MTH1 inhibitor amplifies the lethality of reactive oxygen species to tumor in photodynamic therapy

Abstract

Although photodynamic therapy (PDT) has been clinically applied tumor hypoxia still greatly restricts the performance of this oxygen-dependent oncological treatment. The delivery of oxygen donors to tumor may produce excessive reactive oxygen species (ROS) and damage the peripheral tissues. Herein, we developed a strategy to solve the hypoxia issue by enhancing the lethality of ROS. Before PDT, the ROS-defensing system of the cancer cells was obstructed by an inhibitor to MTH1, which is a key for the remediation of ROS-caused DNA damage. As a result, both nuclei and mitochondrial DNA damages were increased, remarkably promoting cellular apoptosis. The therapeutic results demonstrated that the performance of PDT can be improved by the MTH1 inhibitor, leading to efficient cancer cell killing effect in the hypoxic tumor. This strategy makes better use of the limited oxygen, holding the promise to achieve satisfactory therapeutic effect by PDT without generating redundant cytotoxic ROS.

Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives

“…Inhibitions of PRDX1 and MTH1 could introduce 8-oxo-dG at the 3′-ends of telomeric substrates, which could result in efficient inhibition of telomere extension by telomerase 46 . Additionally, photodynamic therapy (PDT) has been applied to achieve effective cancer treatment through the highly toxic ROS 53 , 54 , and accordingly MTH1 suppression was recently demonstrated to play a synergistic role for PDT on the basis of the improvement of cellular sensitivity to ROS in cancer cells 55 , 56 . These studies open new avenues for targeting oncogenic RAS and telomerase that are notoriously difficult anticancer targets by inhibiting MTH1, and also suggest that MTH1 inhibition might be suitable for polytherapy due to its synergistic effect.…”

Enhancement of tumor lethality of ROS in photodynamic therapy

“…Once the MTH1 inhibitor is combined with the active site of MTH1, it can successfully prevent the ROS defense system from weakening the ROS killing efficiency of the tumor and promoting tumor cell apoptosis 99 . Zhao et al 100 used MTH1 inhibitors to hinder the ROS defense system to improve the lethality of ROS against tumors and achieved a good tumor suppression effect when ROS production was limited. The research team used SiO 2 crosslinked nanomicelles as a carrier to deliver the MTH1 inhibitor TH588 together with the PS Ce6 to tumor tissue for PDT.…”

Learning from Nature: Bioinspired Chlorin-Based Photosensitizers Immobilized on Carbon Materials for Combined Photodynamic and Photothermal Therapy

“…During this execution, sub-cellular membranes are destroyed, leading to the excessive release of calcium ions and metabolic byproducts, which causes multiple forms of dysfunction and damage beyond repair [ 42 , 43 , 44 ]. The release of apoptogenic molecules, cytokines, and ROS cause lethal damage in neighboring tissues, known as the bystander effect, which can propagate to a certain extent [ 45 , 46 ]. PDT may induce programmed cell death through the activation of autophagic cell death and the induction of apoptosis.…”