Triphenylbismuth dichloride inhibits human glyoxalase I and induces cytotoxicity in cultured cancer cell lines

Abstract

Organobismuth compounds, i.e., organic-inorganic hybrid molecules composed of an organic structure and bismuth metal, have been reported to induce cytotoxicity in cancer cells; however, the target proteins associated with this cytotoxicity have not been elucidated. Herein, we investigated the inhibitory effect of five organobismuth compounds on human glyoxalase I (hGLO I), a promising target candidate for cancer therapy. Among these compounds, triphenylbismuth dichloride (Bi-05) exerted a strong inhibitory effect on hGLO I. Indeed, Bi-05 inhibited hGLO I in a dose-dependent manner with an IC 50 value of 0.18 µM. Bi-05 also induced cytotoxicity in human leukemia HL-60 cells and human lung cancer NCI-H522 cells, both of which exhibit high expression levels of GLO I. However, the hGLO I-inhibiting and cytotoxic effects of Bi-05 disappeared when the bismuth atom was replaced with an antimony or phosphorus atom. Bismuth(III) nitrate had little inhibitory effect on hGLO I activity and only slightly reduced the viability of cancer cells. In the culture medium of Bi-05-treated HL-60 cells, the concentration of the GLO I substrate methylglyoxal was markedly elevated. In addition, Bi-05 treatment more strongly inhibited human lung cancer NCI-H522 cell (exhibiting high GLO I expression) proliferation than human lung cancer NCI-H460 cell (exhibiting low GLO I expression) proliferation. Furthermore, the cytotoxicity of Bi-05 was significantly decreased by pre-and co-treatment with the methylglyoxal scavengers N-acetyl-L-cysteine and aminoguanidine. Overall, these results suggest that Bi-05 treatment leads to the accumulation of methylglyoxal via GLO I inhibition, resulting in cytotoxic effects in cancer cells.

The PKM2 inhibitor shikonin enhances piceatannol‐induced apoptosis of glyoxalase I‐dependent cancer cells

“…The human non‐small‐cell lung cancer cell line NCI‐H522 also expresses high levels of GLO I, and proliferation can be substantially suppressed by both pharmacological GLO I inhibition using BBGD (Sakamoto et al, 2001), TLSC702 (Takasawa et al, 2016), triphenylbismuth dichloride (Takasawa et al, 2022), or piceatannol (Takasawa et al, 2017), as well as by siRNA‐mediated knockdown of GLO I (Santarius et al, 2010). Therefore, we also evaluated the antiproliferative effects of combined treatment with piceatannol plus shikonin on NCI‐H522 cells.…”

“…The combined anticancer efficacy of piceatannol plus shikonin was tested using the human GLO I-dependent promyelocytic leukemia cell line HL-60 (Takasawa et al, 2008(Takasawa et al, , 2010(Takasawa et al, , 2016(Takasawa et al, , 2022Thornalley et al, 1996). We first examined the antiproliferative effects of single-agent treatments to determine the optimal test concentration ranges.…”