Costunolide induces micronuclei formation, chromosomal aberrations, cytostasis, and mitochondrial-mediated apoptosis in Chinese hamster ovary cells

Abstract

Costunolide (CE) is a sesquiterpene lactone well-known for its antihepatotoxic, antiulcer, and anticancer activities. The present study focused on the evaluation of the cytogenetic toxicity and cellular death-inducing potential of CE in CHO cells, an epithelial cell line derived from normal ovary cells of Chinese hamster. The cytotoxic effect denoting MTT assay has shown an IC value of 7.56 μM CE, where 50% proliferation inhibition occurs. The oxidative stress caused by CE was confirmed based on GSH depletion induced cell death, conspicuously absent in N-acetylcysteine (GSH precursor) pretreated cells. The evaluation of genotoxic effects of CE using cytokinesis block micronucleus assay and chromosomal aberration test has shown prominent induction of binucleated micronucleated cells and aberrant metaphases bearing chromatid and chromosomal breaks, indicating CE's clastogenic and aneugenic potential. The apoptotic death in CE treated cells was confirmed by an increase in the number of cells in subG1 phase, exhibiting chromatin condensation and membranous phosphatidylserine translocation. The apoptosis induction follows mitochondrial mediation, evident from an increase in the BAX/Bcl-2 ratio, caspase-3/7 activity, and mitochondrial membrane permeability. CE also induces cytostasis in addition to apoptosis, substantiated by the reduced cytokinetic (replicative indices) and mitotic (mitotic indices and histone H3 Ser-10 phosphorylation) activities. Overall, the cellular GSH depletion and potential genotoxic effects by CE led the CHO cells to commit apoptosis and lowered cell division. The observed sensitivity of CHO cells doubts unintended adverse effects of CE on normal healthy cells, suggesting higher essentiality of further studies in order to establish its safety efficacy in therapeutic explorations.

The role of mitochondria in cellular toxicity as a potential drug target

“…It should be further explored whether the variation between nuclear and mitochondrial DNA and degrees of MtDNA mutations may influence the specificity and sensitivity of MtDNA or the processes of MtDNA replication, transcription, and termination. In addition to the measurement of mitochondrial function after drug delivery, drugs can induce micronuclei formation, chromosomal aberrations, cytostasis, and mitochondrial-mediated apoptosis as part of the cytogenetic toxicity in CBT (Singireesu et al 2017).…”

DaHuangWan targets EGF signaling to inhibit the proliferation of hepatoma cells

“…Recent studies have shown that the ethanol extract of Aucklandia lappa Decne has anti-cancer effect on prostate cancer, oral cancer, breast cancer, and cervical cancer [10][11][12]. In addition to its anti-tumor chemo-preventive effect, Costunolide also has anti-cancer activity against various cancer cells such as lung cancer, breast cancer, and liver cancer, and can inhibit the invasion and metastasis of cancer cells [13][14][15][16][17][18][19]. Although Berberine and Costunolide have decent anti-cancer activity, it is not clear whether Berberine and Costunolide are key functional components of DHW, and the benefits of this combination for liver cancer treatment.…”

Stimulation of Eryptosis, the Suicidal Erythrocyte Death, by Costunolide

“…Costunolide is in part effective by decreasing vascular endothelial growth factor (VEGF) [3], interleukin (IL)-1β, IL-6, IL-17 [3], tumor necrosis factor (TNF)-α [3] and transforming growth factor (TGF-β) [3]. Costunolide induces oxidative stress [2,11,[15][16][17][18] and fosters apoptosis of tumor cells [1,2,11,[16][17][18][19][20][21][22][23][24]. On the other hand costunolide protects against oxidative stress [25].…”

“…Signaling involved in the effects of Costulonide includes stimulation of mitogen-activated kinases [20,26] as well as inhibition of the transcription factor NFκB [10,13,15] and the Wnt/β-Catenin Pathway [9]. The stimulation of apoptosis further involves mitochondria [19,27].…”