Simultaneous dual targeting of Par-4 and G6PD: a promising new approach in cancer therapy? Quintessence of a literature review on survival requirements of tumor cells.

The aim of this hypothesis is to propose a new approach in targeted therapy of cancer: The simultaneous, dual targeting of two single molecules, Par-4 and G6PD, rather than inhibition of full-length signaling pathways. RATIONALE: Targeted inhibition of especially two survival signaling pathways (PI3K/AKT/mTOR and MAPK/ERK) is frequently tried, however, a major breakthrough has not yet been reported. Inhibition of complete pathways naturally goes along with a variety of dose-limiting side effects thus contributing to poor efficacy of the administered drugs. This essay offers a synopsis of relevant studies to support the above mentioned idea-targeting of two single molecules which either are crucial for tumor growth and cancer-cell-survival: on one side, Par-4-activation selectively triggers apoptosis of tumor cells thus reversing their characteristic feature-immortality. On the other side inhibition of G6PD breaks the energy supply of tumor cells, weakens their defence against oxidative stress and thereby enhances the sensitivity of tumor cells to oxidative agents (e.g. chemotherapy). Advantage of the proposed dual Par-4/G6PD-therapy is good tolerability and-especially when administered along with conventional therapy-less frequent emergence of resistance.