Neuroprotective Activity of 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (PAN-811), a Cancer Therapeutic Agent

Abstract

ABSTRACT3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a highly-hydrophobic small molecule that was originally developed for cancer therapy (Triapine ® , Vion Pharmaceuticals) due to its ability to inhibit ribonucleotide reductase, a key enzyme required for DNA synthesis. 3-AP has a high affinity for divalent cations, chelating the Fe 2+ at the R2 subunit of the enzyme and inhibiting formation of a tyrosyl radical essential for ribonucleotide reduction. We have demonstrated that 3-AP is also a potent neuroprotectant (as such, it is referred to as "PAN-811"). In vitro it completely blocks ischemic neurotoxicity at a concentration of 0.5 ìM (EC 50 » 0.35 ìM) and hypoxic toxicity at 1.2 ìM (EC 50 » » 0.75 ìM). Full protection of primary cortical and striatal neurons can be achieved with 3-AP when it is added to the medium at up to six hours after an ischemic insult. 3-AP also suppresses cell death induced by neurotoxic agents, including staurosporine, veratridine and glutamate, indicating activity against a central target(s) in the neurodegenerative process. 3-AP acts via neutralization of two important intracellular effectors of excitatory neurotoxicity; calcium and free radicals. Its reported ability to elevate anti-apoptotic proteins is likely to be a consequence of the suppression of excessive intracellular free calcium. In a rat model of transient ischemia, a single bolus delivery of 3-AP 1 h after the initiation of ischemic attack reduced infarct volume by 59% when administered i.c.v. (50 ìg per rat) and by 35% when administered i.v. (1 mg/kg). In Phase I clinical trials in cancer therapy 3-AP had no cardiovascular, CNS or other major adverse effects. Thus, 3-AP has a 77

BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

“…Here, chemical inhibition of RRM2 with triapine undermined viability and tumour initiating capacity of GBM cells due to increased replication and oxidative stress. Importantly, NHA-26 cells were resistant to doses of triapine used to target GBM cells and EC 50-NHA26 was significantly higher, consistent with reports suggesting the use of triapine as a neuroprotectant36. The cellular consequences of replication and oxidative stress depend on the extent of DNA damage and the capacity to activate DDR and repair the damage.…”

“…We came across an RRM2-specific inhibitor triapine (3-aminopyridine-2-carboxaldehydethiosemicarbazone), a drug reportedly effective in two clinical studies on cervical cancer35 and currently assessed in several phase I and II trials in other cancer types (https://clinicaltrials.gov/ct2/results?term=triapine). Triapine exhibits neuroprotective effects in a rat model of transient ischaemia36. We found that the EC 50 values for triapine in 3 representative GBM xenografts were in the nanomolar range (GBM01: 518.6 nM; GBM02: 581.2 nM; GBM03: 307.2 nM) (Fig.…”

Thiosemicarbazonep-Substituted Acetophenone Derivatives Promote the Loss of MitochondrialΔψ, GSH Depletion, and Death in K562 Cells

“…3-AP is a well-known example of this class of TSC compounds. 3-AP has also been suggested to act as a neuroprotectant during the treatment of neurodegenerative diseases [20–22]. Regardless of the mechanisms responsible for the diverse therapeutic effects of TSCs, these compounds are dependent on drug transfer through the plasma membrane.…”

Molecular dynamics of 6‐methyl‐2‐phenyl‐2,3‐dihydro‐4H‐chromen‐4‐one and 6‐methyl‐2‐(4‐nitrophenyl)‐2,3‐dihydro‐4H‐chromen‐4‐one (flavanone) derivatives in a solution studied by NMR spectroscopy

“…Oxime compounds are well known as antidotes for nerve agents, analytical reagents . Semicarbazones and thiosemicarbazones are used in medicine, especially as anticancer chemotherapeutic agents, in the treatment of tuberculosis, and others …”