibited P-gp expression in MCF-7-ADR cells. Conclusion: Our data demonstrate that the combination of downregulation of ABCC4 with overexpression of miR-124-3p significantly increased sensitivity to ADR in MCF-7-ADR cells. This finding suggests that similar dual targeting may serve as a means to enhance therapies for drug-resistant breast cancers. [ABSTRACT FROM AUTHOR]

Abstract Breast cancer is reported a very complex disease along with heterogeneous morphological characteristics and unrelated clinical behavior, and is a leading cancer among female. Nevertheless, chemo-resistance is frequently observed. Adriamycin (ADM) is a always employed drug to treat clinical breast cancer. However, strong resistance to ADM limited its clinical efficacy. Deregulation of HDAC6 activity is linked to various diseases including cancer resulting in accumulating interest for developing HDAC6 inhibitors. In the present study, for the first time, we found that 4-Hydroxybenzoic acid (4-HBA), as histone deacetylase 6 (HDAC6) inhibitor, could successfully reverse ADM resistance in human breast cancer cells. 4-HBA significantly promoted the anticancer effect of ADM on apoptosis induction, as evidenced by the increased expressions of Caspase-3 and PARP cleavage, which was associated with the promotion p53 and homeodomain interacting protein kinase-2 (HIPK2) expressions in ADM-resistant breast cancer cells. Furthermore, the suppressive effect of ADM on drug-resistant breast cancer cells was accelerated by 4-HBA through increasing the number of cells distributed in G2/M phase of cell cycle arrest. Inhibiting HIPK2/p53 pathway could abolish 4-HBA/ADM co-treatment-induced apoptosis and G2/M cell cycle arrest. Importantly, HDAC6 expressions were also significantly down-regulated in ADM-resistance breast cancer cells co-treated with ADM and 4-HBA. Additionally, 4-HBA clearly potentiated the anticancer role of ADM in the MCF-7 breast cancer animal model with low toxicity. Therefore, 4-HBA could be applied as an effective HDAC6 inhibitor to reverse human breast cancer resistance. Herein, the 4-HBA and ADM combination might represent as a useful therapeutic strategy to prevent human breast cancer. Highlights • 4-Hydroxybenzoic acid enhances the sensitivity of MCF-7/ADM to ADM-induced apoptosis. • 4-Hydroxybenzoic acid induces apoptosis in breast cancer cell lines. • 4-Hydroxybenzoic acid induces cell cycle arrest in G2/M phase. [ABSTRACT FROM AUTHOR]

CD155 has been implicated in migration, invasion, proliferation and apoptosis of human cancer cells, and DNA damage response caused by chemotherapeutic agents or reactive oxygen species has been shown to attribute to CD155 induction. Adriamycin (Adr) is one of the most common chemotherapeutic drugs used to treat breast cancer. Here we reported that treatment with Adr upregulated CD155 expression on several in vitro cultured breast cancer cells and in breast cancer cell 4T1 xenografts. We also found that CD155 knockdown or Adr treatment induced apoptosis of in vitro cultured cancer cells and cancer cells in 4T1 xenografts, and a combination of CD155 knockdown with Adr treatment induced more cell death than either of them. Furthermore, we revealed that the combination of CD155 knockdown with Adr treatment suppressed the growth of 4T1 xenografts more significantly than them alone. In summary, our results demonstrate that CD155 downregulation synergizes with Adr to induce breast cancer cell apoptosis, thereby to suppress tumor growth. Our results also suggest that CD155 upregulation may be a mechanism underlying Adr resistance by breast cancer cells. [ABSTRACT FROM AUTHOR]

