KU-55933

The interaction of Tip60 with ATM and DNA-PK was investigated using the specific inhibitors KU55933 and NU7441, respectively. Downregulation of Tip60 enhances the radiation sensitivity of both glioma cells and markedly elevates the radiation sensitivity when combined with DNA-PKi. Therefore, treatment with DNA-PK inhibitors represents a promising approach to augment the radiation sensitivity of glioma cell lines with deficient Tip60 activity in a synergistic manner.

Notably, Na2SeO3-induced ferroptosis was inhibited by ATM kinase inhibitor KU55933 or siATM, suggesting that Na2SeO3-induced ferroptosis was mediated by ATM protein in MDA-MB-231 cells. Our findings suggest a therapeutic strategy by ferroptosis against TNBC and deepened our understanding of ATM function.

For the examination of the function of pATM in VM formation by GSLCs, ATM knockdown by shRNAs and deactivated via ATM phosphorylation inhibitor KU55933 were studied...VM may predict a poor GBM prognosis and is associated with pATM expression. We propose that pATM promotes VM through extracellular matrix modulation and VE-Cadherin / pVEGFR-2 activation, thereby highlighting ATM activation as a potential target for enhancing anti-angiogenesis therapies for GBM.

The standard first-line therapy for OC involves cytoreductive surgical debulking followed by chemotherapy based on platinum and paclitaxel. Using an ATM inhibitor, KU55933, effectively reversed the cisplatin resistance phenotype. In conclusion, our results suggest that met can antagonize the effects of cDDP in specific types of OC cells, leading to a reduction in the chemotherapeutic efficacy of cDDP.

Positive correlation was seen between ATM activity and CD13 protein expression using both "wildtype" (WT) and knockout (KO) ataxia telangiectasia (AT) cells through western blotting; with the same effect shown when treating neuroblastoma cancer cell line SH-SY5Y, as well as AT-WT cells, with ATM inhibitor (ATMi; KU55933)...This suggests an epistatic effect, and that both proteins may be acting in the same signaling pathway that influences cell migration. This work indicates a novel functional interaction between ATM and CD13, suggesting ATM may negatively regulate the degradation of CD13, and subsequently cell migration.

Collectively, our results revealed that kaempferol from A. officinarum inhibits the cell cycle by regulating the ATM/CHEK2/KNL1 pathway in HCC cells. In summary, our research presents an innovative supplementary strategy for HCC treatment.

KU-55933 was predicted as a putative therapeutic drug for BC targeting VAMP7. VAMP7 was upregulated in BC tissue and correlated with poor prognosis of BC patients. VAMP7 may promote BC progression by targeting the cell cycle pathway.

Further analysis revealed that KU-55933 potentiates Olaparib-induced cell apoptosis by inhibiting ATM phosphorylation. Our study demonstrates that inhibiting ATM could enhance the sensitivity of endometrial cancer to Olaparib, thereby providing a potential alternative treatment for the clinical treatment of endometrial cancer.

Inhibition of ATM reduced both glycolytic enzymes and OXPHOS levels in oncogene-driven cancer cells and enhanced apoptosis induced by driver inhibitors thus highlighting the possibility to use ATM and the driver inhibitors in combined regimens of anticancer therapy in vivo.

Of them, two market drugs approved by the Food and Drug Administration (AT-13387 and KU-55933) have emerged as candidates for HCC study. This new signature panel may serve as a potential prognostic marker, engendering the possibility of novel personalized therapy with classification of HCC patients.

In particular, we focused on ATM/ATR involved in DNA damage response (DDR); PKM2, PDK1, LDH-A and complex I of OXPHOS involved in energy metabolism and Bcl-2/Bcl-xL involved in antiapoptotic processes.Material and MethodsH1993, H1975 and A549 oncogene-driven NSCLC cells were treated with TKIs (crizotinib, osimertinib or erlotinib) and in parallel with a combination of two of selected NOA inhibitors (DCA, benserazide, oxamate, IACS-10759, KU55933, M4344 and ABT-263). Finally, PDKs inhibition with DCA caused a significant dose-dependent decrease of glucose consumption and increase of OXPHOS subunits.ConclusionOur preliminary data suggest that targeting these proteins may destabilize tumor environment thus coupling metabolic phenotype and DDR to drug resistance. The major translational relevance of this study is to exploit these new targets for innovative and improved therapeutic strategies in comparison to TKI therapies in NSCLC patients.

Besides, high-risk KIRC patients might benefit from ABT888, AZD6244, AZD7762, Bosutinib, Camptothecin, CI1040, JNK inhibitor VIII, KU55933, Lenalidomide, Nilotinib, PLX4720, RO3306, Vinblastine, and ZM.447439; however, low-risk populations might benefit from Bicalutamide, FH535, and OSI906. Finally, calibration curves were used to validate the nomogram with a satisfactory predictive survival probability. In conclusion, this research provides useful insight that can aid and guide clinical practice and scientific research.

