The efficiency of
nitrogen mustards (NMs), among the first chemotherapeutic agents against
cancer, is limited by their monotonous mechanism of action (MoA). And tumor hypoxia is a significant obstacle in the attenuation of the chemotherapeutic efficacy. To repurpose the drug and combat
hypoxia, herein, we constructed an organo-Ir(III)
prodrug, IrCpNM, with the composition of a
reactive oxygen species (ROS)-inducing moiety (Ir-arene fragment)-a hypoxic responsive moiety (azo linker)-
a DNA-alkylating moiety (
nitrogen mustard), and realized DNA damage response (DDR)-mediated autophagy for hypoxic
lung cancer therapy for the first time.
Prodrug IrCpNM could upregulate the level of
catalase (CAT) to catalyze the decomposition of excessive H2O2 to O2 and downregulate the expression of the
hypoxia-inducible factor (HIF-1α) to relieve
hypoxia. Subsequently, IrCpNM initiates the quadruple synergetic actions under
hypoxia, as simultaneous ROS promotion and
glutathione (GSH) depletion to enhance the redox disbalance and severe oxidative and cross-linking
DNA damages to trigger the occurrence of DDR-mediated autophagy via the ATM/Chk2 cascade and the PIK3CA/PI3K-AKT1-mTOR-RPS6KB1 signaling pathway. In vitro and in vivo experiments have confirmed the greatly antiproliferative capacity of IrCpNM against the hypoxic solid
tumor. This work demonstrated the effectiveness of the DNA damage-responsive organometallic
prodrug strategy with the microenvironment targeting system and the rebirth of traditional chemotherapeutic agents with a new anticancer mechanism.