Figure 1. Roles of NKCC-1 in counteract against the TMZ-mediated glioma apoptosis.

A schematic model illustrates that temozolomide (TMZ) triggers loss of K⁺_i, Cl_i and apoptotic volume decrease (AVD), and leads to apoptotic cell death in glioblastoma cancer cells. In response to TMZ, the novel Cl⁻/volume-sensitive regulatory kinases WNK-mediated signaling transduction pathway is stimulated and activates NKCC-1 protein by phosphorylation. Activation of NKCC-1 accumulates intracellular Na⁺, K⁺, and Cl⁻ and obligated water molecules (regulatory volume increase, RVI) to counteract ionic dysregulation and AVD and promote cell survival of the TMZ-treated cells. In contrast, inhibition of NKCC-1 activity with bumetanide facilitates loss of intracellular K⁺, Cl⁻ and AVD, thus sensitizes glioma cells to the TMZ-mediated apoptosis (adopted from Algharabil, et al [48]).