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  2. Daucosterol disturbs redox homeostasis and elicits oxidative-stress mediated apoptosis in A549 cells via targeting thioredoxin reductase by a p53 dependent mechanism

Daucosterol disturbs redox homeostasis and elicits oxidative-stress mediated apoptosis in A549 cells via targeting thioredoxin reductase by a p53 dependent mechanism

  • Eur J Pharmacol. 2019 Jul 15;855:112-123. doi: 10.1016/j.ejphar.2019.04.051.
Tamilselvam Rajavel 1 Gunasekeran Banu Priya 1 Venkatesan Suryanarayanan 2 Sanjeev Kumar Singh 2 Kasi Pandima Devi 3
Affiliations

Affiliations

  • 1 Department of Biotechnology, Science Campus, Alagappa University, Karaikudi, 630 003, Tamil Nadu, India.
  • 2 Computer Aided Drug Design and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikud, 630003, Tamil Nadu, India.
  • 3 Department of Biotechnology, Science Campus, Alagappa University, Karaikudi, 630 003, Tamil Nadu, India. Electronic address: [email protected].
Abstract

Daucosterol (DS) is a plant phytosterol which is shown to induce oxidative stress mediated Apoptosis in various Cancer cell lines. However, the molecular mechanism underlying its cellular action has not been documented against Non- Small Cell Lung Cancer (NSCLC). Therefore, we attempted to decipher the mechanisms responsible for DS-induced anti-proliferation on human NSCLC cells. The present study showed, DS strongly inhibits the growth of A549 cells after 72 h time point with an IC50 value of ∼20.9 μM. Further DS elicits increased Reactive Oxygen Species level and promote intrinsic apoptotic cell death on A549 cells as evidenced by increased expression of Caspase-3, caspase-9, Bax, PARP inactivation, cytochrome-c release, and diminished expression of Bcl-2 protein. DS failed to display its apoptotic actions upon pretreatment with the Reactive Oxygen Species Inhibitor NAC (N-acetyl cysteine). Indeed, apoptotic signal which was enhanced through p53/p21 activation and knockdown of p53 expression also moderately affected the DS induced Apoptosis. In addition, DS preferentially inhibited the cell growth of p53 wild-type NSCLC cell lines than the mutant p53 models. Further, we show that inhibition of Thioredoxin (TrxR) redox system is principally associated with DS induced oxidative stress mediated apoptotic cell death on A549 cells. Moreover, we also demonstrated that DS stably interacted with serine residues in TrxR active sites. The obtained results confirmed that the anti-proliferative mechanism and increased Reactive Oxygen Species level of DS was associated with down-regulation of TrxR1 pathway which triggers the p53 mediated intrinsic apoptotic mode of cell death in NSCLC cells.

Keywords

Apoptosis; Daucosterol; Lung cancer; Reactive oxygen species; Thioredoxin redox system.

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