Abstract
Methyl jasmonate (MJ) displays antineoplastic potential against numerous neoplastic cells. However, several mechanistic aspects of its antineoplastic action against malignancies of T cell origin remain elusive. The present investigation reports the novel targets of MJ and mechanistic pathways of MJ-mediated antineoplastic and chemosensitizing action against tumor cells derived from murine T-cell lymphoma, designated as Dalton’s lymphoma (DL). The present study demonstrates that MJ directly docks to HIF-1α, hexokinase 2, and Hsp70 at prominent binding sites. MJ exhibits tumoricidal action against tumor cells via induction of apoptosis and necrosis through multiple pathways, including declined mitochondrial membrane potential, enhanced expression of ROS, altered pH homeostasis, an elevated level of cytosolic cytochrome c, and modulated expression of crucial cell survival and metabolism regulatory molecules. Additionally, this study also reports the chemosensitizing ability of MJ against T cell lymphoma accompanied by a declined expression of MDR1. This study sheds new light by demonstrating the implication of novel molecular mechanisms underlying the antitumor action of MJ against T-cell lymphoma and hence has immense translational significance.
Highlights
Methyl jasmonate (MJ; IUPAC name Methyl (1R,2R)-3-Oxo-2-(2Z)-2-pentenyl-cyclopentaneacetate), is a methyl ester of jasmonic acid and is ubiquitously present in plants (Cesari et al, 2014)
The primary mechanism of the antineoplastic activity of MJ is reported to be associated with its ability to dissociate the mitochondrial membrane-bound hexokinase (HK) from voltagedependent anion channel (VDAC) (Goldin et al, 2008) with cytotoxic consequences in the susceptible malignant cells (Hong et al, 2016; Zhang et al, 2016)
MJ up-regulates the generation of ROS (Zhang et al, 2016) and shows inhibitory action on the expression of several key metabolic enzymes involved in the oxidative phosphorylation of tumor cells (Li et al, 2017) and pathways of cell death induction (Cesari et al, 2014; Peng and Zhang, 2017; Wang et al, 2018)
Summary
Methyl jasmonate (MJ; IUPAC name Methyl (1R,2R)-3-Oxo-2-(2Z)-2-pentenyl-cyclopentaneacetate), is a methyl ester of jasmonic acid and is ubiquitously present in plants (Cesari et al, 2014). Methyl jasmonate is demonstrated to display a broad spectrum of antineoplastic activities (Cesari et al, 2014; Hong et al, 2016; Zhang et al, 2016; Yousefi et al, 2020). MJ up-regulates the generation of ROS (Zhang et al, 2016) and shows inhibitory action on the expression of several key metabolic enzymes involved in the oxidative phosphorylation of tumor cells (Li et al, 2017) and pathways of cell death induction (Cesari et al, 2014; Peng and Zhang, 2017; Wang et al, 2018). The mechanism(s) implicated in the antineoplastic activity of MJ exhibits tumor-totumor variation (Cesari et al, 2014), necessitating investigation of the antineoplastic mechanisms in a tumor-specific manner
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