Kidney-Type Glutaminase Inhibitor Hexylselen Selectively Kills Cancer Cells via a Three-Pronged Mechanism

Abstract

Tumor metabolism has been deeply investigated for cancer therapeutics. Here, we demonstrate that glutamine deficiency alone could not completely inhibit cancer cell growth and that many potent kidney-type glutaminase (KGA) inhibitors did not show satisfying in vivo efficacy. The potent KGA allosteric inhibitor, CB-839, resulted in up to 80% growth inhibition of all tested cell lines, whereas Hexylselen (CPD-3B), a KGA/glutamate dehydrogenase (GDH) inhibitor, showed essentially no toxicity to normal cells up to a 10 μM concentration and could completely inhibit the growth of many aggressive cell lines. Further analyses showed that CPD-3B targets not only KGA and GDH but also thioredoxin reductase (TrxR) and amidotransferase (GatCAB), which results in corresponding regulation of Akt/Erk/caspase-9 signaling pathways. In an aggressive liver cancer xenograft model, CPD-3B significantly reduced tumor size, caused massive tumor tissue damage, and prolonged survival rate. These provide important information for furthering the drug design of an effective anticancer KGA allosteric inhibitor.

Biodegradable self-assembly micelles significantly enhanced the solubility, biological stability and in vivo antitumor efficacy of Hexylselen

“…The resulting mixtures were shaken at 25 °C for 24 h, and then the supernatants were collected by centrifugation (10 000 rpm for 5 min) and filtration. This was followed by reversed-phase high-performance liquid chromatography (RP-HPLC) 9 to quantify the dissolved Selen compounds.…”

“…The amount of released CPD-3B was quantified by RP-HPLC to produce the release curve. Meanwhile, the CPD-3B vehicle prepared using a previously reported method 9 was determined to obtain the comparative CPD-3B release profile.…”

“…The stability of the CPD-3B in blood was measured by the β-mercaptoethanol (BME) derivatization method. 37 Briefly, fresh heparin-containing mouse blood (200 μL) in 1.5 mL tubes was preheated at 37 °C, then treated with 1 mM of CPD-3B vehicle 9 (5 μL; the vehicle contained 5% ethanol, 5% Tween80, 10% PEG400 and 3% F68 in PBS buffer and was used in the following experiments) or CPD-3B@SOL micelles (5 μL). After gentle mixing, it was incubated in a 37 °C water bath for 2 min, 5 min, 10 min, 30 min, 1 h, and 2 h. Aliquots of the blood mixtures were derivatized with 1 M of BME (18 μL) in 10 mM of KH 2 PO 4 buffer (pH = 7.4; 100 μL), using Ebselen (1 mM final) as the inner standard.…”

New insights into molecules and pathways of cancer metabolism and therapeutic implications

“…Targeting Gln metabolic pathways, such as glutaminolysis, may provide a therapeutic strategy to kill tumor cells. The oral glutaminase inhibitor CB‐839 was reported to suppress Gln‐derived metabolite production during tumor development [84, 85]. Cohen et al .…”

“…Targeting Gln metabolic pathways, such as glutaminolysis, may provide a therapeutic strategy to kill tumor cells. The oral glutaminase inhibitor CB-839 was reported to suppress Gln-derived metabolite production during tumor development [84,85]. Cohen et al [86] found that cetuximab (which targets EGFR) in combination with CB-839 improved therapeutic efficacy in cetuximab-resistant CRC (Table 2 and Figure 1D).…”