Drug resistance arises from FGF1-mediated differential activation of high-fidelity homologous recombination DNA damage repair. FGFR and ATM inhibitors reverse platinum drug resistance, highlighting novel combination chemotherapy approaches for future clinical trial evaluation.

High-scored patients had a poor prognosis and higher tumor mutation burden (TMB), they were more sensitive to four LUAD therapies (erlotinib, XA V939, gefitinib, and KU-55933) and more clinically responsive to PD-L1 treatment. Our work revealed the potential role of RNA modification patterns in TME, genetic variation, targeted inhibitor therapy, and immunotherapy. Identifying RNA modification pattern of LUAD patients help understand the characteristics of TME and may promote the development of immunotherapy strategies.

KU55933 can potently inhibit the activity of ABCG2 in CRC.

More importantly, it was observed that combination of ACY‑1215 and ATM inhibitors exhibited markedly more potent antitumor activity than the individual compound in xenograft mouse models of breast cancer with mutant p53. Collectively, our results demonstrated that ACY‑1215 is a novel chemotherapeutic agent that could restore mutant p53 function in cancer cells with strong antitumor activity, either alone or in combination with inhibitors of the ATM protein kinase.

The circadian clock gene BMAL1 inhibits the proliferation of NPC cell line CNE1, arrests cell cycle in the G0/G1 phase by up-regulate the expression of P21,P27 and P53.The response of ATM/ATR pathway could be activated after radiotherapy, the overexpression of Bmal1 gene could up-regulate the expression of ATM/ATR pathway upstream genes such as p-chk1 and p-chk2,then inhibited the activity of downstream Cyclin-CDK complexes by phosphorylated CDC25A and CDC25C,finally achieved the function of blocking cell cycle after radiotherapy.

We also observed downregulation of ATM and its phosphorylation after nerolidol treatment; furthermore, treatment with KU-55933, an ATM kinase inhibitor, mimicked the inhibitory effects of nerolidol treatment on cell proliferation and Akt phosphorylation. In conclusion, nerolidol displayed anti-UF activity in a leiomyoma cell model via ROS-induced DNA damage and G1 phase cell cycle arrest by inhibiting the expression and activation of the ATM/Akt pathway. Our data suggests that nerolidol is a potential therapeutic agent for UF.

The results showed that the expression of ATM and BRCA1 was downregulated in BQ-associated HNC, as the BQ ingredient arecoline could suppress the expression of both genes. Transcriptomic analysis showed that inhibition of ATM kinase by KU55933 induced apoptosis signaling and potentiated cisplatin-induced cytotoxicity. These data unveil poor prognosis in the HNC patient subgroup with low expression of ATM and BRCA1 and support the notion of ATM-targeted therapy.

Inhibitions of ATM and ATR potentiated the cytotoxic effects of DNA damaging agents in CCA cells, especially p53 defective HuCCA1 and RMCC1 cell lines.

Our study reveals that HSP90 and ATR inhibitor combination treatment may be an effective therapeutic approach for Ewing's sarcoma irrespective of the p53 status.

KU-55933 treatment also inhibits tumor growth and metastasis in vivo in mouse mammary tumors through inhibition of GLUT1 translocation and vimentin expression. These results suggest that ATM acts as a promoter of tumorigenesis in cancer cells with overactivated Akt, and KU-55933 induces apoptosis and inhibits motility by blocking GLUT1-mediated glucose uptake and glycolysis in these cancer cells, which may lead to the use of KU-55933 and its analogs as new preventive or therapeutic agents against cancer.

Here, we investigate the impact of EGC on CSC chemoresistance.CD24Hi-CD44Hi CSC were FACS-isolated from human colon cancer primary tumors or cell lines and 3D-grown in the presence of murine or human EGC seeded on Transwell filters in vitro in the presence of the chemotherapeutic drug 5-Fluorouracil (5-FU) or injected subcutaneously with(out) EGC in vivo in 5-FU treated-immunodeficient mice...Impact of inhibition of ATM activity and ATM activation by the Mre11-Rad50-Nbs1 (MRN) complex in CSC was tested using 0.1µM KU-55933 and 12µM mirin...Mass spectrometric analyses revealed that IGFBP7, a putative ATM activator, was >100 times more abundant in the CM of 5-FU-treated EGC vs. untreated EGC.Our data strongly indicate that EGC promote CSC chemoresistance via increased ATM signaling. Future studies will investigate the implication of IGFBP7 and downstream targets of ATM involved in DNA repair.

