The effectiveness of existing systemic and targeted therapies remains limited in triple-negative breast cancer (TNBC) treatment. Much research has been conducted on reactive oxygen species (ROS)-media Show more
The effectiveness of existing systemic and targeted therapies remains limited in triple-negative breast cancer (TNBC) treatment. Much research has been conducted on reactive oxygen species (ROS)-mediated cancer cell death to overcome the shortcomings of the currently applied chemotherapeutic treatments. Herein, we have developed novel Ru(II)/Ir(III)-mediated triazolylpyridine complexes as ROS inducers. Upon entering the TNBC cells, the Ru(II) complex effectively accumulated in mitochondria and triggered the creation of ROS, facilitating dysfunction of mitochondria and oxidative DNA damage, ultimately causing death of cells through G2/M phase cell cycle arrest. Eventually, this complex induced the upregulation of BAX (pro-apoptotic protein) and downregulation of BCL-2 (antiapoptotic protein) and triggered the caspase 3/9 pathway and released cytochrome c in the cytosol for apoptosis. The complex JRu (RuII triazolylpyridine) significantly reduced the integrity and viability of TNBC 3D spheroids. Show less
DNA structure has many potential places where endogenous compounds and xenobiotics can bind. Therefore, xenobiotics bind along the sites of the nucleic acid with the aim of changing its structure, its Show more
DNA structure has many potential places where endogenous compounds and xenobiotics can bind. Therefore, xenobiotics bind along the sites of the nucleic acid with the aim of changing its structure, its genetic message, and, implicitly, its functions. Currently, there are several mechanisms known to be involved in DNA binding. These mechanisms are covalent and non-covalent interactions. The covalent interaction or metal base coordination is an irreversible binding and it is represented by an intra-/interstrand cross-link. The non-covalent interaction is generally a reversible binding and it is represented by intercalation between DNA base pairs, insertion, major and/or minor groove binding, and electrostatic interactions with the sugar phosphate DNA backbone. In the present review, we focus on the types of DNAâmetal complex interactions (including some representative examples) and on presenting the methods currently used to study them. Show less
Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we re Show more
Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we recount the evidence identifying the basic leucine zipper transcription factors ATF5, CEBPB, and CEBPD as targets for brain and other malignancies. We describe strategies that exploit the structures of the three factors to create inhibitory dominant-negative (DN) mutant forms that selectively suppress growth and survival of cancer cells. We then discuss and compare four peptides (CP-DN-ATF5, Dpep, Bpep and ST101) in which DN sequences are joined with cell-penetrating domains to create drugs that pass through tissue barriers and into cells. The peptide drugs show both efficacy and safety in suppressing growth and in the survival of brain and other cancers in vivo, and ST101 is currently in clinical trials for solid tumors, including GBM. We further consider known mechanisms by which the peptides act and how these have been exploited in rationally designed combination therapies. We additionally discuss lacunae in our knowledge about the peptides that merit further research. Finally, we suggest both short- and long-term directions for creating new generations of drugs targeting ATF5, CEBPB, CEBPD, and other transcription factors for treating brain and other malignancies. Show less