Repurposing L-Menthol for Systems Medicine and Cancer Therapeutics? L-Menthol Induces Apoptosis through Caspase 10 and by Suppressing HSP90

Abstract

The objective of the present study was to repurpose L-menthol, which is frequently used in oral health and topical formulations, for cancer therapeutics. In this article, we argue that monoterpenes such as L-menthol might offer veritable potentials in systems medicine, for example, as cheaper anti-cancer compounds. Other monoterpenes such as limonene, perillyl alcohol, and geraniol have been shown to induce apoptosis in various cancer cell lines, but their mechanisms of action are yet to be completely elucidated. Earlier, we showed that L-menthol modulates tubulin polymerization and apoptosis to inhibit cancer cell proliferation. In the present report, we used an apoptosis-related gene microarray in conjunction with proteomics analyses, as well as in silico interpretations, to study gene expression modulation in human adenocarcinoma Caco-2 cell line in response to L-menthol treatment. The microarray analysis identified caspase 10 as the important initiator caspase, instead of caspase 8. The proteomics analyses showed downregulation of HSP90 protein (also corroborated by its low transcript abundance), which in turn indicated inhibition of AKT-mediated survival pathway, release of pro-apoptotic factor BAD from BAD and BCLxL complex, besides regulation of other factors related to apoptosis. Based on the combined microarray, proteomics, and in silico data, a signaling pathway for L-menthol-induced apoptosis is being presented for the first time here. These data and literature analysis have significant implications for ''repurposing'' L-menthol beyond oral medicine, and in understanding the mode of action of plant-derived monoterpenes towards development of cheaper anticancer drugs in future.

Apoptosis Induced by Ziziphora tenuior Essential Oil in Human Colorectal Cancer Cells

“…Menthol is another important compound of ZEO. Various studies have shown that menthol activates caspases 3 and 7 through caspase 10 affecting HSP90, followed by apoptosis [30][31][32].…”

The Wonderful Activities of the Genus Mentha: Not Only Antioxidant Properties

“…l -Menthol, one of the main components of Mentha species, has multiple applications in traditional medicine. Faridi et al observed that it modulated tubulin polymerization, induced apoptosis and also suppresses the expression of HSP90 [ 161 ]. In their proposed model, the latter authors suggested that l -menthol provoked apoptosis directly via caspase 10 activation and also activated caspase 9 which indirectly triggered caspase 3 and mitochondrial cell death [ 161 ].…”

“…Faridi et al observed that it modulated tubulin polymerization, induced apoptosis and also suppresses the expression of HSP90 [ 161 ]. In their proposed model, the latter authors suggested that l -menthol provoked apoptosis directly via caspase 10 activation and also activated caspase 9 which indirectly triggered caspase 3 and mitochondrial cell death [ 161 ]. Perillyl alcohol is a monoterpene isolated from lavendin, peppermint, spearmint and some other plants [ 162 ], and several studies showed that this compound could inhibit tumor progression.…”

Medicinal plant-derived therapeutics for treatment of neoplasms in modern and traditional systems of medicine

“…One recent example is that of L-menthol, a naturally occurring cyclic monoterpene obtained from Mentha arvensis (Lamiaceae) that has been traditionally used in oral hygiene products, confectionery, cosmetics and as a flavouring agent. An omics approach indicated that L-menthol modulates tubulin polymerization and apoptosis to inhibit human epithelial colorectal adenocarcinoma cell proliferation (Faridi et al, 2011;2016). Similarly, Puerarin (Pue), belonging to the isoflavone glycoside group and derived from Pueraria lobata, P. thomsonii and P. tuberosa was recommended by the Chinese Health Ministry for treating various ailments in 1993, but later it was found to possess anticancer activity too by virtue of it being an inducer of apoptosis (Ahmad et al, 2020).…”