H2O2 enhances the anticancer activity of TMPyP4 by ROS-mediated mitochondrial dysfunction and DNA damage

Abstract

Cancer is one of the diseases that threatens human health and is a leading cause of mortality worldwide.High levels of reactive oxygen species (ROS) have been observed in cancer tissues compared with normal tissues in vivo, and it is not yet known how this in uences chemotherapeutic drug action. Cationic porphyrin 5,10,15,20-tetra-(N-methyl-4-pyridyl) porphyrin (TMPyP4) is a photosensitizer used in photodynamic therapy (PDT) and a telomerase inhibitor used in the treatment of telomerase-positive cancer. Here, we investigated the anticancer activity of TMPyP4 in A549 and PANC cells cultured in H 2 O 2 .The results showed that compared to TMPyP4 alone, the combination of TMPyP4 and H 2 O 2 exhibited sensitization effects on cell viability and colony formation inhibition and apoptosis in A549 and PANC cells but had no effect in human normal MIHA cells. Mechanistically, the combination of TMPyP4 and H 2 O 2 activates high ROS and mitochondrial membrane potential in A549 and PANC cells, resulting in intense DNA damage and DNA damage responses. Consequently, compared to TMPyP4 alone, TMPyP4 and H 2 O 2 combined treatment upregulates the expression of BAX, cleaved caspase 3, and p-JNK, and downregulates the expression of Bcl-2 in A549 and PANC cells. Taken together, these data suggested that H 2 O 2 enhanced the anticancer activity of TMPyP4-mediated ROS-dependent DNA damage and related apoptotic protein regulation, revealing that the high ROS tumor microenvironment plays an important role in chemotherapeutic drug action.

Bruceine D and afatinib combination inhibits ovarian cancer cells proliferation and migration through DNA damage repair and EGFR pathway

“…Ultimately the crystals were dissolved using 500 μL acetic acid (33%), and the results were calculated by reading absorbance at 560 nm by using an automated Thermo Fisher Multiskan FC Microplate. 25…”

“…The slides were visualized by a Nikon Fluorescence Microscope, and the results were analyzed with CASP. 25…”

“…The combination index (CI) of BD interaction with afatinib was measured via the Chou–Talalay method. 25 The results were performed with the CompuSyn software, where CI < 1, = 1, and > 1 indicate synergistic, additive, and antagonistic effects, respectively.…”

“…Ultimately the crystals were dissolved using 500 mL acetic acid (33%), and the results were calculated by reading absorbance at 560 nm by using an automated Thermo Fisher Multiskan FC Microplate. 25 EdU staining assay A2780 and CP70 cells (5 3 10 4 cells/well in 12-well plates with coverslips) were added in BD or afatinib or the combination of BD and afatinib for 48 h. The 5-Ethynyl-2'deoxyuridine (EDU) Staining Proliferation Kit (Beyotime, China) was used to examine the cells. Ultimately, using Nikon Fluorescence Microscope to observe the cells.…”

Crosstalk between G-quadruplex and ROS

“…The mechanisms underlying G4-mediated ROS production in response to UV irradiation need further investigation. Interestingly, H 2 O 2 can enhance TMPyP4-induced DNA damage and provoke stronger DDR in cancer cells but not in the normal cells [ 105 ]. TMPyP4 inhibits tumor proliferation by directly targeting G4 [ 106 ].…”