The high expression of some ATP-binding cassette (ABC) transporters is linked to multidrug resistance in cancer cells. We aimed to determine if I-CBP112, which is a CBP/p300 bromodomain inhibitor, altered the vulnerability of the MDA-MB-231 cell line to chemotherapy drugs, which are used in neoadjuvant therapy in patients with triple negative breast cancer (TNBC). MDA-MB-231 cells represent TNBC, which is negative for the expression of estrogen and progesterone receptors and HER2 protein. An I-CBP112-induced decrease in the expression of all the studied ABCs in the breast, but also in the lung (A549), and hepatic (HepG2) cancer cell lines was associated with increased accumulation of doxorubicin, daunorubicin, and methotrexate inside the cells as well as considerable cell sensitization to a wide range of chemotherapeutics. Gene promoters repressed by I-CBP112 in MDA-MB-231 cells, such as ABCC1 and ABCC10, were characterized by enhanced nucleosome acetylation and, simultaneously, by considerably lower trimethylation in the transcription-promoting form of H3K4me3. The CBP/p300 bromodomain inhibitor induced the recruitment of LSD1 to the gene promoters, and the inhibition of this demethylase in the presence of I-CBP112 prevented the repression of ABCC1 and ABCC10 and, to a considerable extent, cancer cells’ sensitization to drugs. In conclusion, the CBP/p300 bromodomain inhibitor I-CBP112 can be considered as a potent anti-multidrug-resistance agent, capable of repressing key ABC transporters responsible for drug efflux in various cancer types.
Although cisplatin-based therapies are common among anticancer approaches, they are often associated with the development of cancer drug resistance. This phenomenon is, among others, caused by the overexpression of ATP-binding cassette, membrane-anchored transporters (ABC proteins), which utilize ATP to remove, e.g., chemotherapeutics from intracellular compartments. To test the possible molecular basis of increased expression of ABCC subfamily members in a cisplatin therapy mimicking model, we generated two cisplatin-resistant cell lines derived from non-small cell lung cancer cells (A549) and triple-negative breast cancer cells (MDA-MB-231). Analysis of data for A549 cells deposited in UCSC Genome Browser provided evidence on the negative interdependence between the occurrence of the CoREST complex at the gene promoters and the overexpression of ABCC genes in cisplatin-resistant lung cancer cells. Pharmacological inhibition of CoREST enzymatic subunits—LSD1 and HDACs—restored gene responsiveness to cisplatin. Overexpression of CoREST-free ABCC10 in cisplatin-resistant phenotypes was caused by the activity of EP300 that was enriched at the ABCC10 promoter in drug-treated cells. Cisplatin-induced and EP300-dependent transcriptional activation of ABCC10 was only possible in the presence of p53. In summary, the CoREST complex prevents the overexpression of some multidrug resistance proteins from the ABCC subfamily in cancer cells exposed to cisplatin. p53-mediated activation of some ABCC genes by EP300 occurs once their promoters are devoid of the CoREST complex.
The increased level of hydrogen peroxide accompanies some modes of macrophage specification and is linked to ROS-based antimicrobial activity of these phagocytes. In this study, we show that activation of toll-like receptors with bacterial components such as LPS is accompanied by the decline in transcription of hydrogen peroxide decomposing enzyme-catalase, suppression of which facilitates the polarization of human macrophages towards the pro-inflammatory phenotype. The chromatin remodeling at the CAT promoter involves LSD1 and HDAC1, but activity of the first enzyme defines abundance of the two proteins on chromatin, histone acetylation status and the CAT transcription. LSD1 inhibition prior to macrophage activation with LPS prevents CAT repression by enhancing the LSD1 and interfering with the HDAC1 recruitment to the gene promoter. The maintenance of catalase level with LSD1 inhibitors during M1 polarization considerably limits LPS-triggered expression of some pro-inflammatory cytokines and markers such as IL1β, TNFα, COX2, CD14, TLR2, and IFNAR, but the effect of LSD1 inhibitors is lost upon catalase deficiency. Summarizing, activity of LSD1 allows for the CAT repression in LPS stimulated macrophages, which negatively controls expression of some key pro-inflammatory markers. LSD1 inhibitors can be considered as possible immunosuppressive drugs capable of limiting macrophage M1 specialization.
Background Tissue-engineered blood vessels (TEBV) represent an attractive approach for overcoming reconstructive problems associated with vascular diseases in humankind by providing small caliber vascular grafts. The study evaluates biocompatibility and bioaffinity of vascular prostheses made from chitosan-modified bacterial cellulose (MBC) as potential scaffolds for TEBV. Methods During the study, acute oral toxicity, up-and-down procedure (UDP), OECD test No. 425 on 10 Imp:WIST rats, intradermal reactivity on three Imp:BN albino rabbits, and sensitization on 15 Imp:DH guinea pigs were performed. The local effects were determined 1 month after intramuscular implantation of prostheses in 30 Imp:WIST rats. Histopathological and pathomorphological studies were conducted following complete removal of implants with peri-implant tissue. Results There were no signs of toxicity; the median lethal oral dose (LD50) was greater than 2 g/kg body weight for the rats. No allergic reactions were observed in the case of the guinea pig maximization test. Vascular grafts did not induce significant reactive changes in intradermal reactivity test (Main Irritation Index value 0.03) and do not induce inflammatory changes or hyperplasia of the muscle tissue surrounding the implant. Histopathological examination revealed ingrown vascular-connective bands. Conclusions Tubes made of MBC offer strong potential for use in future TEBV programs for vascular surgery. Lay Summary Currently, the number of autologous grafts for coronary artery disease and for peripheral artery disease is limited. Particularly materials that will have contact with blood must comply with certain requirements such as mechanical strength, biocompatibility, and no potential to evoke adverse reactions. Bacterial nanocellulose modified with chitosan (MBC) due to its mechanical and biological properties is a promising material for replacing small-diameter vessels grafts. Although previous studies have not shown the toxicity of nanocellulose, we want to check whether medical products based on MBC will be safe when testing in vivo. Thirty Imp:WIST rats and 15 Imp:DH guinea pigs were subject of thorough analysis of potential toxicological and sensitization effect that may develop after applying vascular prostheses made from MBC to living organism. The analysis involved also histopathological and pathomorphological studies following complete removal of implants with peri-implant tissue. The results show that MBC prostheses do not cause any allergic, intradermal reactions and finally, do not display acute toxicity towards the organism in which it is implanted. Moreover, they had not induced inflammatory changes or hyperplasia of the muscle tissue surrounding the implantation sites, thus showing good biocompatibility. Obtained results were discussed with other available studies investigating various aspects of bacterial cellulose or modified bacterial cellulose influence on cells and tissues in both in vitro and in vivo studies. This is the first study analyzing the toxicological and sensitization effect which MBC may evoke and confirm the strong potential for use in future TEBV programs for vascular surgery. Graphical Abstract
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