Figure 1

Molecular Mechanisms of CSC Chemoresistance (A). ABC transporters can efflux a wide variety of chemotherapeutics out of cancer cells. The specific ABC transporter pump expressed in the CSCs determines the specificity of chemoresistance. (B). ALDH1 is a cytosolic enzyme, whereas other isoforms can localize to the mitochondria as well as the cytosol. The efficacy of chemotherapeutic drugs such as cyclophosphamide is reduced in ALDH expressing CSCs, as these drugs are substrates for these enzymes. (C). Pro-survival protein BCL-2 binds to pro-apoptotic proteins BAX and BAK, preventing the release of the apoptogenic factor cytochrome c from the mitochondria. Aberrant activity of BCL-2 and other pro-survival BCL-2 family members utilize this mechanism to prevent chemotherapy-mediated apoptosis. (D). Following DNA damage, ATM and ATR recognize breaks in DNA and activate CHK2 and CHK1, respectively. CHK2 and CHK1 can impair cell cycle and promote DNA repair. Activation of these DNA repair proteins in CSCs can impair the efficacy of ICL agents.