[Cu(<i>o</i>‑phthalate)(phenanthroline)]
Exhibits Unique Superoxide-Mediated NCI-60 Chemotherapeutic Action
through Genomic DNA Damage and Mitochondrial Dysfunction
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Abstract
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