Effects of ellipticine on ALDH1A1-expressing breast cancer stem cells—an in vitro and in silico study
Targeting breast cancer stem cells (BCSCs) offers a promising strategy for breast cancer treatment. We examined the plant alkaloid ellipticine for its efficacy to inhibit the expression of aldehyde dehydrogenase 1 class A1 (ALDH1A1)-positive BCSCs by in vitro and in silico methods. At 3 mM concentration, ellipticine decreased the expression of ALDH1A1-positive BCSCs by 62 % (p = 0.073) in the MCF7 cell line and by 53 % (p = 0.024) in the SUM159 cell line compared to vehicle-treated cultures. Ellipticine significantly reduced the formation of mammospheres, whereas paclitaxel enhanced mammosphere formation in both the treated cell lines. Interestingly, when treated with a combination of ellipticine and paclitaxel, the percentage of ALDH1A1-positive BCSCs dropped by several fold in vitro. A homology model of Homo sapiens ALDH1A1 was built using the crystal structure of NAD-bound sheep liver class I aldehyde dehydrogenase [PDB ID: 1BXS] as a template. Molecular simulation and docking studies revealed that the amino acids Asn-117 and Asn-121, Glu-249, Cys-302, and Gln-350, present in the active site of human ALDH1A1, played a vital role in interacting with the drug. The present study suggests that ellipticine reduces the proliferation and self-renewal ability of ALDH1A1-positive BCSCs and can be used in combination with a cytotoxic drug like paclitaxel for potential targeting of BCSCs.
KeywordsBreast cancer stem cell ALDH1A1 Ellipticine Modeller9v11 Dynamics Anticancer therapeutics
At the Tumor Biology Laboratory, National Institute of Pathology, New Delhi, India, we wish to thank Dr. Sourav Verma and Ms. Anvesha Malik for their help in the flow cytometry experiments. We also thank the BD Biosciences Flow Cytometry Core Group for the excellent support in cell sorting. SLP and PSC want to thank the Indian Council of Medical Research, New Delhi, Government of India for the financial support and RSC gratefully acknowledges the University Grant Commission, New Delhi, India for his fellowship.
Conflicts of interest
- 1.National Cancer Registry Programme. http://ncrpindia.org/PBCR_2006_2008/Chapter_2.pdf
- 39.Lindal E, Hess B. Gromacs 3.0: a package for molecular simulation and trajectory analysis. J Mol Model. 2001;7:306–17.Google Scholar
- 40.Berendsen H. Interaction models for water in relation to protein hydration. In: Pullman B, editor. Intermolecular forces. Dordrecht: Reidel; 1981. p. 331–42.Google Scholar
- 41.DeLano WL. The PyMOL molecular graphics system. SanCarlos: DeLano Scientific. http://wwwpymolorg (2006).
- 53.Wang X, Wu X, Wang C, Zhang W, Ouyang Y, Yu Y, He Z. Transcriptional suppression of breast cancer resistance protein (BCRP) by wild-type p53 through the NF-kappaB pathway in MCF-7 cells. FEBS Lett. 2010;584:3392–7.Google Scholar