Role of genomics-based strategies in overcoming chemotherapeutic resistance

Abstract

As cancer is being recognized as a failure of apoptosis, apoptosis-based strategies are being designed. Caspases are critical for the induction of apoptosis and their decreased expression is correlated with increased grade of cancer, while increased expression of caspases rendered the cancer cells susceptible to chemotherapy. However, the endogenous functions of caspases are inhibited by inhibitors of apoptosis (IAPs) that bind activated caspases. Methods to suppress the function of IAP induced apoptosis in chemo-resistant cancer cells. The function of IAPs is inhibited by Second Mitochondria-Derived Activator Of Caspase (Smac) or Direct IAP Binding Protein With Low Pi (DIABLO). Upon apoptotic stimulus Smac/DIABLO is released from the mitochondria, which binds to IAPs and inhibits their caspase-binding activity. Overexpression of Smac/DIABLO sensitized neuroblastoma to TRAIL (TNFalpha-Related Apoptosis-Inducing Ligand). Activation of TRAIL pathway has become an important method of inducing apoptosis except in TRAIL-resistant cells. However, treatment of these cells with other cytotoxic drugs sensitizes them to TRAIL, providing effective therapeutic advantages. In addition to activating apoptotic pathways, inhibiting or suppression of cell proliferation is necessary to sensitize cancer cells to apoptosis. Critical among these proteins are NFkappaB and Akt. NFkappaB blocked apoptosis by interfering with the function of TNFalpha/TRAIL and/or through the activation of antiapoptotic proteins of the Bcl2 family. Similarly, Akt mediate cell survival via the regulation of cell survival proteins and by blocking the function of proapoptotic Bad by phosphorylation. Altering the expression of Akt by dominant negative constructs or by expression of PTEN interferes with Akt function. In summary, this review points out the complexity of interactions of the cell survival and death pathways and highlights some methods to manipulate them to achieve therapeutic advantage.