A drug combination targeting hypoxia induced chemoresistance and stemness in glioma cells
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Akansha Jalota1,2, Mukesh Kumar1, Bhudev C. Das3,4, Ajay K. Yadav3, Kunzang Chosdol2 and Subrata Sinha1,2
1National Brain Research Centre, Manesar, Gurgaon-122051, India
2Department of Biochemistry, All India Institute of Medical Sciences, New Delhi-110029, India
3Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi-110007, India
4Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida-201313, India
Keywords: BCNU; hypoxia; PGE2; chemosensitization; COX-2 inhibitor
Received: July 05, 2017 Accepted: February 21, 2018 Published: April 06, 2018
Hypoxia is a characteristic of solid tumors especially Glioblastoma and is critical to chemoresistance. Cancer stem cells present in hypoxic niches are known to be a major cause of the progression, metastasis and relapse. We tried to identify synergistic combinations of drugs effective in both hypoxia and normoxia in tumor cells as well as in cancer stem cells. Since COX-2 is over-expressed in subset of glioblastoma and is also induced in hypoxia, we studied combinations of a prototype Cyclooxygenase (COX-2) inhibitor, NS-398 with various drugs (BCNU, Temozolomide, 2-Deoxy-D-glucose and Cisplatin) for their ability to abrogate chemoresistance under both severe hypoxia (0.2% O2) and normoxia (20% O2) in glioma cells. The only effective combination was of NS-398 and BCNU which showed a synergistic effect in both hypoxia and normoxia. This synergism was evident at sub-lethal doses for either of the single agent. The effectiveness of the combination resulted from increased pro- apoptotic and decreased anti-apoptotic molecules and increased caspase activity. PGE2 levels, a manifestation of COX-2 activity were increased during hypoxia, but were reduced by the combination during both hypoxia and normoxia. The combination reduced the levels of epithelial-mesenchymal transition (EMT) markers. It also resulted in a greater reduction of cell migration. While single drugs could reduce the number of gliomaspheres, the combination successfully abrogated their formation. The combination also resulted in a greater reduction of the cancer stem cell marker CD133. This combination could be a prototype of possible therapy in a tumor with a high degree of hypoxia like glioma.
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