Glucose-regulated protein of M(r) 78kDa (GRP78) is a resident protein of endoplasmic reticulum (ER). We have previously shown that the cells become resistant to topoisomerase II alpha (topo II alpha) targeted cancer chemotherapeutic drug such as etoposide (VP-16) when GRP78 is up-regulated by various means. Up-regulation of GRP78 in V79 Chinese hamster cell lines was achieved by treating the cells with NAD antagonist 6-aminonicotinamide (6AN), inhibitor of glucose metabolism such as 2-deoxyglucose (2dG). Further, up-regulation of GRP78 was also observed in V79-derived cell lines which are deficient in poly(ADP-ribose) polymerase (PARP1) metabolism. However, mechanisms of association of GRP78 up-regulation and resistance to VP-16 remained obscured under the conditions outlined above. In the manuscript, using various methods, we demonstrate, for the first time, that up-regulation of GRP78, using approaches depicted above, causes down-regulation of topo II alpha and its activity. We have also discussed the clinical implications of our findings.