Adriamycin (ADM) is a commonly used drug in clinical breast cancer treatment. However, some breast cancer types or breast cancers subjected to repeated ADM exposure develop strong resistance to ADM thus limiting its clinical efficacy. In this study, we found for the first time that toosendanin (TSN), a triterpenoid extracted from the traditional Chinese medicine Melia toosendan Sieb et Zucc, could successfully reverse adriamycin resistance in human breast cancer cells. Immunofluorescence and HPLC analysis demonstrated that TSN promoted adriamycin accumulation in breast cancer cells, especially in the nucleus. Furthermore, TSN could significantly reduce ABCB1 expression. We then found that TSN was capable of suppressing adriamycin-induced Akt phosphorylation, probably due to downregulation of the PI3K catalytic subunits P110α and P110β, and inhibition of DNA-PKcs. Importantly, the inhibitory effect of TSN on PI3K P110α and P110β expression was specifically observed in breast cancer cells but not in normal human cells. Moreover, TSN significantly potentiated the anti-cancer effect of ADM in the 4T1 breast cancer model and its inhibition rate was nearly 90%. Thus, TSN could be used as a novel PI3K inhibitor to reverse breast cancer resistance. The combination of ADM and TSN may represent a useful strategy for human breast cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Neuropilin-1 (NRP-1), a non-tyrosine kinase glycoprotein receptor, is associated with poor prognosis breast cancer, however transcriptomic changes triggered by NRP-1 overexpression and its association with chemoresistance in breast cancer have not yet been explored.Methods: BT-474 NRP-1 variant cells were generated by stable overexpression of NRP-1 in the BT-474 breast cancer cell line. RNA sequencing and qRT-PCR were conducted to identify differentially expressed genes. The role of an upregulated oncogene, Tenascin C (TNC) and its associated pathway was investigated by siRNA-mediated knockdown. Resistant variants of the control and BT-474 NRP-1 cells were generated by sequential treatment with four cycles of Adriamycin/Cyclophosphamide (4xAC) followed by four cycles of Paclitaxel (4xAC + 4xPAC).Results: NRP-1 overexpression increased cellular tumorigenic behavior. RNA sequencing identified upregulation of an oncogene, Tenascin-C (TNC) and downregulation of several tumor suppressors in BT-474 NRP-1 cells. Additionally, protein analysis indicated activation of the TNC-associated integrin β3 (ITGB3) pathway via focal adhesion kinase (FAK), Akt (Ser473) and nuclear factor kappa B (NF-kB) p65. siRNA-mediated TNC knockdown ablated the migratory capacity of BT-474 NRP-1 cells and inactivated FAK/Akt473 signaling. NRP-1 overexpressing cells downregulated breast cancer resistance protein (BCRP/ABCG2). Consequently, sequential treatment with Adriamycin/Cyclophosphamide (AC) cytotoxic drugs to generate resistant cells indicated that BT-474 NRP-1 cells increased sensitivity to treatment by inactivating NRP-1/ITGB3/FAK/Akt/NF-kB p65 signaling compared to wild-type BT-474 resistant cells.Conclusions: We thus report a novel mechanism correlating high baseline NRP-1 with upregulated TNC/ITGB3 signaling, but decreased ABCG2 expression, which sensitizes BT-474 NRP-1 cells to Adriamycin/Cyclophosphamide. The study emphasizes on the targetability of the NRP-1/ITGB3 axis and its potential as a predictive biomarker for chemotherapy response. [ABSTRACT FROM AUTHOR]

DNA damage activated by Adriamycin (ADR) promotes ubiquitin–proteasome system-mediated proteolysis by stimulating both the activity of ubiquitylating enzymes and the proteasome. In ADR-resistant breast cancer MCF7 (MCF7ADR) cells, protein ubiquitylation is significantly reduced compared to the parental MCF7 cells. Here, we used tandem ubiquitin-binding entities (TUBEs) to analyze the ubiquitylation pattern observed in MCF7 or MCF7ADRcells. While in MCF7, the level of total ubiquitylation increased up to six-fold in response to ADR, in MCF7ADRcells only a two-fold response was found. To further explore these differences, we looked for cellular factors presenting ubiquitylation defects in MCF7ADRcells. Among them, we found the tumor suppressor p53 and its ubiquitin ligase, Mdm2. We also observed a drastic decrease of proteins known to integrate the TUBE-associated ubiquitin proteome after ADR treatment of MCF7 cells, like histone H2AX, HMGB1 or β-tubulin. Only the proteasome inhibitor MG132, but not the autophagy inhibitor chloroquine partially recovers the levels of total protein ubiquitylation in MCF7ADRcells. p53 ubiquitylation is markedly increased in MCF7ADRcells after proteasome inhibition or a short treatment with the isopeptidase inhibitor PR619, suggesting an active role of these enzymes in the regulation of this tumor suppressor. Notably, MG132 alone increases apoptosis of MCF7ADRand multidrug resistant ovarian cancer A2780DR1 and A2780DR2 cells. Altogether, our results highlight the use of ubiquitylation defects to predict resistance to ADR and underline the potential of proteasome inhibitors to treat these chemoresistant cells. [ABSTRACT FROM PUBLISHER]

