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

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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 IC50 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.

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Abbreviations

BAX:

Bcl2-associated X-protein

Bcl-2:

B cell lymphoma 2 protein

BHT:

Butylhydroxytoluene

CA:

Chromosomal aberrations

CHO cells:

Chinese hamster ovary cells

GSH:

Glutathione

MI:

Mitotic index

MN:

Micronucleus

NAC:

N-acetyl cysteine

phospho-histone H3 (ser10):

Phosphorylated from of histone-3 at serine 10 position

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Acknowledgements

The author S.S.S.N.Rao (CSIR-UGC fellow) sincerely thank the University Grants Commission, New Delhi, for providing fellowship. The facilities provided due respect to the Director for permitting us to carry out the research work at the CSIR-IICT campus. We are very thankful to Dr. Kiranmayee Rao (UGC-Postdoctoral Fellow) and Dr. Bhuvaneswari Chodisetti (UGC-Postdoctoral Fellow) for their valuable guidance in documentation and Dr. Archnagiri, Assistant professor, Centre for Biotechnology, JNTU, for her valuable scientific inputs.

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Authors and Affiliations

  1. Genetic Toxicology Laboratory, Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India

    Soma Shiva Nageswara Rao Singireesu & Sunil Misra

  2. Biomaterials Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India

    Sujan Kumar Mondal

  3. Chemical Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India

    Suresh Yerramsetty

  4. Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India

    Nivedita Sahu

  5. Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India

    Suresh Babu K

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Singireesu, S.S.N.R., Misra, S., Mondal, S.K. et al. Costunolide induces micronuclei formation, chromosomal aberrations, cytostasis, and mitochondrial-mediated apoptosis in Chinese hamster ovary cells. Cell Biol Toxicol 34, 125–142 (2018). https://doi.org/10.1007/s10565-017-9411-z

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