Natural Agents-Mediated Targeting of Histone Deacetylases.

In the past few years, basic and clinical scientists have witnessed landmark achievements in many research projects, such as those conducted by the US National Institutes of Health Roadmap Epigenomics Mapping Consortium, the International Human Epigenome Consortium, The Cancer Genome Atlas Network and the International Cancer Genome Consortium, which have provided near-complete resolution of epigenetic landscape in different diseases. Furthermore, genome sequencing of tumors has provided compelling evidence related to frequent existence of mutations in readers, erasers and writers of epigenome in different cancers. Histone acetylation is an intricate mechanism modulated by two opposing sets of enzymes and deeply studied as a key biological phenomenon in 1964 by Vincent Allfrey and colleagues. The research group suggested that this protein modification contributed substantially in transcriptional regulation. Subsequently, histone deacetylases (HDACs), histone acetyltransferases and acetyl-Lys-binding proteins were identified as transcriptional mediators, which further deepened our comprehension regarding biochemical modifications. Overwhelmingly increasing high-impact research is improving our understanding of this molecularly controlled mechanism; moreover, quantification and identification of lysine acetylation by mass spectrometry has added new layers of information. We partition this multi-component review into how both activity and expression of HDAC are targeted using natural agents. We also set spotlight on how oncogenic fusion proteins tactfully utilize HDAC-associated nano-machinery to modulate expression of different genes and how HDAC inhibitors regulate TRAIL-induced apoptosis in cancer cells. HDAC inhibitors have been reported to upregulate expression of TRAIL receptors and protect TRAIL from proteasomal degradation. Deeper understanding of HDAC biology will be useful for stratification and selection of patients who are responders, non-responders and poor-responders for HDACi therapy, and for the rational design of combination studies using HDACi.

Rutin mediated targeting of signaling machinery in cancer cells.

Progress in our understanding of molecular oncology has started to shed light on dysregulation of spatio-temporally controlled signaling pathways, inactivation of tumor suppressor genes, tumour and normal stem cell quiescence, overexpression of oncogenes, extracellular and stromal microenvironments, epigenetics and autophagy. Sequentially and characteristically it has been shown that cancer cells acquire the ability to escape from apoptotic cell death, proliferate uncontrollably, sustain angiogenesis and tactfully reconstitute intracellular pathways to avoid immune surveillance. We have attempted to provide a recent snapshot of most recent progress with emphasis on how rutin modulates wide ranging intracellular signaling cascades as evidenced by in-vitro and in-vivo research. It is worth describing that 'single-cell proteomics' analysis has further improved our understanding regarding intracellular signaling pathways frequently activated in cancer cells resistant to therapeutics and can provide biomarkers for cancer diagnosis and prognosis. Data obtained from preclinical studies will prove to be helpful for scientists to bridge basic and translational studies.