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1.  Normal Sequence and Activity but Reduced Levels of DNA-Pkcs in Human Lymphoblastic Cells Implicate Impaired Protein Stability with Radiosensitive Phenotype 
Journal of Cancer  2013;4(8):606-613.
Background: Non-homologous end joining (NHEJ) is the main repair pathway for DNA double strand breaks (DSBs) induced by ionizing radiation in mammalian cells. Subsets of cancer patients are hypersensitive to radiotherapy after standard doses. We sought to determine the radiosensitivity of human lymphoblastic cells (LB0005) for the abnormality in NHEJ components.
Methods: Lymphoblastic (LB0005) cells are derived from an adult cancer patient with late radionecrosis. A low magnesium in vitro DNA-end joining assay was performed to examine for any defect in NHEJ activity. Single-nucleotide polymorphism (SNP) and sequence analysis were performed to examine for abnormality if any, in the genetic sequence of known NHEJ components.
Results: LB0005 cells showed a gain of functional abnormality in the NHEJ pathway. While genetic sequence analysis showed no apparent mutational variations in the known classical NHEJ components, DNA-PKcs (DNA-dependent protein kinase catalytic subunit) protein is reduced in quantity compared to normal control, in spite of higher transcript levels.
Conclusions: Taken together cells derived from a radiosensitive patient showed an abnormality in NHEJ activity. Proteins other than the classical NHEJ factors may regulate the NHEJ activity. Furthermore, the defect in theses regulatory proteins may have an impact on the stability of DNA-PKcs.
doi:10.7150/jca.6453
PMCID: PMC3805988  PMID: 24155772
DNA-PKcs; Non-homologous end joining; NHEJ
2.  The diverse and complex roles of radiation on cancer treatment: therapeutic target and genome maintenance 
Cancer is a genetic disease, grows exponentially with the development of intrinsic and acquired treatment resistance. Past decade has witnessed a considerable progress towards the treatment and understanding of proposed hallmarks of cancer and together with advances in early detection and various treatment modalities. Radiation therapy is an integral part of cancer treatment armamentarium. In developed countries more than half of all cancer patients receive radiation therapy during their course of illness. Although radiation damages both cancer and normal cells, the goal of radiation therapy is to maximize the radiation dose to abnormal cancer cells while minimizing exposure to normal cells, which is adjacent to cancer cells or in the path of radiation. In recent years, life expectancy increases among cancer patients and this increase is due to the results of early diagnosis, screening efforts, improved treatments and with less late effects mostly secondary cancer development. Therefore, cancer survivorship issues have been gaining prominence in the area of radiation oncology research. Understanding the tradeoff between the expected decreases in normal tissue toxicity resulting from an improved radiation dose distribution to the targeted site is an increasingly pertinent, yet needed attention and research in the area of radiation oncology. In recent years, a number of potential molecular targets that involve either with radiation increased tumor cell killing or protecting normal cells have been identified. For clinical benefits, translating these findings to maximize the toxicity of radiation on tumor cells while safeguarding early or late normal cell toxicities using molecular targeted radioprotectors will be useful in radiation treatment.
PMCID: PMC3410581  PMID: 22860229
Cancer; radiation therapy; radioprotectors; normal genome maintenance
3.  Cancer and Radiation Therapy: Current Advances and Future Directions 
In recent years remarkable progress has been made towards the understanding of proposed hallmarks of cancer development and treatment. However with its increasing incidence, the clinical management of cancer continues to be a challenge for the 21st century. Treatment modalities comprise of radiation therapy, surgery, chemotherapy, immunotherapy and hormonal therapy. Radiation therapy remains an important component of cancer treatment with approximately 50% of all cancer patients receiving radiation therapy during their course of illness; it contributes towards 40% of curative treatment for cancer. The main goal of radiation therapy is to deprive cancer cells of their multiplication (cell division) potential. Celebrating a century of advances since Marie Curie won her second Nobel Prize for her research into radium, 2011 has been designated the Year of Radiation therapy in the UK. Over the last 100 years, ongoing advances in the techniques of radiation treatment and progress made in understanding the biology of cancer cell responses to radiation will endeavor to increase the survival and reduce treatment side effects for cancer patients. In this review, principles, application and advances in radiation therapy with their biological end points are discussed.
doi:10.7150/ijms.3635
PMCID: PMC3298009  PMID: 22408567
Cancer; Radiation therapy; Linear energy transfer; Cell death.
4.  Emerging role of radiation induced bystander effects: Cell communications and carcinogenesis 
Genome Integrity  2010;1:13.
Ionizing radiation is an invaluable diagnostic and treatment tool used in various clinical applications. On the other hand, radiation is a known cytotoxic with a potential DNA damaging and carcinogenic effects. However, the biological effects of low and high linear energy transfer (LET) radiations are considerably more complex than previously thought. In the past decade, evidence has mounted for a novel biological phenomenon termed as "bystander effect" (BE), wherein directly irradiated cells transmit damaging signals to non-irradiated cells thereby inducing a response similar to that of irradiated cells. BE can also be induced in various cells irrespective of the type of radiation, and the BE may be more damaging in the longer term than direct radiation exposure. BE is mediated either through gap-junctions or via soluble factors released by irradiated cells. DNA damage response mechanisms represent a vital line of defense against exogenous and endogenous damage caused by radiation and promote two distinct outcomes: survival and the maintenance of genomic stability. The latter is critical for cancer avoidance. Therefore, efforts to understand and modulate the bystander responses will provide new approaches to cancer therapy and prevention. This review overviews the emerging role of BE of low and high LET radiations on the genomic instability of bystander cells and its possible implications for carcinogenesis.
doi:10.1186/2041-9414-1-13
PMCID: PMC2949714  PMID: 20831828
5.  Thymoquinone Induces Telomere Shortening, DNA Damage and Apoptosis in Human Glioblastoma Cells 
PLoS ONE  2010;5(8):e12124.
Background
A major concern of cancer chemotherapy is the side effects caused by the non-specific targeting of both normal and cancerous cells by therapeutic drugs. Much emphasis has been placed on discovering new compounds that target tumour cells more efficiently and selectively with minimal toxic effects on normal cells.
Methodology/Principal Findings
The cytotoxic effect of thymoquinone, a component derived from the plant Nigella sativa, was tested on human glioblastoma and normal cells. Our findings demonstrated that glioblastoma cells were more sensitive to thymoquinone-induced antiproliferative effects. Thymoquinone induced DNA damage, cell cycle arrest and apoptosis in the glioblastoma cells. It was also observed that thymoquinone facilitated telomere attrition by inhibiting the activity of telomerase. In addition to these, we investigated the role of DNA-PKcs on thymoquinone mediated changes in telomere length. Telomeres in glioblastoma cells with DNA-PKcs were more sensitive to thymoquinone mediated effects as compared to those cells deficient in DNA-PKcs.
Conclusions/Significance
Our results indicate that thymoquinone induces DNA damage, telomere attrition by inhibiting telomerase and cell death in glioblastoma cells. Telomere shortening was found to be dependent on the status of DNA-PKcs. Collectively, these data suggest that thymoquinone could be useful as a potential chemotherapeutic agent in the management for brain tumours.
doi:10.1371/journal.pone.0012124
PMCID: PMC2920825  PMID: 20711342

Results 1-5 (5)