Effects of KR-33028, a novel Na+/H+ exchanger-1 inhibitor, on glutamate-induced neuronal cell death and ischemia-induced cerebral infarct

KR-33028, a potent inhibitor of the Na+/H+ exchanger NHE1, suppresses metastatic potential of triple-negative breast cancer cells

“…Interestingly, the co-adjuvant effect of EMD87580 or HMA with paclitaxel was not observed in hormone receptor-positive, luminal MCF-7 cells, or MDA-MB-231 cells lacking NHE1 expression [9]. In our hands, when MDA-MB-231 cells were treated with EMD87580 alone, even at high concentrations (≥ 100 μM), we did not see significant effects 18 on metastatic potential, while HMA alone was cytotoxic at concentrations ≥ 10 μM, so any significant effect on migration and invasion could not be properly assessed (unpublished observations). In contrast, KR-33028 was not cytotoxic at the concentrations used in this study, had a demonstrable inhibition of metastatic potential in these cells, and shows promise as a potential anti-cancer agent.…”

“…KR-33028, a potent and selective inhibitor of NHE1 has previously been evaluated for its protective effects against ischemic injury in myocardial and cerebral infarction [18,22].…”

“…KR-33028 was previously evaluated for cardioprotective effects [16] and was shown to reduce myocardial infarction due to ischemiareperfusion injury in rats and dogs [17]. Similarly, KR-33028 was also found to be protective against cell death due to glutamate toxicity in cultured neuronal cells and significantly reduced the size of cerebral infarcts due to ischemic injury in rats [18]. We evaluated the potential chemotherapeutic effects of KR-33028 against triple-negative breast cancer (TNBC) for which targeted therapies do not currently exist.…”

Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases

“…Activation of NHE leads to a decrease in the activity of the Na + -Ca 2+ exchanger. Because intracellular Ca 2+ elevation can exacerbate the process of cell death, inhibition of NHE has been proposed to attenuate ischemia-induced cell death in various cells [25] .…”

“…Excess levels of glutamate in the CNS can result in elevated intracellular Ca 2+ levels, which in turn cause a rise in the Ca 2+ concentration in sensitive organelles such as mitochondria and the endoplasmic reticulum [16] . Because of the essential role of Ca 2+ in promoting cell death, blocking Ca 2+ flux from the endoplasmic reticulum to the mitochondria or buffering intracellular Ca 2+ can reduce cellular sensitivity to apoptotic stimuli [25] . The NMDA-mediated excessive Ca 2+ entry into the cytosol activates calcineurin, which induces apoptosis in both rat hippocampal neurons and stable cell lines such as HeLa cells [26][27][28] .…”