Journal
MOLECULAR ONCOLOGY
Volume 15, Issue 2, Pages 381-406Publisher
WILEY
DOI: 10.1002/1878-0261.12849
Keywords
cancer cell lines; DNA mutation; drug response; gene expression; natural products; single nucleotide variation
Categories
Funding
- National Cancer Institute, National Institutes of Health [HHSN261200800001E]
- Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research
- National Cancer Institute's Beau Biden Cancer MoonshotSM Program
Ask authors/readers for more resources
Investigation revealed associations between gene expression and the response of cancer cells to specific categories of natural products, suggesting potential mechanisms of action and paving the way for future targeted cancer chemotherapy agent discovery and design.
Natural products remain a significant source of anticancer chemotherapeutics. The search for targeted drugs for cancer treatment includes consideration of natural products, which may provide new opportunities for antitumor cytotoxicity as single agents or in combination therapy. We examined the association of molecular genomic features in the well-characterized NCI-60 cancer cell line panel with in vitro response to treatment with 1302 small molecules which included natural products, semisynthetic natural product derivatives, and synthetic compounds based on a natural product pharmacophore from the Developmental Therapeutics Program of the US National Cancer Institute's database. These compounds were obtained from a variety of plant, marine, and microbial species. Molecular information utilized for the analysis included expression measures for 23059 annotated transcripts, lncRNAs, and miRNAs, and data on protein-changing single nucleotide variants in 211 cancer-related genes. We found associations of expression of multiple genes including SLFN11, CYP2J2, EPHX1, GPC1, ELF3, and MGMT involved in DNA damage repair, NOTCH family members, ABC and SLC transporters, and both mutations in tyrosine kinases and BRAF V600E with NCI-60 responses to specific categories of natural products. Hierarchical clustering identified groups of natural products, which correlated with a specific mechanism of action. Specifically, several natural product clusters were associated with SLFN11 gene expression, suggesting that potential action of these compounds may involve DNA damage. The associations between gene expression or genome alterations of functionally relevant genes with the response of cancer cells to natural products provide new information about potential mechanisms of action of these identified clusters of compounds with potentially similar biological effects. This information will assist in future drug discovery and in design of new targeted cancer chemotherapy agents.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available