Modulation of oxidative stress and subsequent induction of apoptosis and endoplasmic reticulum stress allows citral to decrease cancer cell proliferation

Abstract

The monoterpenoid, citral, when delivered through PEG-b-PCL nanoparticles inhibits in vivo growth of 4T1 breast tumors. Here, we show that citral inhibits proliferation of multiple human cancer cell lines. In p53 expressing ECC-1 and OVCAR-3 but not in p53-deficient SKOV-3 cells, citral induces G1/S cell cycle arrest and apoptosis as determined by Annexin V staining and increased cleaved caspase3 and Bax and decreased Bcl-2. In SKOV-3 cells, citral induces the ER stress markers CHOP, GADD45, EDEM, ATF4, Hsp90, ATG5, and phospho-eIF2α. The molecular chaperone 4-phenylbutyric acid attenuates citral activity in SKOV-3 but not in ECC-1 and OVCAR-3 cells. In p53-expressing cells, citral increases phosphorylation of serine-15 of p53. Activation of p53 increases Bax, PUMA, and NOXA expression. Inhibition of p53 by pifithrin-α, attenuates citral-mediated apoptosis. Citral increases intracellular oxygen radicals and this leads to activation of p53. Inhibition of glutathione synthesis by L-buthionine sulfoxamine increases potency of citral. Pretreatment with N-acetylcysteine decreases phosphorylation of p53 in citral-treated ECC-1 and OVCAR-3. These results define a p53-dependent, and in the absence of p53, ER stress-dependent mode of action of citral. This study indicates that citral in PEG-b-PCL nanoparticle formulation should be considered for treatment of breast and other tumors.

Genipin Enhances the Therapeutic Effects of Oxaliplatin by Upregulating BIM in Colorectal Cancer

“…ER stress is reported to induce the activation of BIM via IRE1a/JNK, IRE1a/CHOP, or PERK/ATF4/CHOP pathways (18,35). Usually, ER stress is induced by oxidative agents that modulate cancer cell survival (36). Consistent with these reports, we found that ER stress induced by genipin markedly upregulates BIM by inducing the IRE1a/JNK/BIM pathway in colorectal cancer cell lines.…”

In vitro antiproliferative activity of Melissa officinalis L (Lamiaceae) leaves essential oil

“…The mechanism of action of citral is due to its geranial isoform component (Nakamura et al, 2003). Recent studies have shown citral to inhibit cell intracellular levels of oxygen radicals and, consequently, by the modulation of cellular oxidative status, leading to reduction of cancer cell proliferation and ultimately resulting in cell death (Kapur et al, 2016;Sanches et al, 2017). Citral was also shown to induce caspase activation and subsequent apoptosis induction in several cancer cell types, including colorectal cancer and glioblastoma (Dudai et al, 2005;Queiroz et al, 2014;Sheikh et al, 2017).…”

Effectiveness assessment of mouthwashes formulated from the essential oils of some beninese medicinal plants against oral germs

“…Inducer of the glutathione-Stransferase enzyme, geranial induce apoptosis and inhibit the promotion of skin cancers (Kapur et al, 2016).…”