Paclitaxel (PTX), the most widely used anticancer drug, is applied for the treatment of various types of malignant diseases. Mechanisms of PTX action represent several ways in which PTX affects cellular processes resulting in programmed cell death. PTX is frequently used as the first-line treatment drug in breast cancer (BC). Unfortunately, the resistance of BC to PTX treatment is a great obstacle in clinical applications and one of the major causes of death associated with treatment failure. Factors contributing to PTX resistance, such as ABC transporters, microRNAs (miRNAs), or mutations in certain genes, along with side effects of PTX including peripheral neuropathy or hypersensitivity associated with the vehicle used to overcome its poor solubility, are responsible for intensive research concerning the use of PTX in preclinical and clinical studies. Novelties such as albumin-bound PTX (nab-PTX) demonstrate a progressive approach leading to higher efficiency and decreased risk of side effects after drug administration. Moreover, PTX nanoparticles for targeted treatment of BC promise a stable and efficient therapeutic intervention. Here, we summarize current research focused on PTX, its evaluations in preclinical research and application clinical practice as well as the perspective of the drug for future implication in BC therapy.

Metastasis represents a serious complication in the treatment of cancer. Flavonoids are plant secondary metabolites exerting various health beneficiary effects. The effects of flavonoids against cancer are associated not only with early stages of the cancer process, but also with cancer progression and spread into distant sites. Flavonoids showed potent anti-cancer effects against various cancer models in vitro and in vivo, mediated via regulation of key signaling pathways involved in the migration and invasion of cancer cells and metastatic progression, including key regulators of epithelial-mesenchymal transition or regulatory molecules such as MMPs, uPA/uPAR, TGF-β and other contributors of the complex process of metastatic spread. Moreover, flavonoids modulated also the expression of genes associated with the progression of cancer and improved inflammatory status, a part of the complex process involved in the development of metastasis. Flavonoids also documented clear potential to improve the anti-cancer effectiveness of conventional chemotherapeutic agents. Most importantly, flavonoids represent environmentally-friendly and cost-effective substances; moreover, a wide spectrum of different flavonoids demonstrated safety and minimal side effects during long-termed administration. In addition, the bioavailability of flavonoids can be improved by their conjugation with metal ions or structural modifications by radiation. In conclusion, anti-cancer effects of flavonoids, targeting all phases of carcinogenesis including metastatic progression, should be implemented into clinical cancer research in order to strengthen their potential use in the future targeted prevention and therapy of cancer in high-risk individuals or patients with aggressive cancer disease with metastatic potential.

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Breast cancer (BC) is the most prevalent cancer in women. BC is heterogeneous, with distinct phenotypical and morphological characteristics. These are based on their gene expression profiles, which divide BC into different subtypes, among which the triple-negative breast cancer (TNBC) subtype is the most aggressive one. The growing interest in tumor metabolism emphasizes the role of altered glucose metabolism in driving cancer progression, response to cancer treatment, and its distinct role in therapy resistance. Alterations in glucose metabolism are characterized by increased uptake of glucose, hyperactivated glycolysis, decreased oxidative phosphorylation (OXPHOS) component, and the accumulation of lactate. These deviations are attributed to the upregulation of key glycolytic enzymes and transporters of the glucose metabolic pathway. Key glycolytic enzymes such as hexokinase, lactate dehydrogenase, and enolase are upregulated, thereby conferring resistance towards drugs such as cisplatin, paclitaxel, tamoxifen, and doxorubicin. Besides, drug efflux and detoxification are two energy-dependent mechanisms contributing to resistance. The emergence of resistance to chemotherapy can occur at an early or later stage of the treatment, thus limiting the success and outcome of the therapy. Therefore, understanding the aberrant glucose metabolism in tumors and its link in conferring therapy resistance is essential. Using combinatory treatment with metabolic inhibitors, for example, 2-deoxy-D-glucose (2-DG) and metformin, showed promising results in countering therapy resistance. Newer drug designs such as drugs conjugated to sugars or peptides that utilize the enhanced expression of tumor cell glucose transporters offer selective and efficient drug delivery to cancer cells with less toxicity to healthy cells. Last but not least, naturally occurring compounds of plants defined as phytochemicals manifest a promising approach for the eradication of cancer cells via suppression of essential enzymes or other compartments associated with glycolysis. Their benefits for human health open new opportunities in therapeutic intervention, either alone or in combination with chemotherapeutic drugs. Importantly, phytochemicals as efficacious instruments of anticancer therapy can suppress events leading to chemoresistance of cancer cells. Here, we review the current knowledge of altered glucose metabolism in contributing to resistance to classical anticancer drugs in BC treatment and various ways to target the aberrant metabolism that will serve as a promising strategy for chemosensitizing tumors and overcoming resistance in BC.

Naturally-occurring mixtures of phytochemicals present in plant foods are proposed to possess tumor-suppressive activities. In this work, we aimed to evaluate the antitumor effects of Thymus vulgaris L. in in vivo and in vitro mammary carcinoma models. Dried T. vulgaris (as haulm) was continuously administered at two concentrations of 0.1% and 1% in the diet in a chemically-induced rat mammary carcinomas model and a syngeneic 4T1 mouse model. After autopsy, histopathological and molecular analyses of rodent mammary carcinomas were performed. In addition, in vitro evaluations using MCF-7 and MDA-MB-231 cells were carried out. In mice, T. vulgaris at both doses reduced the volume of 4T1 tumors by 85% (0.1%) and 84% (1%) compared to the control, respectively. Moreover, treated tumors showed a substantial decrease in necrosis/tumor area ratio and mitotic activity index. In the rat model, T. vulgaris (1%) decreased the tumor frequency by 53% compared to the control. Analysis of the mechanisms of anticancer action included well-described and validated diagnostic and prognostic markers that are used in both clinical approach and preclinical research. In this regard, the analyses of treated rat carcinoma cells showed a CD44 and ALDH1A1 expression decrease and Bax expression increase. Malondialdehyde (MDA) levels and VEGFR-2 expression were decreased in rat carcinomas in both the T. vulgaris treated groups. Regarding the evaluations of epigenetic changes in rat tumors, we found a decrease in the lysine methylation status of H3K4me3 in both treated groups (H3K9m3, H4K20m3, and H4K16ac were not changed); up-regulations of miR22, miR34a, and miR210 expressions (only at higher doses); and significant reductions in the methylation status of four gene promoters—ATM serin/threonine kinase, also known as the NPAT gene (ATM); Ras-association domain family 1, isoform A (RASSF1); phosphatase and tensin homolog (PTEN); and tissue inhibitor of metalloproteinase-3 (TIMP3) (the paired-like homeodomain transcription factor (PITX2) promoter was not changed). In vitro study revealed the antiproliferative and proapoptotic effects of essential oils of T. vulgaris in MCF-7 and MDA-MB-231 cells (analyses of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS); 5-bromo-20-deoxyuridine (BrdU); cell cycle; annexin V/PI; caspase-3/7; Bcl-2; PARP; and mitochondrial membrane potential). T. vulgaris L. demonstrated significant chemopreventive and therapeutic activities against experimental breast carcinoma.