Targeting oncogenic mutations in colorectal cancer using cryptotanshinone

PLoS One. 2021 Feb 17;16(2):e0247190. doi: 10.1371/journal.pone.0247190. eCollection 2021.

Abstract

Colorectal cancer (CRC) is one of the most prevalent types of cancer in the world and ranks second in cancer deaths in the US. Despite the recent improvements in screening and treatment, the number of deaths associated with CRC is still very significant. The complexities involved in CRC therapy stem from multiple oncogenic mutations and crosstalk between abnormal pathways. This calls for using advanced molecular genetics to understand the underlying pathway interactions responsible for this cancer. In this paper, we construct the CRC pathway from the literature and using an existing public dataset on healthy vs tumor colon cells, we identify the genes and pathways that are mutated and are possibly responsible for the disease progression. We then introduce drugs in the CRC pathway, and using a boolean modeling technique, we deduce the drug combinations that produce maximum cell death. Our theoretical simulations demonstrate the effectiveness of Cryptotanshinone, a traditional Chinese herb derivative, achieved by targeting critical oncogenic mutations and enhancing cell death. Finally, we validate our theoretical results using wet lab experiments on HT29 and HCT116 human colorectal carcinoma cell lines.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Death / drug effects
  • Cell Death / genetics
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics*
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Mutation / genetics
  • Phenanthrenes / therapeutic use*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics

Substances

  • Phenanthrenes
  • cryptotanshinone

Grants and funding

This work was supported in part by the US National Science Foundation under Grants ECCS-1609236 and ECCS-1917166 and in part by the TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering (CBGSE) startup funds to A.D. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.