Abstract B73: The monoterpene, citral, increases intracellular oxygen radicals and inhibits cancer cell proliferation by inducing apoptosis and endoplasmic reticulum stress .

Abstract

The terpene-enriched steam distilled extract of ginger rhizomes has potent anti-tumor activity. Screening of the components of ginger extract demonstrated citral, a commonly used food flavoring agent, as the major monoterpene that inhibits proliferation of human and murine cancer cell lines A2780, ECC-1, OVCAR-3, SKOV-3, ID8 and MOVCAR. Citral initiates a rapid decrease in intracellular levels of glutathione and a corresponding increase in oxygen radicals. In wild-type p53-expressing ECC-1 cells, citral treatment increases phosphorylation of the Ser-15 residue of p53 and causes apoptosis. Inhibition of intracellular oxygen radicals by N-acetylcysteine and p53 activity by pifithrin-α inhibits citral-induced apoptosis in ECC-1 cells. Apoptosis in mutant p53 (Arg248Glu) expressing OVCAR-3 cells was also inhibited by N-acetylcysteine and was associated with a decrease in phosphorylation of Ser-15 of p53. Finally, in cells not expressing p53, citral inhibited proliferation, but not through apoptosis. Instead in the p53-negative SKOV-3 cells, citral treatment caused endoplasmic reticulum stress indicated by increase in phosphorylation of eIF2α and the expression of CHOP, GADD45, EDEM, ATF4 and Hsp90 and increased ATG5 and LC3-II suggesting the cells were undergoing autophagy. The study identifies the mechanism that allows citral to produce its cytotoxic effects. Combined with our recent results that nanoparticle-encapsulated citral decreases in vivo growth of 4T1 murine breast tumors, the results from the current study suggest that citral and its analogs be considered as chemotherapeutic agents. Since citral mediates its cytotoxic effects primarily by inducing oxidative stress, it is likely that this monoterpenes and its derivatives can be used for the treatment of a variety of solid tumors including ovarian cancer. Citation Format: Arvinder Kapur, Mildred Felder, Lucas Fass, Justanjyot kaur, Austin Czarnecki, Kavya Rathi, Manish Patankar. The monoterpene, citral, increases intracellular oxygen radicals and inhibits cancer cell proliferation by inducing apoptosis and endoplasmic reticulum stress . [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B73.

Induction of programmed cell death in Trypanosoma cruzi by Lippia alba essential oils and their major and synergistic terpenes (citral, limonene and caryophyllene oxide)

“…These positive interactions could have been due to the simultaneal action of these compounds on diverse and additive mechanisms that lead to cell death in susceptible lineages. Such mechanisms may include: a) polymerization microtubules disruption (citral) [ 60 ]; b) endoplasmic reticulum stress induction (citral) [ 60 ]; c) PIP3/AKT survival pathway inhibition (limonene, citral, and caryophyllene oxide) [ 52 , 61 , 62 ]; d) oxidative stress stimulation (limonene, citral, and caryophyllene oxide) [ 52 , 57 , 63 ]; and e) apoptosis by caspases activation (citral and limonene) [ 61 – 63 ], among others.…”

Essential oil from Cymbopogon flexuosus as the potential inhibitor for HSP90

“…A component of LO i.e. citral, an important monoterpene and a flavouring agent is reported to inhibit the proliferation of human and murine cancer cell lines A2780, ECC-1, OVCAR-3, SKOV-3, ID8 and MOVCAR [ 11 ]. Citral is reported to induce benign and atypical prostate hyperplasia [ 12 ] and also the hormone sensitive tissue responsiveness was reported by its anti-estrogenic actions [ 13 ].…”