As a well-known angiogenic factor in different histology and pathological conditions, the pro-progressive role of vasohibin2 (VASH2) has been reported in various types of tumors. However, its role in drug resistance of breast cancer has not been reported so far. The present study demonstrated that MCF-7 cells with increased expression of VASH2 demonstrate stronger adriamycin (ADM) resistance compared with MDA-MB-231 cells with decreased expression of VASH2. Overexpression of VASH2 in MDA-MB-231 cells increased ADM resistance and silencing VASH2 in MCF-7 cells inhibited ADM resistance. Furthermore, in newly established ADM resistant cell lines, VASH2 was significantly upregulated. These results revealed the promotive role of VASH2 in the ADM resistance of breast cancer cells. In addition, overexpression of VASH2 in MDA-MB-231 cells significantly upregulated ATP-binding cassette sub-family G member 2 (ABCG2), however silencing VASH2 in MCF-7 cells inhibited ABCG2 significantly. Silencing ABCG2 abrogated increase of ADM resistance induced by VASH2 overexpression in MDA-MB-231 cells. This proved that VASH2 induced ADM resistance through promoting expression of ABCG2, at least in part. Further study regarding the underlying molecular mechanism demonstrated that VASH2 promoted ABCG2 via the protein kinase B (AKT) signaling pathway. Overall, VASH2 may promote drug resistance of breast cancer cells through regulating ABCG2 via the AKT signaling pathway. This suggests a novel therapeutic target to inhibit drug resistance in breast cancer, for a more efficient therapeutic outcome. [ABSTRACT FROM AUTHOR]

In recent years, tumor necrosis factor receptor 2 (TNFR2) has attracted increasing attention for its important roles in promoting proliferation, migration and angiogenesis in several types of cancer. However, its role in drug resistance remain unclear. In the present study, TNFR2 expression levels in MDA‑MB‑231 and MCF‑7 breast cancer cells were demonstrated to be associated with Adriamycin (ADM) resistance. Silencing of TNFR2 in MCF‑7 cells significantly inhibited ADM resistance, while overexpression of TNFR2 in MDA‑MB‑231 cells significantly enhanced ADM resistance. ADM treatment induced phosphorylation of the histone family 2A variant X (pH2AX), an established marker of DNA damage. Silencing of TNFR2 in MCF‑7 cells further induced pH2AX levels but inhibited the expression of the DNA damage repair protein, poly(ADP‑ribose) polymerase (PARP). By contract, overexpression of TNFR2 in MDA‑MB‑231 cells decreased pH2AX levels and enhanced PARP expression. Of note, treatment with the PARP inhibitor ABT888 significantly abrogated the effects of TNFR2 on pH2AX expression. On a molecular mechanism level, TNFR2 significantly affected the phosphorylation of AKT serine/threonine kinase 1 (AKT) in both cell lines, and treatment with the AKT inhibitor LY294002 effectively abrogated TNFR2‑induced PARP expression. A drug resistance assay demonstrated that treatment with either LY294002 or ABT888 inhibited ADM resistance in breast cancer cells, and combination treatment with both LY294002 and ABT888 exhibited a significantly stronger inhibition effect on ADM resistance. The present results indicated that TNFR2 promoted ADM resistance in breast cancer cells by regulating the DNA damage repair protein PARP via the AKT signaling pathway. [ABSTRACT FROM AUTHOR]

Anthracycline/taxane-based chemotherapy regimens are usually used as neoadjuvant chemotherapies to decrease tumour size and prevent metastasis of advanced breast cancer. However, patients have a high risk of developing chemo-resistance during treatment through still unknown mechanisms. Glutathione S-transferase P1 (GSTP1), which belongs to the family of phase II metabolic enzymes, has been reported to function in detoxifying several anti-cancer drugs by conjugating them with glutathione. Previous studies have identified GSTP1 as a predictor of prognosis and chemo-resistance in breast cancer patients, but the mechanisms governing GSTP1-dependent drug resistance are still unclear. We have found that GSTP1 expression is much higher in adriamycin-resistant cells and their corresponding exosomes. The role of GSTP1-containing exosomes in conferring drug resistance was analysed through cell apoptosis and immunofluorescence staining assays. Furthermore, we analysed 42 cases of paired breast cancer tissues collected before and after anthracycline/taxane-based neoadjuvant chemotherapy by immunohistochemistry. Higher GSTP1 expression was shown in the progressive disease (PD)/stable disease (SD) group than in the partial response (PR)/complete response (CR) group both in the samples collected before and after the chemotherapy treatment. Interestingly, GSTP1 partly re-localized from the cell nucleus to the cytoplasm upon treatment, and similar results were obtained for the exosomal marker Tumour susceptibility gene 101 protein (TSG101), which also increased in the cytoplasm after chemotherapy. After analysing the serum exosomes of 30 patients treated with anthracycline/taxane-based neoadjuvant chemotherapy, we discovered that the levels of GSTP1 in exosomes from patients in the PD/SD group were significantly higher than those in the PR/CR group. Here, for the first time, we investigated a novel role for GSTP1-containing exosomes and their capability to transfer drug resistance and evaluated their clinical use in predicting chemo-resistance. [ABSTRACT FROM AUTHOR]

