Comparative Chemogenomics To Examine the Mechanism of Action of DNA-Targeted Platinum-Acridine Anticancer Agents

Abstract

Platinum-based drugs have been used to successfully treat diverse cancers for several decades. Cisplatin, the original compound of this class, cross-links DNA, resulting in cell cycle arrest and cell death via apoptosis. Cisplatin is effective against several tumor types, yet it exhibits toxic side effects and tumors often develop resistance. To mitigate these liabilities while maintaining potency, we generated a library of non-classical platinum-acridine hybrid agents and assessed their mechanisms of action using a validated genome-wide screening approach in Saccharomyces cerevisiae and in the distantly related yeast Schizosaccharomyces pombe. Chemogenomic profiles from both S. cerevisiae and S. pombe demonstrate that several of the platinum-acridines damage DNA differently than cisplatin based on their requirement for distinct modules of DNA repair.

Redesigning the DNA‐Targeted Chromophore in Platinum–Acridine Anticancer Agents: A Structure–Activity Relationship Study

“…[6] It also demonstrated that cytotoxic action on non-DNA targets involved in RNA metabolism as well as on components of the translational machinery (ribosomal subunits) compromise cell viability. [6] The distinct nucleic acid damage profile of P1 – B1 in cancer cells warrants further experimentation to determine if RNA-mediated mechanisms may be involved in its cell kill.…”

“…[3] They effectively inhibit DNA synthesis in treated cells and lead to stalled replication forks and DNA double-strand breaks, which elicits responses from specialized DNA damage recognition and repair modules. [6] In addition, the hybrid adducts are significantly more potent inhibitors of RNA polymerase II (Pol II)-mediated transcription than the cross-links. [7] Fluorescent post-labeling in whole lung cancer cells recently revealed high levels of DNA adducts in all phases of the cell cycle, both in the loosely packaged and the condensed chromatin.…”

“…[9] Hybrids derived from the general structure in Figure 1 effectively kill cancer cells at low-nanomolar concentrations, which places them among the most cytotoxic platinum-containing anticancer agents described in the literature to date. [6] …”

Transition Metal Intercalators as Anticancer Agents—Recent Advances

“…This activity has been attributed to the unique hybrid of DNA binding by these complexes which utilize both intercalation and nonfunctional adduct formation, which are more disruptive than those formed by cisplatin. The acridine moiety is able to intercalate whilst the platinum metal forms a monofunctional adduct with DNA adjacent to the intercalation site [35]. These lesions inhibit DNA synthesis through stalled replication forks and DNA double-strand breaks [35].…”

“…The acridine moiety is able to intercalate whilst the platinum metal forms a monofunctional adduct with DNA adjacent to the intercalation site [35]. These lesions inhibit DNA synthesis through stalled replication forks and DNA double-strand breaks [35]. Furthermore, these adducts inhibit RNA polymerase II-mediated transcription more prominently than compared to cross-links by cisplatin [36].…”