2 research outputs found
[Cu(<i>o</i>‑phthalate)(phenanthroline)] Exhibits Unique Superoxide-Mediated NCI-60 Chemotherapeutic Action through Genomic DNA Damage and Mitochondrial Dysfunction
The <i>in cellulo</i> catalytic production of reactive
oxygen species (ROS) by copper(II) and iron(II) complexes is now recognized
as a major mechanistic model in the design of effective cytotoxins
of human cancer. The developmental complex, [Cu(<i>o</i>-phthalate)(1,10-phenanthroline)] (<b>Cu-Ph</b>), was recently
reported as an intracellular ROS-active cytotoxic agent that induces
double strand breaks in the genome of human cancer cells. In this
work, we report the broad-spectrum action of <b>Cu-Ph</b> within
the National Cancer Institute’s (NCI) Developmental Therapeutics
Program (DTP), 60 human cancer cell line screen. The activity profile
is compared to established clinical agentsvia the COMPARE
algorithmand reveals a novel mode of action to existing metal-based
therapeutics. In this study, we identify the mechanistic activity
of <b>Cu-Ph</b> through a series of molecular biological studies
that are compared directly to the clinical DNA intercalator and topoisomerase
II poison doxorubicin. The presence of ROS-specific scavengers was
employed for <i>in vitro</i> and intracellular evaluation
of prevailing radical species responsible for DNA oxidation with superoxide
identified as playing a critical role in this mechanism. The ROS targeting
properties of <b>Cu-Ph</b> on mitochondrial membrane potential
were investigated, which showed that it had comparable activity to
the uncoupling ionophore, carbonyl cyanide <i>m</i>-chlorophenyl
hydrazine. The induction and origins of apoptotic activation were
probed through detection of Annexin V and the activation of initiator
(8,9) and executioner caspases (3/7) and were structurally visualized
using confocal microscopy. Results here confirm a unique radical-induced
mechanistic profile with intracellular hallmarks of damage to both
genomic DNA and mitochondria
Regulating Bioactivity of Cu<sup>2+</sup> Bis-1,10-phenanthroline Artificial Metallonucleases with Sterically Functionalized Pendant Carboxylates
The
synthetic chemical nuclease, [Cu(1,10-phenanthroline)<sub>2</sub>]<sup>2+</sup>, has stimulated research within metallonuclease development
and in the area of cytotoxic metallodrug design. Our analysis reveals,
however, that this agent is “promiscuous” as it binds
both dsDNA and protein biomolecules, without specificity, and induces
general toxicity to a diversity of cell lineages. Here, we describe
the synthesis and characterization of small-molecule metallonucleases
containing the redox-active cation, [Cu(RCOO)(1,10-phen)<sub>2</sub>]<sup>+</sup>, where 1,10-phen = 1,10-phenanthroline and R = −H,
−CH<sub>3</sub>, −C<sub>2</sub>H<sub>5</sub>, −CH(CH<sub>3</sub>)<sub>2</sub>, and −C(CH<sub>3</sub>)<sub>3</sub>.
The presence of coordinated carboxylate groups in the complex cation
functions to enhance dsDNA recognition, reduce serum albumin binding,
and offer control of toxicity toward human cancer cells, Gram positive
and negative bacteria, and fungal pathogens. The induction of genomic
dsDNA breaks (DSBs) were identified in ovarian adenocarcinoma cells
using immunodetection of γ-H2AX. Formate, acetate, and pivalate
functionalized complexes induced DSBs in a higher percentage of cells
compared with [Cu(1,10-phen)<sub>2</sub>]<sup>2+</sup>, which supports
the importance of inner-sphere modification toward enhancing targeted
biological application