Gap junctions (GJs) serve the principal role in the antineoplastic (cytotoxicity and induced apoptosis) effect of chemical drugs. The aim of the present study was to determine the effect of GJ intercellular communication (GJIC) composed of connexin 43 (Cx43) on adriamycin cytotoxicity in breast cancer cells. Four cell lines (Hs578T, MCF-7, MDA-MB-231 and SK-BR-3) with different degree of malignancy were used in the study. The results of western blotting and immunofluorescence revealed that, in Hs578T and MCF-7 cells, which have a low degree of malignancy, the expression levels of Cx43 and GJIC were higher than those in MDA-MB-231 and SK-BR-3 cells (which have a high degree of malignancy). In Hs578T and MCF-7 cells, where GJ could be formed, the function of GJ was modulated by a pharmacological potentiators [retinoid acid (RA)]/inhibitors [oleamide and 18-a-glycyrrhetinic acid (18-a-GA)] and small interfering RNA (siRNA). In high-density cells (where GJ was formed), enhancement of GJ function by RA increased the cytotoxicity of adriamycin, while inhibition of GJ function by oleamide/18-a-GA and siRNA decreased the cytotoxicity caused by adriamycin. Notably, the modulation of GJ did not affect the survival of cells treated with adriamycin when cells were in low density (no GJ was formed). The present study illustrated the association between GJIC and the antitumor effect of adriamycin in breast cancer cells. The cytotoxicity of adriamycin on breast cancer cells was increased when the function of gap junctions was enhanced. [ABSTRACT FROM AUTHOR]

Objectives: miR-181a is involved in immunity, metabolism, tumor suppression or carcinogenesis reported by many other studies. However, its role in the development of chemosensitivity to adriamycin in low-invasive breast cancer cells remains unclear. The aim of this study is to define the function role of miR-181a in promoting the efficacy of adriamycin-based neoadjuvant chemotherapy. Methods: Cell survival analysis was detected by Cell Counting Kit-8 assay. Apoptotic cells were quantitatively detected using FITC Annexin V apoptosis Detection Kit I. Bcl-2 protein expression was measured by western blot. Luciferase reporter vector with the putative BCL-2 3' untranslated region (3'UTR) was constructed to explore whether BCL-2 was a direct target gene of miR-181a. Real-time PCR was performed to test the expression of miR-181a and Bcl-2 in the selected breast cancer tissue samples. Results: The down-regulation of miR-181a decreased adriamycin-induced apoptosis in MCF-7 cells. Transfected with miR-181a mimic in cells resulted in the decreased expression of Bcl-2. The alteration of miR-181a expression did not significantly affect the chemosensitivity to adriamycin in MCF-7 and MCF-7/ADR cells with genetic knockout of Bcl-2. miR-181a may suppress Bcl-2 expression by forming imperfect base pairing with the 3'UTR of Bcl-2 gene such that a negative relationship between miR-181a and Bcl-2 in MCF-7 and MCF-7/ADR cells is observed. Conclusions: At least in part, the detection of miR-181a may direct the clinical medication in patients with neoadjuvant chemotherapy because of miR-181a enhanced adriamycin-induced apoptosis via targeting Bcl-2.

The aim of the present study was to determine the effect of the combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and adriamycin (ADM) on the human breast cancer cell line MCF-7 and to identify potential mechanisms of apoptosis. Cell viability was analyzed by the MTT assay and the synergistic effect was assessed by the Webb coefficient. Apoptosis was quantified using the annexin V-FITC and propidium iodide staining flow cytometry. The mRNA expression of TRAIL receptors was measured by RT-PCR. Changes in the quantities of Bax and caspase-9 proteins were determined by Western blot. MCF-7 cells were relatively resistant to TRAIL (IC50 >10 µg/mL), while MCF-7 cells were sensitive to ADM (IC50

