Developing strategies for the radiosensitization of cancer cells by the inhibition of genes, which harbor low toxicity to normal cells, will be useful for improving cancer radiotherapy. Here, we focused on a β-site of amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1; β-secretase, memapsin-2). By functional inhibition of this peptidase by siRNA, it has also recently been shown that the DNA strand break marker, γH2AX foci, increased, suggesting its involvement in DNA damage response. To investigate this possibility, we knocked down BACE1 with siRNA in cancer cell lines, and sensitization to γ-irradiation was examined by a colony formation assay, γH2AX foci and level analysis, and flow cytometry. BACE1 knockdown resulted in the sensitization of HeLa, MDA-MB-231, U2OS, and SAOS cells to γ-irradiation in a diverse range. BACE1 knockdown showed a weak radiosensitization effect in osteosarcoma U2OS cells, which has a normal p53 function. HeLa and SAOS cells, which harbor p53 dysfunction, exhibited a greater level of radiosensitization. These results suggest that BACE1 may be a potential target for the radiosensitization in particular cancer cells.

Despite advances in targeted therapies, treatment resistance and disease recurrence remain major obstacles in leukemia management. Structural modification of clinically successful kinase inhibitors represents a promising approach for discovering novel anti-leukemic agents with improved biological activities. In the present study, we investigated the anti-leukemic activity and mechanism of action of MO2455, a newly synthesized imatinib-derived compound, in monocytic leukemia U937, THP−1, and T-cell leukemia CCRF-CEM cells. MO2455 showed substantial cytotoxic activity against all three cell lines, with IC₅₀ values of 0.83 μM, 0.43 μM, and 0.57 μM in U937, THP−1, and CCRF-CEM cells, respectively. Treatment with MO2455 induced early mitochondrial membrane depolarization, internucleosomal DNA laddering, a significant accumulation of sub−G1 population and increased Annexin V positivity, suggesting typical apoptosis without cell cycle arrest in U937 cells. MO2455 induced γ-H2AX induction and upregulated the pro-apoptotic NOXA and BBC3 genes. THP−1 and CCRF-CEM cells displayed distinct large DNA fragmentation with smearing. In PBMCs from two healthy donors, IC₅₀ values were 0.99 and 0.60 μM, respectively, although the cells remained morphologically healthy without obvious extensive cell death. Overall, MO2455 exhibits substantial anti-leukemic activity and induces cell death through apoptosis and other mechanisms, supporting further investigation as an anti-leukemic agent.

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) with radiation therapy can enhance the sensitivity of cancer cells by inhibiting DNA repair pathways. To determine the most suitable PARP inhibitor for radiosensitization in cancer cells, we compared various types of clinically used PARPis in lung cancer A549 cells. We found that most PARP inhibitors showed radiosensitization effects on A549 cells. ER10 values for talazoparib, olaparib rucaparib, ABT888 and niraparib were 1.5, 1.8, 2.8, 1.4, and 1.4, respectively. Talazoparib showed a radiosensitization effect at its lowest concentration. Talazoparib is a potent PARP inhibitor and has been used in clinical settings for several types of cancer as an anti-cancer agent. We thus focused on how talazoparib causes radiosensitization in lung cancer A549 cells. As a result of the combination of talazoparib and γ-irradiation, we observed an increased level of cellular senescence accompanied by a decrease in mitochondrial membrane potential. When the p21 gene was knocked down, both the decrease in mitochondrial membrane potential and senescence level were attenuated, suggesting that p21 is involved in senescence induction after γ-irradiation combined with talazoparib treatment. Taken together, we showed that PARP inhibitor talazoparib treatment in combination with γ-irradiation causes cellular senescence in lung cancer cells, involving p21 function.