Reactive oxygen species mediate hepatotoxicity induced by the Hsp90 inhibitor geldanamycin and its analogs

Abstract

Geldanamycin (GM), a benzoquinone ansamycin antibiotic, is a natural product inhibitor of Hsp90 with potent and broad anti-cancer properties. Because of its adverse effects on liver, its less toxic derivatives 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) are currently being evaluated for the treatment of cancer. Previously, it has been demonstrated that the redox cycling of GM by NADPH-cytochrome P450 reductase leads to the formation of the GM semiquinone and superoxide radicals, the latter being identified using spin-trapping. We hypothesized that the different hepatotoxicity induced by GM, 17-AAG and 17-DMAG reflects the redox active properties of the quinone moiety and possibly the extent of superoxide formation, which may stimulate cellular oxidative injury. Our data demonstrate that superoxide can be efficiently trapped during the reduction of GM, 17-AAG and 17-DMAG by NADPH-cytochrome P450 reductase, and that superoxide formation rate followed the order 17-DMAG > 17-AAG > GM. In the absence of superoxide scavengers, the rate of NADPH oxidation followed the order 17-DMAG > GM > 17-AAG. The half-wave one-electron reduction potentials (E1/2) of GM, 17- AAG and 17-DMAG in DMSO have been determined to be −0.37, −0.13 and −0.015 V (vs. Ag/AgCl), respectively. If the same order of E1/2 follows in neutral aqueous media, thermodynamic considerations imply that 17-DMAG is more readily reduced by the P450 reductase as well as by superoxide. The order of the drug cytotoxicity toward rat primary hepatocytes, as determined by their effect on cell viability and on intracellular oxidant level, was opposite to the order of E1/2 of the respective quinone/semiquinone couples. These results suggest that hepatotoxicity exhibited by the Hsp90 inhibitors belonging to benzoquinone ansamycins could be attributed to superoxide. The apparent discrepancy between the order of toxicity and the orders of superoxide formation rate, which is correlated with E1/2, is discussed.

PU-H71: An improvement on nature's solutions to oncogenic Hsp90 addiction

“…Once appropriately positioned, geldanamycin forms hydrogen bonds within the ATP binding pocket, including interactions between the macrocycle carbamate carbonyl and a key aspartate residue at the bottom of the pocket, thereby mimicking the actions of ATP [33]. While this activity potently inhibits Hsp90 function, the antibiotic was never investigated at the clinical level due to its poor in vivo stability and toxicity stemming from the benzoquinone moiety that undergoes reductive metabolism by nicotinamide adenine dinucleotide phosphate (NADPH): quinone oxidoreductase (NQ01) before it acts against Hsp90 [34][35][36].…”

Computational Polypharmacology Analysis of the Heat Shock Protein 90 Interactome

“…17,18 Seventeen Hsp90 inhibitors are currently undergoing clinical trials but none of them has thus far been approved, mainly because of hepatotoxicity. 19 Hsp90 inhibitors in clinical trial are also evaluated in combination with other anticancer drugs such as taxanes, cisplatin, proteasome inhibitors, death receptor ligands, histone 4 deacetylase inhibitors, and protein kinase inhibitors. 20 Remarkably, many of these ligands bind to biological targets that belong to the Hsp90 interactome.…”

The role of heat shock protein 90 in modulating ischemia–reperfusion injury in the kidney

“…Newer Hsp90 inhibition agents, some of which have good oral bioavailability, lack the hepatotoxic profile of firstgeneration Hsp90 inhibitors possibly due to an altered quinone moiety and rate of superoxide formation [139]. This allows for repeated administration at higher concentrations.…”