Adriamycin (Adr) is a potent chemotherapeutic agent for chemotherapy of breast cancer patients. Despite impressive initial clinical responses, some developed drug resistance to Adr-based therapy and the mechanisms underlying breast cancer cells resistance to Adr are not well known. In our previous study, in vitro, we verified that miR-222 was upregulated in Adr-resistant breast cancer cells (MCF-7/Adr) compared with the sensitive parental cells (MCF-7/S). Here, miR-222 inhibitors or mimics were transfected into MCF-7 cell lines. RT-qPCR and western blot were used to detect the expression of p27 kip1 . Immunofluorescence showed that miR-222 altered the subcellular location of p27 kip1 in nucleus. MTT was employed to verify the sensitivity of breast cancer cell lines to Adr. Flow cytometry showed the apoptosis and cell cycles of the cells after adding Adr. The results showed that downregulation of miR-222 in MCF-7/Adr increased sensitivity to Adr and Adr-induced apoptosis, and arrested the cells in G1 phase, accompanied by more expressions of p27 kip1 , especially in nucleus. Furthermore, overexpressed miR-222 in MCF-7/S had the inverse results. Taken together, the results found that miR-222 induced Adr-resistance at least in part via suppressing p27 kip1 expression and altering its subcellular localization, and miR-222 inhibitors could reverse Adr-resistance of breast cancer cells. These results disclosed that the future holds much promise for the targeted therapeutic in the treatment of Adr-resistant breast cancer. [ABSTRACT FROM AUTHOR]

While adriamycin (adr) offers improvement in survival for breast cancer (BCa) patients, unfortunately, drug resistance is almost inevitable. Mounting evidence suggests that exosomes act as a vehicle for genetic cargo and constantly shuttle biologically active molecules including microRNAs (miRNAs) between heterogeneous populations of tumor cells, engendering a resistance-promoting niche for cancer progression. Our recent study showed that exosomes from docetaxel-resistance BCa cells could modulate chemosensitivity by delivering miRNAs. Herein, we expand on our previous finding and explore the relevance of exosome-mediated miRNA delivery in resistance transmission of adr-resistant BCa sublines. We now demonstrated the selective packing of miRNAs within the exosomes (A/exo) derived from adr-resistant BCa cells. The highly expressed miRNAs in A/exo were significantly increased in recipient fluorescent sensitive cells (GFP-S) after A/exo incorporation. Gene ontology analysis of predicted targets showed that the top 30 most abundant miRNAs in A/exo were involved in crucial biological processes. Moreover, A/exo not only loaded miRNAs for its production and release but also carried miRNAs associated with Wnt signaling pathway. Furthermore, A/exo co-culture assays indicated that miRNA-containing A/exo was able to increase the overall resistance of GFP-S to adr exposure and regulate gene levels in GFP-S. Our results reinforce our earlier reports that adr-resistant BCa cells could manipulate a more deleterious microenvironment and transmit resistance capacity through altering gene expressions in sensitive cells by transferring specific miRNAs contained within exosomes. [ABSTRACT FROM AUTHOR]

In 1977 at the age of nine, I was diagnosed with Ewing sarcoma of the left fibula. At that time, the therapeutic strategy for Ewing sarcoma was being established. I was treated with multi-drug chemotherapy (Doxorubicin 490 mg, Vincristine 22.3 mg, Cyclophosphamide 10.8 g, and Dactinomycin 13,500 mcg), external beam radiation (54.0 Gy), and surgical excision (partial fibulectomy). This essay discusses the diagnosis and treatment of late effects of cancer therapy from a physician–patient's perspective. Six areas of clinical care and research are addressed: limb pain, systemic effects, hypothermia, pathology, genetics, and exercise. [ABSTRACT FROM AUTHOR]

Objective: This study aims to investigate the protective and sensitive effects of melatonin (MLT) in the treatment of breast cancer. Materials and Methods: ER+ breast cancer rat model was established and then rats were randomly divided into five different groups as follows: control group, Diss group, adriamycin (ADM) group, MLT group, and MLT combined with adriamycin (M+A) group. Tumor weights and one month survival rate were compared among these groups. In addition, changes of tumor tissues and expression of Ecadherin were observed under optical microscopy or electro-microscopy. Results: Tumor weights were significantly lighter in M+A group than those in ADM group (p < 0.05). Under optical and electro-microscopy, tumor cell apoptosis was obviously increased in MLT group, and tumor cell injury was more severe in M+A group than that in ADM group; additionally, expression of E-cadherin was higher in MLT group and M+A group than that in other groups. Moreover, MLT group had the highest one month survival rate (100%), there was the poorest life quality in ADM group, but the best life quality in MLT. Conclusion: MLT could enhance the sensitivity of tumor to ADM in vivo and improve patient's life quality. [ABSTRACT FROM AUTHOR]