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.

Oxidative Stress and Cognitive Alterations Induced by Cancer Chemotherapy Drugs: A Scoping Review

“…Compared to in vivo studies, relatively few in vitro studies have investigated the direct effects of anticancer drugs on neurons [38][39][40]. In primary cultures of rat neural stem cells or progenitor cells and hippocampal neurons, cisplatin and temozolomide induced mitochondrial DNA damage, impaired respiratory activity, and increased oxidative stress [39,40].…”

Neuro-protective effect of rutin against Cisplatin-induced neurotoxic rat model

“…Cisplatin-related side effects (ototoxicity, nephrotoxicity, neurotoxicity and cerebral disorders) limits its clinical use at the desired dosage [ 6 , 7 ]. Several studied have investigated the mechanisms of cisplatin toxicity but the mechanisms for induction of peripheral neuropathies is poorly understood [ 8 – 10 ]. One study showed the ability of cisplatin to penetrate into the brain where it inhibits neuronal stem cell proliferation [ 11 ].…”

PAN-811 prevents chemotherapy-induced cognitive impairment and preserves neurogenesis in the hippocampus of adult rats

“…Both MTX and 5-FU can pass the blood-brain barrier (BBB) in amounts that are sufficient to cause cognitive impairment [ 2 , 9 – 11 ], possibly by increasing oxidative stress (OS) [ 10 , 12 , 13 ]. In line with this mechanism, we previously demonstrated that MTX/5-FU-induced in vitro neurotoxicity is OS-dependent [ 14 ]. Increased OS, which is associated with various forms of chemotherapy [ 10 ], can elicit apoptosis of primary neural precursor cells and reduce the number of proliferation cells in the hippocampus of rodents [ 15 , 16 ].…”

“…In the present study, PAN-811 fully preserved neurogenesis in the DG of hippocampus under MTX/5-FU insult. Since MTX/5-FU most likely damaged neurons by oxidative stress in the same way as it is toxic to cultured neurons [ 14 ], the preservation of these neurons by PAN-811 may be via suppression of MTX/5-FU-elicited oxidative stress. In support of this hypothesis, our previous study revealed that PAN-811 can inhibit ischemic or hypoxic neurotoxicity to post-mitotic neurons by scavenging free radicals and suppressing OS [ 31 ].…”

“…PAN-811 has shown a capability of scavenging stable free radicals in a cell-free environment, and the ability to inhibit H 2 O 2 -induced neurotoxicity [ 31 – 33 ]. We have recently demonstrated that PAN-811 blocks OS-dependent in vitro neurotoxicity of 5-FU or MTX [ 14 ].…”