Effects of Ionizing Radiation on Chromosome Replication and its Modification by HDAC Inhibitors

Ionizing radiation causes lethal injuries either directly or indirectly inducing damage to the biological macromolecules, most importantly the genetic material or DNA. Cells transiently halt their cell cycle progression to provide sufficient time for repair machinery to act on for the repair of radiation-induced DNA damages. This may include delay in replication or S-phase of cell cycle besides activating other cell cycle checkpoints. Multiple replicons (replicon cluster equivalent to a chromosome band) along the length of a chromosome fire in a definite pattern for the timely completion of replication. Histone deacetylase inhibitors (HDACi) have been shown to alter the pattern of DNA replication origin activity including earlier replication in S-phase of normally late replicating chromosome bands. This may also indicate an acceleration of repair steps since DNA damage acts as an impediment for replication. Trichostatin A (TSA), a well-known HDACi, was studied for its effect on replication initiation using Indian Muntjac cell as a model. It was found that TSA treatment enhanced the replication rate and increased the number of replicon clusters firing at any given time per chromosome. It also compensated the decline of replication rate in irradiated cells, helped in their revival and brought them to the control level

Normal Tissue Protectors Against Radiation Injury (Review Paper)

Radiation damages normal tissues that can adversely affect the success of cancer radiotherapy, safety of nuclear installation workers and military personnel, and public exposed to nuclear accidents. Certain chemicals are able to protect against the harmful effects of radiation. But more than 50 years of research has produced only one approved radioprotective drug, WR-2721 or amifostine. The general utility of WR-2721 is limited by its inherent toxicity and high cost. Efforts to find non-toxic radioprotectors have revealed the promising properties of some medicinal plants. This is an attempt to review the recent publications on radioprotectors and to identify the research needs relevant to developing countries.Defence Science Journal, 2011, 61(2), pp.105-112, DOI:http://dx.doi.org/10.14429/dsj.61.82

Role of some epigenetic factors in DNA damage response pathway

The current review gives a brief account of the DNA damage response pathway and involvement of various epigenetic mechanisms in DNA damage response pathway. The main focus is on histone modifications leading to structural alterations in chromatin since the compact chromatin structure poses a major limitation in the DNA repair process. Based on this hypothesis, our laboratory has also evaluated certain histone deacetylase inhibitors as potential radiomitigators and the same has been discussed in brief at the end of the review

Immunological Aspect of Radiation-Induced Pneumonitis, Current Treatment Strategies, and Future Prospects

Delivery of high doses of radiation to thoracic region, particularly with non-small cell lung cancer patients, becomes difficult due to subsequent complications arising in the lungs of the patient. Radiation-induced pneumonitis is an early event evident in most radiation exposed patients observed within 2–4 months of treatment and leading to fibrosis later. Several cytokines and inflammatory molecules interplay in the vicinity of the tissue developing radiation injury leading to pneumonitis and fibrosis. While certain cytokines may be exploited as biomarkers, they also appear to be a potent target of intervention at transcriptional level. Initiation and progression of pneumonitis and fibrosis thus are dynamic processes arising after few months to year after irradiation of the lung tissue. Currently, available treatment strategies are challenged by the major dose limiting complications that curtails success of the treatment as well as well being of the patient’s future life. Several approaches have been in practice while many other are still being explored to overcome such complications. The current review gives a brief account of the immunological aspects, existing management practices, and suggests possible futuristic approaches

Modifications of cell signalling and redox balance by targeting protein acetylation using natural and engineered molecules: implications in cancer therapy

Acetylation of proteins with the addition of an acetyl group on the lysine residue is one of the vital posttranslational modifications that regulate protein stability, function and intracellular compartmentalization. Like other posttranslational modifications, protein acetylation influences many if not all vital functions of the cell. Protein acetylation has been originally associated with histone acetylation regulated by Histone Acetyl Transferase (HAT) and Histone Deacetylase (HDAC) and was mainly considered to be involved in epigenetic regulation through chromatin remodelling. It is now widely referred to as lysine acetylation orchestrated by lysine acetyl transferase (KAT) and lysine deacetylase (KDAC) and influences many cellular functions. Protein acetylation fine tunes the redox balance and cell signalling in the context of cancer by exerting its control on expression of two very important redox sensors viz. Nrf2 and NF-kappa B. Accumulating evidences show that inhibitors of deacetylase (KDACi), responsible for cytotoxic effects in cancer cells, mediate their actions by inhibiting the deacetylases, thereby simulating an hyperacetylation state of histone as well as non-histone proteins, similar to the one created by KATs. Emergence of calreticulin (CRT) mediated protein acetylation system using polyphenolic acetates as donors coupled with over expression of CRT has opened new avenues for targeting protein acetylation for improving cancer therapy. Modifiers of protein acetylation are therefore, emerging as a class of anticancer therapeutics and adjuvant as they inhibit growth, induce differentiation and death (apoptosis) differentially in cancer cells and also exhibit chemo-radiation sensitizing potential. Although pre-clinical investigations with many natural and synthetic KDAC inhibitors have been very promising, their clinical utility has so far been limited to certain types of cancers of the hematopoietic system. The future of protein acetylation modifiers appears to depend on the development of newer engineered molecules and their rational combinations that can exploit the differences in the regulation of protein acetylation between tumor and normal cells/tissues