Hexokinase 2 Inhibition and Biological Effects of BNBZ and Its Derivatives: The Influence of the Number and Arrangement of Hydroxyl Groups

Abstract

Hexokinase 2 (HK2), an enzyme of the sugar kinase family, plays a dual role in glucose metabolism and mediating cancer cell apoptosis, making it an attractive target for cancer therapy. While positive HK2 expression usually promotes cancer cells survival, silencing or inhibiting this enzyme has been found to improve the effectiveness of anti-cancer drugs and even result in cancer cell death. Previously, benitrobenrazide (BNBZ) was characterized as a potent HK2 inhibitor with good anti-cancer activity in mice, but the effect of its trihydroxy moiety (pyrogallol-like) on inhibitory activity and some cellular functions has not been fully understood. Therefore, the main goal of this study was to obtain the parent BNBZ (2a) and its three dihydroxy derivatives 2b–2d and to conduct additional physicochemical and biological investigations. The research hypothesis assumed that the HK2 inhibitory activity of the tested compounds depends on the number and location of hydroxyl groups in their chemical structure. Among many studies, the binding affinity to HK2 was determined and two human liver cancer cell lines, HepG2 and HUH7, were used and exposed to chemicals at various times: 24 h, 48 h and 72 h. The study showed that the modifications to the structures of the new BNBZ derivatives led to significant changes in their activities. It was also found that these compounds tend to aggregate and exhibit toxic effects. They were found to contribute to: (a) DNA damage, (b) increased ROS production, and (c) disruption of cell cycle progression. It was observed that, HepG2, occurred much more sensitive to the tested chemicals than the HUH7 cells; However, regardless of the used cell line it seems that the increase in the expression of HK2 in cancer cells compared to normal cells which have HK2 at a very low level, is a serious obstacle in anti-cancer therapy and efforts to find the effective inhibitors of this enzyme should be intensified.

Establishment of a Prognostic Model for Hepatocellular Carcinoma Based on Bioinformatics and the Role of NR6A1 in the Progression of HCC

“…Cells of a human HCC cell line, Huh7 were purchased from the Chinese Academy of Sciences (Beijing, China) and cultured in Dulbecco’s modified Eagle’s medium (DMEM, Biological Industries, Kibbutz Beit Haemek, Israel) supplemented with 10% fetal bovine serum (Biological Industries) in a 5% CO 2 incubator at 37°C, and then used in the following experiments. 29 …”

Single‐cell RNA sequencing of retina revealed novel transcriptional landscape in high myopia and underlying cell‐type‐specific mechanisms

“…and those in Hk2 mutant mice by Zhang et al 33,34 . Importantly, Hk2 knockdown contributed to ROS as possible by‐products of excessive OXPHOS in mitochondria, because HK2 could help to limit ROS generation by maintaining local ADP levels 35,36 . ROS is closely linked with myopia 17 .…”

“…This result was consistent with those performed in a hepatocellular carcinoma cell line by DeWaal et al and those in Hk2 mutant mice by Zhang et al 33,34 Importantly, Hk2 knockdown contributed to ROS as possible by-products of excessive OXPHOS in mitochondria, because HK2 could help to limit ROS generation by maintaining local ADP levels. 35,36 ROS is closely linked with myopia. 17 It may induce upregu-lation of HIF-1α or proinflammatory cytokines, which have been elaborated to promote myopia development.…”

Related mechanisms, current treatments, and new perspectives in meningioma

“…143 This mechanism participates in glucose metabolism, which is important for cell survival, and mediates cancer cell apoptosis. 144 HK2 is not found in normal tissues; however, some tissues sensitive to insulin show its expression, such as the heart, skeletal muscle, and adipose tissues. 145,146 However, HK2 is strongly expressed in a variety of cancers that spread and have a poor overall survival rate.…”