Arsenic is a global health concern at present and it is well reported for causing systemic toxicity. It is also well known for generation of free radical and inducing apoptosis in different cell types. Paradoxically arsenic is reported to be a susceptible carcinogen as well. There are several reports demonstrating diverse mechanism of apoptosis in different cell types. However, the universal scenario of instrumental genes and their interaction leading to amplification of apoptotic signal are yet to be completely uncovered, which is predicted here. Conventional studies on signaling pathway aided by time and concentration kinetics data are inadequate for prediction of anchored genes for apoptotic signal amplification. Therefore, expression profile-based approach is adopted. Core apoptosis related and glutathione metabolism genes in 1 and 10 μM of arsenic-treated HepG2 cells were analyzed after 12 h of incubation. An arsenic treatment of 1 μM exhibits no cell death at 12 h, whereas 10 μM arsenic treatment reveals around 50% cell death at 12 h. Results depict 28 and 44 affected genes in 1 and 10 μM arsenic-treated cells, respectively. Early initiation of apoptotic signaling is detected in no cell death regimens (at 1 μM), whereas amplified apoptotic signal is demonstrated at 50% cell death regimens (at 10 μM). Instrumental genes involved in progression of apoptosis in the concourse of cell death and survival is designated from the responsive genes common to both the condition. We predict the initiation process is fairly aided by the activation of intrinsic pathway, which is amplified via TNF signaling and extrinsic pathway. Furthermore, regulatory genes involved in interplay between apoptosis/anti-apoptosis and their interactions are demonstrated here.