1. Academic Validation
  2. Cytostatic and Cytotoxic Natural Products against Cancer Cell Models

Cytostatic and Cytotoxic Natural Products against Cancer Cell Models

  • Molecules. 2019 May 26;24(10):2012. doi: 10.3390/molecules24102012.
Taotao Ling 1 Walter H Lang 2 Julie Maier 3 Marizza Quintana Centurion 4 Fatima Rivas 5
Affiliations

Affiliations

  • 1 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital. 262 Danny Thomas Place. Memphis, TN 38105-3678, USA. [email protected].
  • 2 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital. 262 Danny Thomas Place. Memphis, TN 38105-3678, USA. [email protected].
  • 3 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital. 262 Danny Thomas Place. Memphis, TN 38105-3678, USA. [email protected].
  • 4 Dirección de Investigación Biológica/Museo Nacional de Historia Natural del Paraguay, Casilla de Correo 19.004. Sucursal 1, Campus UNA. 169 CDP San Lorenzo, Central XI, Paraguay. [email protected].
  • 5 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital. 262 Danny Thomas Place. Memphis, TN 38105-3678, USA. [email protected].
Abstract

The increasing prevalence of drug resistant and/or high-risk cancers indicate further drug discovery research is required to improve patient outcome. This study outlines a simplified approach to identify lead compounds from Natural Products against several Cancer cell lines, and provides the basis to better understand structure activity relationship of the natural product cephalotaxine. Using high-throughput screening, a natural product library containing fractions and pure compounds was interrogated for proliferation inhibition in acute lymphoblastic leukemia cellular models (SUP-B15 and KOPN-8). Initial hits were verified in control and counter screens, and those with EC50 values ranging from nanomolar to low micromolar were further characterized via mass spectrometry, NMR, and cytotoxicity measurements. Most of the active compounds were alkaloid Natural Products including cephalotaxine and homoharringtonine, which were validated as protein synthesis inhibitors with significant potency against several Cancer cell lines. A generated BODIPY-cephalotaxine probe provides insight into the mode of action of cephalotaxine and further rationale for its weaker potency when compared to homoharringtonine. The steroidal Natural Products (ecdysone and muristerone A) also showed modest biological activity and protein synthesis inhibition. Altogether, these findings demonstrate that Natural Products continue to provide insight into structure and function of molecules with therapeutic potential against drug resistant Cancer cell models.

Keywords

antiproliferation agents; cancer; cephalotaxine; natural product alkaloids; protein synthesis inhibition.

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