Effects of ellipticine on ALDH1A1-expressing breast cancer stem cells--an in vitro and in silico study.

Abstract

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.

• Authors: Santhi Latha Pandrangi, Rajasekhar Chikati, Pradeep Singh Chauhan, Chitta Suresh Kumar, Anropa Banarji, Sunita Saxena
• Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine (Tumour Biol) Vol. 35 Issue 1 Pg. 723-37 (Jan 2014) ISSN: 1423-0380 [Electronic] Netherlands
• PMID: 23982874 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Ellipticines
• ellipticine
• Aldehyde Dehydrogenase 1 Family
• Aldehyde Dehydrogenase
• ALDH1A1 protein, human
• Retinal Dehydrogenase
• Paclitaxel

Topics

• Aldehyde Dehydrogenase (chemistry, genetics, metabolism)
• Aldehyde Dehydrogenase 1 Family
• Amino Acid Sequence
• Antineoplastic Agents (chemistry, pharmacology)
• Breast Neoplasms (genetics, metabolism)
• Catalytic Domain
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Ellipticines (chemistry, pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• MCF-7 Cells
• Molecular Docking Simulation
• Molecular Dynamics Simulation
• Molecular Sequence Data
• Neoplastic Stem Cells (drug effects, metabolism)
• Paclitaxel (pharmacology)
• Protein Binding
• Protein Conformation
• Retinal Dehydrogenase
• Spheroids, Cellular
• Tumor Cells, Cultured