Abstract
The aim of the manuscript is to discuss the influence of plant polyphenols in overcoming multidrug resistance in four types of solid cancers (breast, colorectal, lung and prostate cancer). Effective treatment requires the use of multiple toxic chemotherapeutic drugs with different properties and targets. However, a major cause of cancer treatment failure and metastasis is the development of multidrug resistance. Potential mechanisms of multidrug resistance include increase of drug efflux, drug inactivation, detoxification mechanisms, modification of drug target, inhibition of cell death, involvement of cancer stem cells, dysregulation of miRNAs activity, epigenetic variations, imbalance of DNA damage/repair processes, tumor heterogeneity, tumor microenvironment, epithelial to mesenchymal transition and modulation of reactive oxygen species. Taking into consideration that synthetic multidrug resistance agents have failed to demonstrate significant survival benefits in patients with different types of cancer, recent research have focused on beneficial effects of natural compounds. Several phenolic compounds (flavones, phenolcarboxylic acids, ellagitannins, stilbens, lignans, curcumin, etc.) act as chemopreventive agents due to their antioxidant capacity, inhibition of proliferation, survival, angiogenesis, and metastasis, modulation of immune and inflammatory responses or inactivation of pro-carcinogens. Moreover, preclinical and clinical studies revealed that these compounds prevent multidrug resistance in cancer by modulating different pathways. Additional research is needed regarding the role of phenolic compounds in the prevention of multidrug resistance in different types of cancer.
Highlights
Cancer is one of the leading cause of death worldwide
Due to ability of cancer cells to survive by occurrence of additional mutations, new generations of tyrosine kinase inhibitors (TKI) against epidermal growth factor receptor (EGFR) or other molecular targets are needed to be developed to overcome multidrug resistance (MDR) and side effects associated with anticancer therapy
The PI3K/AKT is one of the most important signaling pathways that mediates the process of Epithelial to Mesenchymal Transition (EMT) through (i) direct activation of transcription factors which increases the expression of mesenchymal markers (N-cadherin), decreases the expression of epithelial markers (E-cadherin, claudin, occluding) and upregulates AKT gene, which is involved in drug resistance in breast cancer, (ii) increased activity of integrin-linked kinase and (iii) activation of matrix-degrading proteases (MMP2, MMP9) [55,174]
Summary
Cancer is one of the leading cause of death worldwide. It is usually caused by genome instability and mutations, which may be inherited, induced by environmental factors or represent a consequence of DNA replication errors [1]. Main risk factors include alterations of gut microbiota [23], Western diet [24], obesity, hormonal status or chronic inflammatory bowel diseases [25]. Genetic factors such as mutations in KRAS, BRAF, PI3K genes and polymorphisms in nucleic acid-binding protein 1, laminin γ 1, cyclin D2, T-box 3 are involved in colorectal cancer etiology [26,27]. Risk factors for prostate cancer include age, obesity, other diseases (diabetes), lifestyle behaviors (diet, lack of physical activity) and sexually transmitted diseases [29].
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