Systematic analysis of anti-cancer compound 6e

Open Access
Author:
Pei, Luxin
Area of Honors:
Biochemistry and Molecular Biology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Yanming Wang, Thesis Supervisor
  • David Scott Gilmour, Honors Advisor
  • Richard John Frisque, Faculty Reader
Keywords:
  • cancer
  • cancer therapy
  • autophagy
  • ER stress
Abstract:
The need for novel anti-cancer drugs is constantly under high demand due to the emergence of drug resistance. In order to increase the efficiency of understanding the working mechanism and genetic perturbation of new compounds, network maps are developed to simplify the identification process. These networks correlate the gene expression and biological function of new compounds to those of known drugs based on mRNA expression assayed on DNA microarrays. Based on these maps, novel anticancer compound, 6e, is shown to have similar gene expression with drugs such as thapsigargin tunicamycin, and tosedostat. The preliminary predictions of 6e mechanism are validated using biochemical analysis and imaging. Results showed the induction of cellular stress and the disruption of autophagy leading to cancer cell death by 6e, which corresponds with the working mechanism of thapsigargin and tosedostat predicted by the network maps. 6e can disrupt the progression of autophagy as a prosurvival mechanism, thus preventing cancer cells from escaping from drug induced stress and cell death. 6e is also tested in combination treatments with clinically used drugs. The potential synergistic effects of the drug combinations could lead to the discovery of better treatments for cancer. These results show the possibility of introducing 6e as a novel chemotherapy compound in cancer treatment as well as the prospect of generating networks on a larger scale to simplify the identification of novel drug mechanism.