Title: Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents
Authors: Priebbenow, DL
Leaver, DJ
Nguyen, N
Cleary, B
Lagiakos, HR
Sanchez, J
Xue, L
Huang, F
Sun, YX
Mujumdar, P
Mudududdla, R
Varghese, S
Teguh, S
Charman, SA
White, KL
Shackleford, DM
Katneni, K
Cuellar, M
Strasser, JM
Dahlin, JL
Walters, MA
Street, IP
Monahan, BJ
Jarman, KE
Sabroux, HJ
Falk, H
Chung, MC
Hermans, SJ
Downer, NL
Parker, MW
Voss, AK
Thomas, T
Baell, JB
Issue Year: 2020
Publisher AMER CHEMICAL SOC
Series JOURNAL OF MEDICINAL CHEMISTRY:
Abstract Background Silica nanoparticles (nanoSiO(2)) are promising systems that can deliver biologically active compounds to tissues such as the heart in a controllable manner. However, cardiac toxicity induced by nanoSiO(2) has been recently related to abnormal calcium handling and energetic failure in cardiomyocytes. Moreover, the precise mechanisms underlying this energetic debacle remain unclear. In order to elucidate these mechanisms, this article explores the ex vivo heart function and mitochondria after exposure to nanoSiO(2). Results The cumulative administration of nanoSiO(2) reduced the mechanical performance index of the rat heart with a half-maximal inhibitory concentration (IC50) of 93 mu g/mL, affecting the relaxation rate. In isolated mitochondria nanoSiO(2) was found to be internalized, inhibiting oxidative phosphorylation and significantly reducing the mitochondrial membrane potential (Delta psi(m)). The mitochondrial permeability transition pore (mPTP) was also induced with an increasing dose of nanoSiO(2) and partially recovered with, a potent blocker of the mPTP, Cyclosporine A (CsA). The activity of aconitase and thiol oxidation, in the adenine nucleotide translocase, were found to be reduced due to nanoSiO(2) exposure, suggesting that nanoSiO(2) induces the mPTP via thiol modification and ROS generation. In cardiac cells exposed to nanoSiO(2), enhanced viability and reduction of H2O2 were observed after application of a specific mitochondrial antioxidant, MitoTEMPO. Concomitantly, CsA treatment in adult rat cardiac cells reduced the nanoSiO(2)-triggered cell death and recovered ATP production (from 32.4 to 65.4%). Additionally, we performed evaluation of the mitochondrial effect of nanoSiO(2) in human cardiomyocytes. We observed a 40% inhibition of maximal oxygen consumption rate in mitochondria at 500 mu g/mL. Under this condition we identified a remarkable diminution in the spare respiratory capacity. This data indicates that a reduction in the amount of extra ATP that can be produced by mitochondria during a sudden increase in energy demand. In human cardiomyocytes, increased LDH release and necrosis were found at increased doses of nanoSiO(2), reaching 85 and 48%, respectively. Such deleterious effects were partially prevented by the application of CsA. Therefore, exposure to nanoSiO(2) affects cardiac function via mitochondrial dysfunction through the opening of the mPTP. Conclusion The aforementioned effects can be partially avoided reducing ROS or retarding the opening of the mPTP. These novel strategies which resulted in cardioprotection could be considered as potential therapies to decrease the side effects of nanoSiO(2) exposure.
URI: https://publications.svi.edu.au/publications/7190
Other Identifiers 10.1021/acs.jmedchem.9b02071
Publication type Article