PAN-811 Blocks Chemotherapy Drug-Induced in Vitro Neurotoxicity, while Not Affecting Suppression of Cancer Cell Growth

Abstract

Chemotherapy often results in cognitive impairment, and no neuroprotective drug is now available. This study aimed to understand underlying neurotoxicological mechanisms of anticancer drugs and to evaluate neuroprotective effects of PAN-811. Primary neurons in different concentrations of antioxidants (AOs) were insulted for 3 days with methotrexate (MTX), 5-fluorouracil (5-FU), or cisplatin (CDDP) in the absence or presence of PAN-811·Cl·H2O. The effect of PAN-811 on the anticancer activity of tested drugs was also examined using mouse and human cancer cells (BNLT3 and H460) to assess any negative interference. Cell membrane integrity, survival, and death and intramitochondrial reactive oxygen species (ROS) were measured. All tested anticancer drugs elicited neurotoxicity only under low levels of AO and elicited a ROS increase. These results suggested that ROS mediates neurotoxicity of tested anticancer drugs. PAN-811 dose-dependently suppressed increased ROS and blocked the neurotoxicity when neurons were insulted with a tested anticancer drug. PAN-811 did not interfere with anticancer activity of anticancer drugs against BNLT3 cells. PAN-811 did not inhibit MTX-induced death of H460 cells but, interestingly, demonstrated a synergistic effect with 5-FU or CDDP in reducing cancer cell viability. Thus, PAN-811 can be a potent drug candidate for chemotherapy-induced cognitive impairment.