The present evidence indicates that 14c induced DNA damage responses in RCC and augmented γδ T cell-mediated cytotoxicity primarily through NKG2D/NKG2DLs pathways, suggesting potential cancer immunotherapy for harnessing γδ T cells and small compounds that induce DNA damage responses.

In this study, EBV-infected cell lines derived from gastric cancers and Burkitt lymphomas were incubated with HIF-1α-stabilizing drugs: the iron chelator deferoxamine (Desferal [DFO]), a neddylation inhibitor (pevonedistat [MLN-4924]), and a prolyl hydroxylase inhibitor (roxadustat [FG-4592])...Conversely, KU-55933, a drug that inhibits ataxia telangiectasia mutated, thereby preventing p53 phosphorylation, inhibited DFO-induced EBV reactivation...Fortunately, p53 phosphorylation can also be provided by drugs such as Nutlin-3, leading to synergistic reactivation of EBV. These findings indicate that some HIF-1α-stabilizing drugs may be helpful as part of a lytic-induction therapy for treating patients with EBV-positive malignancies that contain wild-type p53.

The PIKK inhibitors applied at non-cytotoxic concentrations: caffeine (1 mM) and KU55933 (2.5 μM) had no significant influence on the DBC cytotoxicity, however NU7026 (5 μM) caused significant increase in the cell viability by about 25%...The obtained results confirm that DBC is cytotoxic and causes damage to the genetic material including DSB. The DNA-PK inhibitor, NU7026 increases cell viability after exposure to DBC and reduces DNA damage, what indicates an important role of the sensor kinase in mediating the effect.

Our study provides a proof-of-concept that warrants the clinical evaluation of DCZ3301 as a novel anti-tumor compound against BTZ resistance in MM.

Characterized sensitivity of models to ATRi as well as inhibitors of checkpoint kinase 1 (Chk1, LY2606368), ataxia-telangiectasia mutated (ATM, KU55933) poly (ADP-ribose) polymerase (PARP, BMN-673 and MK-4827) and combination with cisplatin (CDDP) and a cyclin D kinase 4/6 inhibitor (PD-0332991). We find that metronomic treatment of ovarian cancer cells with ATRi induces resistance to ATRi and Chk1i. ATRi-resistant cells remain sensitive to PARP inhibitors and are sensitized to CDDP when combined with ATRi. ATRi-resistant cells further exhibit a G1-phase cell cycle arrest response to ATRi and alterations in G1/S phase proteins, including loss of CDC25A.

Characterized sensitivity of models to ATRi as well as inhibitors of checkpoint kinase 1 (Chk1, LY2606368), ataxia-telangiectasia mutated (ATM, KU55933) poly (ADP-ribose) polymerase (PARP, BMN-673 and MK-4827) and combination with cisplatin (CDDP) and a cyclin D kinase 4/6 inhibitor (PD-0332991). We find that metronomic treatment of ovarian cancer cells with ATRi induces resistance to ATRi and Chk1i. ATRi-resistant cells remain sensitive to PARP inhibitors and are sensitized to CDDP when combined with ATRi. ATRi-resistant cells further exhibit a G1-phase cell cycle arrest response to ATRi and alterations in G1/S phase proteins, including loss of CDC25A.

Characterized sensitivity of models to ATRi as well as inhibitors of checkpoint kinase 1 (Chk1, LY2606368), ataxia-telangiectasia mutated (ATM, KU55933) poly (ADP-ribose) polymerase (PARP, BMN-673 and MK-4827) and combination with cisplatin (CDDP) and a cyclin D kinase 4/6 inhibitor (PD-0332991). We find that metronomic treatment of ovarian cancer cells with ATRi induces resistance to ATRi and Chk1i. ATRi-resistant cells remain sensitive to PARP inhibitors and are sensitized to CDDP when combined with ATRi. ATRi-resistant cells further exhibit a G1-phase cell cycle arrest response to ATRi and alterations in G1/S phase proteins, including loss of CDC25A.

Characterized sensitivity of models to ATRi as well as inhibitors of checkpoint kinase 1 (Chk1, LY2606368), ataxia-telangiectasia mutated (ATM, KU55933) poly (ADP-ribose) polymerase (PARP, BMN-673 and MK-4827) and combination with cisplatin (CDDP) and a cyclin D kinase 4/6 inhibitor (PD-0332991). We find that metronomic treatment of ovarian cancer cells with ATRi induces resistance to ATRi and Chk1i. ATRi-resistant cells remain sensitive to PARP inhibitors and are sensitized to CDDP when combined with ATRi. ATRi-resistant cells further exhibit a G1-phase cell cycle arrest response to ATRi and alterations in G1/S phase proteins, including loss of CDC25A.

Specific PDRG1 gene silencing may inhibit the growth and metastasis of gastric cancer cells through the activation of ATM/p53 pathway.