Genomic instability in human cancer: molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition

Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology

Study of the Role of SIRT6 in Cellular Response to Stress

Epigenetic modifications do not involve changes in the DNA sequence and eventhough heritable, but reversible. It has been proposed that the ageing phenotype is, at least in part, due to the progressive divergance from a youthful chromatin modifications to one that contributes to molecular signatures of ageing. The Sirtuin family of NAD+-dependent lysine deacetylases has a long and controversial relation with ageing. My research has focused on the SIRT6, with a particular emphasis on elucidating how SIRT6 contributes to oxidative stress response and epigenetic maintenance pathways. Using a series of molecular, cellular, proteomics experiments, I identify several novel pathways by which SIRT6 contributes to epigenetic maintenance, including recruitment of BAF complex to promoter of anti-oxidant genes, monitoring the chromatin topology, stimulation of DNA DSB repair, rejuvenation of senescent transcriptome to juvenile state, and inhibition of cellular growth under growth factor deprivation through suppression of ribosome biogenesis. Given that DNA repair pathway, metabolism and the stress response are linked with lifespan, the overlapping function of SIRT6 regarding metabolism, epigenome and DNA repair provides evidence that chromatin modifiers can integrate distinct cellualar processes such as metabolic, epigenetic regulation and the DNA damage response to influence longevity

Osmunda japonica Thunb.

原著和名: ハゼンマイ科名: ゼンマイ科 = Osmundaceae採集地: 千葉県 四街道市 物井〜千代田 (下総 四街道市 物井〜千代田)採集日: 1983/5/4採集者: 萩庭丈壽整理番号: JH038935国立科学博物館整理番号: TNS-VS-98893

Designing a broad-spectrum integrative approach for cancer prevention and treatment.

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered.Multiple funders. See acknowledgments within article for details.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.semcancer.2015.09.00