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  3. β-Sitosterol targets Trx/Trx1 reductase to induce apoptosis in A549 cells via ROS mediated mitochondrial dysregulation and p53 activation

β-Sitosterol targets Trx/Trx1 reductase to induce apoptosis in A549 cells via ROS mediated mitochondrial dysregulation and p53 activation

  • Sci Rep. 2018 Feb 1;8(1):2071. doi: 10.1038/s41598-018-20311-6.
Tamilselvam Rajavel 1,  Pandian Packiyaraj 1,  Venkatesan Suryanarayanan 2,  Sanjeev Kumar Singh 2,  Kandasamy Ruckmani 3,  Kasi Pandima Devi 4
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, Karaikudi- 630003, Tamil Nadu, India.
  • 3 National Facility for Drug Development (NFDD) for Academia, Pharmaceutical and Allied Industries, Bharathidasan, Institute of Technology, Anna University, Tiruchirappalli, 620024, Tamil Nadu, India.
  • 4 Department of Biotechnology, Science Campus, Alagappa University, Karaikudi-630 003, Tamil Nadu, India. devikasi@yahoo.com.
PMID: 29391428 DOI: 10.1038/s41598-018-20311-6
Abstract

β-Sitosterol (BS), a major bioactive constituent present in Plants and vegetables has shown potent Anticancer effect against many human Cancer cells, but the underlying mechanism remain elusive on NSCLC cancers. We found that BS significantly inhibited the growth of A549 cells without harming normal human lung and PBMC cells. Further, BS treatment triggered Apoptosis via ROS mediated mitochondrial dysregulation as evidenced by Caspase-3 & 9 activation, Annexin-V/PI positive cells, PARP inactivation, loss of MMP, Bcl-2-Bax ratio alteration and cytochrome c release. Moreover, generation of ROS species and subsequent DNA stand break were found upon BS treatment which was reversed by addition of ROS scavenger (NAC). Indeed BS treatment increased p53 expression and its phosphorylation at Ser15, while silencing the p53 expression by pifithrin-α, BS induced Apoptosis was reduced in A549 cells. Furthermore, BS induced Apoptosis was also observed in NCI-H460 cells (p53 wild) but not in the NCI-H23 cells (p53 mutant). Down-regulation of Trx/Trx1 reductase contributed to the BS induced ROS accumulation and mitochondrial mediated apoptotic cell death in A549 and NCI-H460 cells. Taken together, our findings provide evidence for the novel anti-cancer mechanism of BS which could be developed as a promising chemotherapeutic drug against NSCLC cancers.

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