Thymus hirtus sp. algeriensis Boiss. and Reut. volatile oil enhances TRAIL/Apo2L induced apoptosis and inhibits colon carcinogenesis through upregulation of death receptor pathway

Abstract

Background: The aim of the study is to determine the anticancer activity of Thymus algeriensis (TS) and its underlying mechanisms using in vitro and in animal models. Methods: HCT116 cells were treated with TS essential oil alone or with TRAIL, and then its anticancer effect was determined by using MTT assay, live dead assay, caspase activation and PARP cleavage. Further mechanisms of its anticancer effects was determined by analyzing expression of death receptor signaling pathway using Western blotting. A mouse model was also used to assess the antitumor potential of thyme essential oil. Results: TS oily fraction showed tumor growth inhibitory effect even at lower concentration. TS induces apoptotic cell death as indicated by cleavage of PARP, and activation of the initiator and effector caspases (caspase-3, -8 and -9). Further, results showed that TS increases the expression of death receptors (DRs) and reduces the expression of TRAIL decoy receptors (DcRs). In addition, upregulation of signaling molecules of MAPK pathway (p38 kinase, ERK, JNK), down-regulation of c-FLIP, and overexpression of SP1 and CHOP were observed by TS. Further in animal model, intragastric administration of TS (12.5 mg/ml and 50 mg/ml) prevented colorectal carcinogenesis by blocking multi-steps in carcinoma. Conclusion: Overall, these results indicate that thymus essential oil promotes apoptosis in HCT116 cells and impedes tumorigenesis in animal model. Moreover, thyme potentiates TRAIL-induced cell death through upregulation of DRs, CHOP and SP1 as well as downregulation of antiapoptotic proteins in HCT116 cells. However, therapeutic potential of TS needs to be further explored.

Caper (Capparis spinosa L.): An Updated Review on Its Phytochemistry, Nutritional Value, Traditional Uses, and Therapeutic Potential

“…As suggested, these plant extracts/compounds could trigger the bacterial cell membrane, coagulate the cytoplasm and bind lipids and proteins (Viuda-Martos et al, 2011). The cytotoxic effect of phytochemicals has been reported to be a result of many mechanisms including the activation of the apoptosisinducing enzymes (Caspases 3, 8, and 9) of cancer cell lines and the expression of death receptors (Khan et al, 2020;Guesmi et al, 2021). However, given the complexity of biological systems, it would be very difficult to extrapolate these data on Caper without resorting to animal and clinical experiments.…”

Unraveling the Phytochemistry, Traditional Uses, and Biological and Pharmacological Activities of Thymus algeriensis Boiss. & Reut

“…This study also showed that T. algeriensis increased MAPK pathway signaling molecules (p38 kinase, ERK, and JNK), downregulated c-FLIP, and overexpressed SP1 and CHOP. The in vivo model of cancer showed that intragastric injection of T. algeriensis extract (12.5 and 50 mg/mL) inhibited colorectal carcinogenesis in an animal model by preventing multiple phases in the carcinoma [ 96 ]. To sum up, the anticancer potential of T. algeriensis extracts is mainly attributed to their capacity to enhance the apoptosis-stimulating enzymes and receptors in tumor cells, to downregulate the oncogenic miRNA and genes, and to inhibit the antiapoptotic proteins.…”

Thymus hirtus Willd. ssp. algeriensis Boiss. and Reut: A Comprehensive Review on Phytochemistry, Bioactivities, and Health-Enhancing Effects

“…Some chemotypes are similar to those of the Algerian oils, such as camphor [ 49 , 143 ], linalool [ 48 , 85 , 150 , 151 ], thymol [ 85 ], and α -pinene [ 85 , 152 ]. Others are different such as 1,8-cineole, 1,8-cineole/camphor, 1,8-cineole/ α -pinene, 4-terpineol/camphor, camphor/4-terpineol, caryophyllene oxide, cis -sabinene hydrate, cis -sabinene hydrate/1,8-cineole, eucalyptol, eucalyptol/2-carene, eucalyptol/viridiflorol, terpinen-4-ol, terpinyl acetate/1,8-cineole, viridiflorol, viridiflorol/cyclo-hexene,1-(1-butenyl), and viridiflorol/ α -pinene [ 48 , 50 , 86 , 143 , 150 , 151 , 152 , 153 ].…”

“…Monoterpenes (2-carene, borneol, bornyl acetate, camphene, campholenal, cis -sabinene hydrate, endo -borneol, geraniol, iso -pulegol, linalool oxide, linalyl acetate, myrtenal, o -cymene, p -cymene, pinocarveol, sabinene, terpinyl acetate, verbenone, α -phellandrene, α -terpineol, α -terpinylacetate, β -ocimene, β -phellandrene, β -pinene, and γ -terpinene) have been identified in Tunisian populations of T. algeriensis ( Figure 3 ). The (+)- epi -bicyclosesquiphellandrene, allo -aromadendrene, cis - α -bisabolene, elemol, epiglobulol, germacrene B, ledol, spathulenol, α -cadinol, α -copaene, α -humulene, β -caryophyllene, β -eudesmol, γ -cadinene, and γ -gurjunene are the sesquiterpenoid compounds that have also been detected in plants [ 48 , 50 , 86 , 143 , 150 , 151 , 152 , 153 ]. The phenolic compound carvacrol was only seen at 2.55% in the flowers and leaves of a species at the vegetative and flowering stage in the Oued Oum Ali region [ 143 ].…”

“…The cancer chemopreventive effect was studied by Guesmi et al [ 153 ]. HCT116 cells were treated with Tunisian essential oil alone or with TRAIL (TNF-related apoptosis-inducing ligand), which has anticancer effects.…”