DNA-targeted antitumor agents have played an important role in treating aggressive forms of cancer and saving lives for the past few decades. To unravel the mechanism of a potent platinum-acridine antitumor agent, a Pearson correlation analysis of activity data acquired by the National Cancer Institute (NCI) in 60 cancer cell lines was performed. Importantly, platinum-acridines show up to 1000-fold higher activity in certain cancers, such as non-small-cell lung cancer, than other major oncology drugs. The results demonstrate that the SLC47A1 gene, which encodes the membrane transport protein hMATE1, plays a critical role in promoting the nanomolar potency of the platinum-acridine agent. The chemosensitivity profile of the test compound was then further investigated using Gene Set Enrichment Analysis (GSEA) in conjunction with gene ontology and curated gene sets of the MSigDB database for potential clues related to specific genes that may play a role in the mechanism of the platinum-acridine agent in tumor cells. The results suggest that DNA is a major target of platinum-acridine agents, which work best in cancers that show impaired DNA double-strand break repair. These findings will have to be validated by experiments in cancer cells. Additionally, the chemosensitivity screening data also provide strong evidence for the uniqueness of platinum-acridines considering the differences that exist between these agents and commercial anticancer drugs. The outstanding performance of platinum-acridines in various types of cancer cells is proposing a potentially more efficient cure combined with epigenetics sensitization in treating notorious cancers that are chemoresistant.

Using chemosensitivity screening and pharmaco-omics analysis to unravel the mechanism of platinum-acridine antitumor agents

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.