Induction of Lung Cancer Cell Apoptosis through a p53 Pathway by [6]-Shogaol and Its Cysteine-Conjugated Metabolite M2

Abstract

Dietary chemoprevention of cancer offers the possibility to suppress or inhibit cancer growth before it develops into more advanced and lethal stages. To this end, identification of novel compounds and their mechanisms of action is constantly needed. In this study, we describe that a major component of dry ginger (Zingiber officinalis), [6]-shogaol (6S), can be quickly metabolized in A549 human lung cancer cell line. One of the resulting metabolites, the cysteine-conjugated 6S (M2), exhibits toxicity to cancer cells similar to the parent compound 6S, but is relatively less toxic toward normal cells than 6S. We further demonstrate that both compounds can cause cancer cell death by activating the mitochondrial apoptotic pathway. Our results show that the cancer cell toxicity is initiated by early modulation of glutathione (GSH) intracellular content. The subsequently generated oxidative stress activates a p53 pathway that ultimately leads to the release of mitochondria-associated apoptotic molecules such as cytochrome C, and cleaved caspases 3 and 9. In a xenograft nude mouse model, a dose of 30 mg/kg of 6S or M2 was able to significantly decrease tumor burden, without any associated toxicity to the animals. This effect was correlated with an induction of apoptosis and reduction of cell proliferation in the tumor tissues. Taken together, our results show that 6S metabolism is an integral part of its anticancer activities in vitro and in vivo. This allows us to characterize M2 as a novel compound with superior in vivo chemopreventive properties that targets similar anticancer mechanisms as 6S.

Promotion of Mitochondrial Biogenesis via Activation of AMPK‐PGC1ɑ Signaling Pathway by Ginger (Zingiber officinale Roscoe) Extract, and Its Major Active Component 6‐Gingerol

“…It was reported that 6‐gingerol attenuated oxidative damage on cell death of neurons (Lee, Park, Kim, & Jang, ), while it damaged the mitochondrial function resulting in cellular apoptosis in several other cell types (Mansingh, O J, Sali, & Vasanthi, ; Nigam, Bhui, Prasad, George, & Shukla, ; Yang et al., ). 6‐Shogaol was consistently reported to damage mitochondrial function of cells (Annamalai, Kathiresan, & Kannappan, ; Chen et al., ; Warin, Chen, Soroka, Zhu, & Sang, ). We hypothesized that the concentration of 6‐gingerol and 6‐shogaol used in various experimental settings may cause the above inconsistency.…”

Comparison of Inhibitory Capacities of 6-, 8- and 10-Gingerols/Shogaols on the Canonical NLRP3 Inflammasome-Mediated IL-1β Secretion

“…Based on the functional binding sites existing in the promoter region, the expression of caspase-1 gene is demonstrated to be activated by several transcriptional factors, such as IRF-1, signal transducer and activator of transcription (STAT) 1, p53, and p73 and E26 transformation-specific sequence 1 (Ets-1) [ 27 ]. On the other hand, 6-shogaol was demonstrated to induce lung cancer cell apoptosis through activating p53 pathway and to increase the expression of p21, p27, SOCS1, and IRF1 in prostate cancer cells [ 28 , 29 ]. The inducing effect of these effective ginger phytochemicals, especially 6-shogaol, on caspase-1 gene expression might be partially attributed to their activating effect on p53 and IRF1.…”

Anti-Colon Cancer Effects of 6-Shogaol Through G2/M Cell Cycle Arrest by p53/p21-cdc2/cdc25A Crosstalk

“…6-shogaol [1-(4-hydroxy-3-methoxyphenyl)-4-decen-3-one] found in small quantities in fresh ginger is even more abundant in processed ginger. Accumulating in vitro evidence suggests the involvement of multiple signaling pathways by which 6-shogaol suppresses growth of human cancer cells (Weng et al, 2010;Saha et al, 2014;Warin et al, 2014).…”