Article

ADDENDUM: A therapeutic method for the direct reprogramming of human liver cancer cells with only chemicals

Scientific Reports (Impact Factor: 5.58). 10/2012; 2:280. DOI: 10.1038/srep00280
Source: PubMed

ABSTRACT Various methods for the direct reprogramming of human somatic cells have been developed. However, a therapeutic method to reprogram and eliminate human solid tumor cells has not been developed. Here we show a novel therapeutic method to reprogram and eliminate human solid tumor cells with chemicals. This therapeutic method may be applicable to various human solid tumor cells that express aldo-keto reductase family 1 member B10 (AKR1B10) and retinoid X receptors (RXRs).

0 Followers
 · 
324 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Biological activity of natural retinoids requires the oxidation of retinol to retinoic acid (RA) and its binding to specific nuclear receptors in target tissues. The first step of this pathway, the reversible oxidoreduction of retinol to retinaldehyde, is essential to control RA levels. The enzymes of retinol oxidation are NAD-dependent dehydrogenases of the cytosolic medium-chain (MDR) and the membrane-bound short-chain (SDR) dehydrogenases/reductases. Retinaldehyde reduction can be performed by SDR and aldo-keto reductases (AKR), while its oxidation to RA is carried out by aldehyde dehydrogenases (ALDH). In contrast to SDR, AKR and ALDH are cytosolic. A common property of these enzymes is that they only use free retinoid, but not retinoid bound to cellular retinol binding protein (CRBP). The relative contribution of each enzyme type in retinoid metabolism is discussed in terms of the different subcellular localization, topology of membrane-bound enzymes, kinetic constants, binding affinity of CRBP for retinol and retinaldehyde, and partition of retinoid pools between membranes and cytoplasm. The development of selective inhibitors for AKR enzymes 1B1 and 1B10, of clinical relevance in diabetes and cancer, granted the investigation of some structure-activity relationships. Kinetics with the 4-methyl derivatives of retinaldehyde isomers was performed to identify structural features for substrate specificity. Hydrophilic derivatives were better substrates than the more hydrophobic compounds. We also explored the inhibitory properties of some synthetic retinoids, known for binding to retinoic acid receptors (RAR) and retinoid X receptors (RXR). Consistent with its substrate specificity towards retinaldehyde, AKR1B10 was more effectively inhibited by synthetic retinoids than AKR1B1. A RARβ/γ agonist (UVI2008) inhibited AKR1B10 with the highest potency and selectivity, and docking simulations predicted that its carboxyl group binds to the anion-binding pocket.
    Chemico-biological interactions 12/2012; DOI:10.1016/j.cbi.2012.11.014 · 2.98 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To some extent, it might be not a dream in the future to reverse the aging and aging-related diseases. Certainly, aging was thus far programmed by natural selection during evolution so eventually inevitable [1-2]. However, performance can come from a cost. Through systematical modifications of the Genome Regulatory Network (GRN) and/or proteome, human cell and tissue engineering could couple with such inevitability by means of cellular reprogramming, genome editing [3] and tissue regenerative engineering. Many reviews previously speculated that the exhaustion of adult stem cell promotes the ageing and degenerative diseases, shortening the longevity [4]. Indeed, one of latest exciting investigations shows us the case of age reversal: implanting young stem cells to rejuvenate aging stem cells. Interestingly, the research team injected the stem like /progenitor cells into the abdomens of 17-day-old progeria mice, which generally have a lifespan of 21 to 28 days, some of them have a robust health and a life span up to 66 days [5]. Progeria is a disease that causes abnormally accelerated aging, such as loss of muscle mass,mesodermal/mesenchymal defects, accelerated atherosclerosis, neurodegeneration, osteoporosis, and trembling. It has been genetically shown that the deficiency of Lamina A (also the components of its embedded Mi-2/Nucelosome Remodeling and histone Deacetylation, i.e. NuRD complex) causes the chromatin old and leads thus to ageing [4,6]. After receiving the injection of stem cells, the mice recipients showed new blood vessel growth in the brain and muscle, improvement of health and increase of longevity. The injections of stem cells also delayed the onset of the majority of aging-related symptomsin a less acute model of accelerated aging. Intriguingly, the "labelled" injected cells went all over the place rather than home in on muscle or one kind of tissue.It raised the suspicion that the cells were secreting something that was kick-start regenerative capacity in whole organisms but effectively staving off aging [5]. This somehow mimics the kick-start of OSKM reprogramming of the cell pluripotency in cellular engineering [3,7], namely, to hit one node in the network, then spread to the whole system. We can view it with system biology: as on one balloon, to touch one starting point, the pressure reshapes the whole balloon. Caner is certainly the leading ageing –related lethal disease. Through Mi-2/NuRD chromatin remodeling –related cancer attractors theory, we could understand better the carcinogenesis, especially for germline gene -reactivated cancers [1-2,8], and hence develop strategy to reprogram the cancerous diseased cells to normal-like cells[9]. Hereby we focus on another ageing -related disease. It is well-known that cartilage makes the movement of joints smooth and the fading-away and breakdown of articular cartilage by injury or age-related "wear and tear" causes osteoarthritis (OA), the most common degenerative chronic disease, which is further characterized by synovial inflammation, pain, subchondral bone alterations, loss of tissue cellularity and extracellular matrix (ECM) damages, a major cause of decreased quality of life in adults in the world. Yet therapy remains a challenge because cartilage has minimal ability to repair and renew itself. Alongside studies for decades, in clinical trials in patients with established or advanced OA, candidate disease-modifying drugs have failed to show efficacy, as the case in cancer research [1-2].
  • Source
    09/2012; DOI:10.4172/2161-0436.1000e104

Preview

Download
9 Downloads
Available from