Inducers of Senescence, Toxic Compounds, and Senolytics – We herein describe in vitro and in vivo effects of fifteen Nrf2-interacting natural compounds (tocotrienols, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, silybin, phenethyl isothiocyanate, sulforaphane, triptolide, allicin, berberine, piperlongumine, fisetin, and phloretin) on cellular senescence and discuss their use in adjuvant cancer therapy.
Cancer, aging and cellular senescence – Normal cells do not divide indefinitely due to a process termed cellular or replicative senescence. Several lines of evidence suggest that replicative senescence evolved to protect higher eukaryotes, particularly mammals, from developing cancer. Senescent cells differ from their pre-senescent counterparts in three way:
- They arrest growth and cannot be stimulated to reenter the cell cycle by physiological mitogens;
- They become resistant to apoptotic cell death;
- They acquire altered differentiated functions.
Replicative senescence occurs because, owing to the biochemistry of DNA replication, cells acquire one or more critically short telomere. The mechanism by which a short telomere induces the senescent phenotype is unknown. Recent findings suggest that certain types of DNA damage and inappropriate mitogenic signals can also cause cells to adopt a senescent phenotype. Thus, cells respond to a number of potentially oncogenic stimuli by adopting a senescent phenotype. These findings suggest that the senescence response is a fail-safe mechanism that protects cells from tumorigenic transformation.
Despite the protection from cancer conveyed by cellular senescence and other mechanisms that suppress tumorigenesis, the development of cancer is almost inevitable as mammalian organisms age. Why is this the case? Certainly, aging predisposes cells to accumulate mutations, several of which are necessary before malignant transformation occurs, particularly in humans. However, many benign or relatively well-controlled tumors may also harbor many potentially oncogenic mutations, suggesting that the tissue microenvironment can suppress the expression of many malignant phenotypes. Although the idea remains controversial, cellular senescence has also been proposed to contribute to organismal aging. Senescent cells have recently been shown to accumulate with age in human tissues. One possibility is that the tissue microenvironment is disrupted by the accumulation of dysfunctional senescent cells. Thus, mutation accumulation may synergize with the accumulation of senescent cells, leading to increasing risk for developing cancer that is a hallmark of mammalian aging.
Anticancer Efficacy of Polyphenols and Their Combinations – Polyphenols are classified based on the number of phenol rings and the structural elements that bind these rings to one another. The groups include: phenolic acids, stilbenes, lignans, and flavonoids. Flavonoids, which have both antioxidant and anti-inflammatory properties, are found in fruits, vegetables, legumes, red wine, and green tea. They are subdivided into six classes: flavonols, flavones, isoflavones, flavanones, anthocyanidins, and flavanols (catechins and proanthocyanidins). Flavonols, the most ubiquitous flavonoids in foods, are generally present at relatively low concentrations. Quercetin and kaempferol are the main representatives, and their richest sources are onions, curly kale, leeks, broccoli, and blueberries.
Efflux (microbiology) – All microorganisms, with a few exceptions, have highly conserved DNA sequences in their genome that are transcribed and translated to efflux pumps. Efflux pumps are capable of moving a variety of different toxic compounds out of cells, such as antibiotics, heavy metals, organic pollutants, plant-produced compounds, quorum sensing signals, bacterial metabolites and neurotransmitters via active efflux, which is vital part for xenobiotic metabolism. Efflux pumps are proteinaceous transporters localized in the cytoplasmic membrane of all kinds of cells. They are active transporters, meaning that they require a source of chemical energy to perform their function.