photo of Mamta Naidu

Mamta Naidu, PhD


Associate Investigator
Center of Cancer Systems Biology

Email: mamta [at] cancer-systems-biology.org
 

Education and Training:

1988 B.Sc., Microbiology University of Bombay, India
1990 M.Sc., Biochemistry M.S. University of Baroda, India
1997 Ph.D., Biochemistry University of Bombay, India
work completed at Bhabha Atomic Research Centre (BARC), Mumbai, India
1997–2003 Postdoctoral training North Shore University Hospital, Manhasset, NY, USA and
University of Nebraska-Lincoln, Lincoln, NE, USA

Research Interests:

Base excision repair pathway, target for cancer therapy
Base excision repair (BER) is the predominant DNA repair pathway induced in response to small base damage, produced in response to oxidative stress. As defects in BER have resulted in hypersensitivity to alkylating agents and ionizing radiation, molecular player(s) of this pathway have gained relevance as therapeutic targets, mainly in conjunction with alkylating agents like temozolomide (TMZ) and PARP inhibitors. More importantly, inhibiting BER could lead to better understanding of this DNA repair pathway, as when these inhibitors are used together, they may likely reveal a cross talk mechanism that could be exploited for a targeted approach. Search for small molecule inhibitors of the BER pathway has resulted in identification of a few compounds that are effective in the μM range, albeit most with unclear mechanisms of action. One such set of inhibitors is the thioxanthenones, including lucanthone and hycanthone, which were used in the 1980s as antitumor agents. Lucanthone is a selective inhibitor of the endonuclease activity of Apurinic endonuclease-1 (APE1) that does not affect the protein's redox activity. Our studies (PLoS ONE, Sep 2011) have shown that inhibition of APE1 by lucanthone was a result of direct (protein alone) and not indirect (via DNA intercalation) modulation of APE1. Further, we consider it important to see if the conformational changes, which are induced in APE1, could be compared to possible altered APE1 conformation by therapeutic measures like alkylating agents and low dose radiation. Previous studies, including our 2010 report in the Journal of Radiation Research, showed that lucanthone is a good radiosensitizer for glioblastoma multiforme (GBM) cell lines. We also find that these GBM cells showed cleavage of APE1 with increase in Thioxanthenones, with the cleavage being resistant to free radical quenchers. The innovative feature of this work is in coating the graphene nanoribbons with these thioxanthenones, for tumor inhibition by only targeting the endonuclease activity of APE1 in the glioma stem cell (GSC) subpopulation (a more radio/chemo resistant population) of GBM cell lines, using experimental and modeling approaches. The experimental focus of this research may thus lead to efficacious small molecule inhibitors for therapy against glioma tumors, with clear targets of BER repair pathway in GSC compartment.

Low or High LET- radiation induced DNA repair alters glial/oligodendrocyte progenitor cell (OPC) differentiation in vitro and in vivo
NASA's radiation research program emphasizes understanding of the mechanisms of radiation-induced DNA damage. As radiation research on the central nervous system (CNS) has predominantly focused on neurons, with few studies addressing the role of glial cells, we had focused our first NASA grant proposal on identifying the major DNA repair pathways induced by oxidative stress due to high atomic number (Z) and energy (HZE) radiation in glial cells. Ionizing radiation (IR) causes degeneration of myelin, the insulating sheaths of neuronal axons, leading to neurological impairment. Recent data with lower doses of 600 MeV/n of 56Fe particle radiation not only show dose-dependent decrease in viable neurons (like X-rays), but also reveal an adverse effect on astrocytes and OL progenitor cells (OPC). However, with higher doses, there was an increase in the proportion of OPC-derived astrocytes, suggesting astrocytosis. Thus, astronauts exposed to protons and HZE radiation may risk adverse effects during their missions as well as latent health effects. Moreover, patients undergoing fractionated radiotherapy show higher DNA repair activity in their normal cells as compared to their tumor cells. Both of these irradiated human cohorts would benefit from an increased understanding of DNA repair. Because base excision repair (BER) is a pathway up-regulated in response to oxidative stress by low-LET radiation, it is important to determine how high-LET-induced BER affects the fate of OPC. BER is even more important in mitochondria, the predominant sites of oxidative metabolism, where other DNA repair pathways are more limiting or absent. Our current studies show significant induction of the central BER enzyme apurinic endonuclease-1 (APE1 protein) in rat glial progenitor cell (GPC) line CG-4 and increased demyelination and cognitive defects in rats with dose fractionation. Thus, this project will determine the mechanism of altered cognitive changes from HZE particles and proton exposures with development of APE1 as a radiation biomarker to quantify these changes and predict radiation risks to CNS.

Selected Publications:
(click on title to go to manuscript abstract)