Epidermal growth factor receptor (EGFR), a tyrosine kinase receptor, is over-expressed in many tumors, including almost half of triple-negative breast cancers. The latter belong to a very-aggressive and drug-resistant form of malignancy. Although humanized anti-EGFR antibodies can work efficiently against these cancers both as monotherapy and in combination with genotoxic drugs, instability and high production costs are some of their known drawbacks in clinical use. In addition, the development of antibodies to target membrane proteins is a very challenging task. Accordingly, the main focus of the present work is the design of supramolecular agents for the targeting of membrane proteins in cancer cells and, hence, more-specific drug delivery. These were produced using a novel double-imprinting approach based on the solid-phase method for preparation of molecularly imprinted polymer nanoparticles (nanoMIPs), which were loaded with doxorubicin and targeted toward a linear epitope of EGFR. Additionally, upon binding, doxorubicin-loaded anti-EGFR nanoMIPs elicited cytotoxicity and apoptosis only in those cells that over-expressed EGFR. Thus, this approach can provide a plausible alternative to conventional antibodies and sets up a new paradigm for the therapeutic application of this class of materials against clinically relevant targets. Furthermore, nanoMIPs can promote the development of cell imaging tools against difficult targets such as membrane proteins.
Cancer-related metabolism has recently emerged as one of the "hallmarks of cancer". It has several important features, including altered metabolism of glucose and glutamine. Importantly, altered cancer metabolism connects different biochemical pathways into the one fine-tuned metabolic network, which stimulates high proliferation rates and plasticity to malignant cells. Among the keystones of cancer metabolism are one-carbon metabolism and nucleotide biosynthesis, which provide building blocks to anabolic reactions. Accordingly, the importance of these metabolic pathways for anticancer therapy has well been documented by more than fifty years of clinical use of specific metabolic inhibitors -methotrexate and nucleotides analogs. In this review we discuss one-carbon metabolism and nucleotide biosynthesis as common and specific features of many, if not all, tumors. The key enzymes involved in these pathways also represent promising anti-cancer therapeutic targets. We review different aspects of these metabolic pathways including their biochemistry, compartmentalization and expression of the key enzymes and their regulation at different levels. We also discuss the effects of known inhibitors of these pathways as well as the recent data on other enzymes of the same pathways as perspective pharmacological targets.
The epithelial–mesenchymal transition (EMT) plays a pivotal role in the differentiation of vertebrates and is critically important in tumorigenesis. Using this evolutionarily conserved mechanism, cancer cells become drug-resistant and acquire the ability to escape the cytotoxic effect of anti-cancer drugs. In addition, these cells gain invasive features and increased mobility thereby promoting metastases. In this respect, the process of EMT is critical for dissemination of solid tumors including breast cancer. It has been shown that miRNAs are instrumental for the regulation of EMT, where they play both positive and negative roles often as a part of a feed-back loop. Recent studies have highlighted a novel association of p53 and EMT where the mutation status of p53 is critically important for the outcome of this process. Interestingly, p53 has been shown to mediate its effects via the miRNA-dependent mechanism that targets master-regulators of EMT, such as Zeb1/2, Snail, Slug, and Twist1. This regulation often involves interactions of miRNAs with lncRNAs. In this review, we present a detailed overview of miRNA/lncRNA-dependent mechanisms that control interplay between p53 and master-regulators of EMT and their importance for breast cancer.
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