Identification of a novel catalytic inhibitor of topoisomerase II alpha that engages distinct mechanisms in p53wt or p53-/- cells to trigger G2/M arrest and senescence.

We report a novel topoisomerase IIα inhibitor, mercaptopyridine oxide (MPO), which induces G2/M arrest and senescence with distinctly different cell cycle regulators (p21 or p14ARF) in HCT116p 53WT and HCT116 p53-/- cells, respectively. MPO treatment induced defective topoisomerase IIα-mediated decatenation process and inhibition of the enzyme's catalytic activity that stalled entry into mitosis. Topoisomerase IIα inhibition was associated with ROS-mediated activation of ATM-Chk2 kinase axis in HCT116 p53WT cells, but not in HCT116 p53-/- cells displaying early Chk1 activation. Results suggest that E2F1 stabilization might link MPO-induced p53 phospho-activation in HCT116 p53WT cells or p14ARF induction in HCT116 p53-/- cells. Also, interaction between topoisomerase IIα and Chk1 was induced in both cell lines, which could be important for decatenation checkpoint activation, even upon p53 ablation. Notably, TCGA dataset analyses revealed topoisomerase IIα upregulation across a wide array of cancers, which was associated with lower overall survival. Corroborating that increased topoisomerase IIα expression might offer susceptibility to the novel inhibitor, MPO (5 µM) induced strong inhibition in colony forming ability of pancreatic and hepatocellular cancer cell lines. These data highlight a novel topoisomerase IIα inhibitor and provide proof-of-concept for its therapeutic potential against cancers even with loss-of-function of p53.

Selenium status in food grains of northern districts of India.

The selenium status in the food grains of the agricultural lands of northern parts of India was estimated by using the HG-AAS technique. The areas where lesser rains were received or less irrigation water was available in northern Indian states viz. Rajasthan and southern parts of the Haryana had higher selenium levels in food grains. Punjab, Himachal Pradesh and northern parts of the Haryana states had normal levels of selenium in their food grains, except for slightly lower selenium levels in a few areas that were affected by floods along the river Yamuna.

Selenium status in soils of northern districts of India.

The HG-AAS technique was used to estimate the soil selenium status of the agricultural lands of northern parts of India. The drier lands where lesser rains were received or where less irrigation water was available in Rajasthan and southern parts of the Haryana states had above normal soil selenium levels. These soils were also found to be alkaline. Punjab, Himachal Pradesh and northern parts of the Haryana states had normal levels of selenium in their soils, except with slightly lower selenium levels in a few areas that were affected by floods along the river Yamuna. The results were also confirmed using the ICP-OES technique.