Potential of Novel Methyl Jasmonate Analogs as Anticancer Agents to Metabolically Target HK-2 Activity in Glioblastoma Cells

Abstract

Change in the energy metabolism of cancer cells, which display significant differences compared to normal cells, is a rising phenomenon in developing new therapeutic approaches against cancers. One of the metabolic enzymes, hexokinase-II (HK-II) is involved in glycolysis, and inhibiting the HK-II activity may be a potential metabolic target for cancer therapy as most of the drugs in clinical use act on DNA damage. Methyl jasmonate (MJ) is one of the compounds blocking HK-II activity in cancer cells. In a previous study, we showed that the novel MJ analogs inhibit HK-II activity through VDAC detachment from the mitochondria. In this study, to evaluate the potential of targeting HK-2 activity, through patient cohort analysis, we first determined HK-2 expression levels and prognostic significance in highly lethal glioblastoma (GBM) brain tumor. We then examined the in vitro therapeutic effects of the novel analogs in the GBM cells. Here, we report that, among all, compound-10 (C-10) showed significant in vitro therapeutic efficacy as compared to MJ which is in use for preclinical and clinical studies. Afterward, we analyzed cell death triggered by C-10 in two different GBM cell lines. We found that C-10 treatment increased the apoptotic/necrotic cells and autophagy in GBM cells. The newly developed analog, C-10, was found to be lethal against GBM by the activation of cell death authorities, mostly in a necrotic and autophagic fashion at the early stages of the treatment. Considering that possibly decreased intracellular ATP levels by C-10 mediated inhibition of HK-2 activity and disabled VDAC interaction, a more detailed analysis of HK-2 inhibition–mediated cell death can provide a deep understanding of the mechanism of action on the oncosis/necroptosis axis. These findings provide an option to design clinically relevant and effective novel HK-II inhibitors and suggest novel MJ analogs to further study them as potential anticancer agents against GBM.

Targeting HK2 in Anticancer Therapy

“…In vitro studies of therapeutic effects of new MJ derivatives on glioblastoma brain tumours that are aggressive and malignant and highly lethal are due to overexpression of HK2. One of the novel analogs of MJ (Figure 11) more effectively reduces glioblastoma cell viability than MJ [85]. This 1,2,4-oxadiazole derivative inhibited HK2 more strongly and irreversibly than MJ with a value IC 50 of 0.27 µM, and 7.47 µM, respectively [88].…”

“…The main targets of MJ treatment in cancer cells are HK2-VDAC complex, Reactive Oxygen Species (ROS), 5 lipoxygenase (5-LOX) pathway, MAPK signaling pathway and NF-κB pathway. The anticancer effects of MJ have been assessed in many types of various human and mouse cancer cell lines such as melanoma, lymphoma cells, prostate, melanoma, lymphoblastic leukemia, and breast [85]. All cytotoxic effects of MJ on cells were observed at millimolar concentrations [84].…”

“…Destruction of the HK2-VDAC1 complex by MJ resulted in loss of mitochondrial function, among others, by inducing the transition of mitochondrial permeability and subsequent release of cytochrome c from mitochondria, leading to cell necrosis and apoptosis [86,87]. The discovery of MJ as a candidate for cancer treatment has resulted in the design and synthesis of derivatives of MJ [85]. In vitro studies of therapeutic effects of new MJ derivatives on glioblastoma brain tumours that are aggressive and malignant and highly lethal are due to overexpression of HK2.…”

“…This 1,2,4-oxadiazole derivative inhibited HK2 more strongly and irreversibly than MJ with a value IC 50 of 0.27 µM, and 7.47 µM, respectively [88]. The mechanism of action involved dissociation of the HK2-VDAC complex associated with mitochondria [85]. Clotrimazole (CTZ) and Bifnazole: Clotrimazole-an azole derivative is a popular antifungal drug.…”

Facile modular synthesis of jasmonoyl-l-isoleucine analogs possessing a pyrazolidin-3-one core

“… 14 The prepared analogs permitted structure activity relationship (SAR) studies through which the main structural features required to keep or to potentiate such activities were identified. SAR studies have been done on activities in plants such as tendril coiling 15 or secondary metabolites accumulation, 16 and even in humans, such as anti-inflammatory, 17 neoplastic, 18 or anticancer, 19 because of the structural similarity of these compounds to prostaglandins in mammals. Notwithstanding, all existing routes to JAs analogs are mainly linear, including de novo syntheses 20–22 and partial syntheses starting from commercially available methyl jasmonate or cis -jasmone.…”