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Predicting Anticancer Drug Responses Using a Dual-Layer Incorporated Mobile Line-Drug Circle Product.
The air-breathing magur catfish (Clarias magur) regularly face the problem of exposure to high environmental ammonia (HEA) as one of the major pollutants in their natural habitats that causes considerable toxic effects at the cellular level including that of oxidative stress. The major objective of the present study was to demonstrate the antioxidant activity of endogenously produced nitric oxide (NO) to defend against the ammonia-induced oxidative stress in primary hepatocytes of magur catfish during exposure to HEA. Exposure to NH4Cl (5 mM) led to a significant increase of intracellular ammonia concentration with a sharp rise of hydrogen peroxide (H2O2) and malondialdehyde (MDA) concentrations within 3 h in primary hepatocytes, which decreased gradually at later stages of treatment. This phenomenon was accompanied by a significant increase of superoxide dismutase (SOD) and catalase (CAT) activities as a consequence of induction of corresponding genes. HEA exposure also led to the stimulation of NO production due to induction of inducible nitric oxide synthase (iNOS) activity, as a consequence of up-regulation of nos2 gene. Most interestingly, when NO production by hepatocytes under ammonia stress was blocked by adding certain inhibitors (aminoguanidine and BAY) in the culture media, there was a further rise of H2O2 and MDA concentrations in hepatocytes. These were accompanied by the lowering of SOD and CAT activities with less expression of corresponding genes. Thus, it can be contemplated that magur catfish uses the strategy of stimulation of NO production, which ultimately induces the SOD/CAT enzyme system to defend against the ammonia-induced oxidative stress. © 2020. Published by The Company of Biologists Ltd.Prostate cancer (PC) patients with tumors harboring defects in DNA-repair genes (DRD) generally do not respond well to AR-directed therapy. Furthermore, canonical pathways evolve during disease progression and may impact treatment with existing therapies. Due to the limited treatment options after failure of hormonal and taxane therapy, and the tumor heterogeneity induced by DRD, we sought to characterize the alterations in primary and metastatic PC. Tumors from 1027 advanced PC patients that underwent comprehensive genomic profiling for routine clinical care were reviewed to assess DRD mutation rates (27 gene panel) and co-occurring mutations in select canonical PC pathways. DRD alterations were identified in 20 genes and in 17% of patients (BRCA2 and ATM most common) occurring with slightly higher frequency in specimens from metastatic biopsy sites and men older than 50 years of age. MSI-H and TMB-H occurred with 3% frequency in the overall cohort but were not enriched in metastatic disease. Biomarkers previously associated with anti-tumor immunity are found at high frequencies in MSI-H patients, including JAK1 (68%) and PTEN (32%). Lastly, mutations in TP53, AR, PTEN, APC, CTNNB1 and PIK3CA were all significantly enriched in metastatic samples. We identified clinically significant subgroups of patients demonstrating (1) defects in DNA repair pathways, (2) intrinsic PC signaling pathways that may prevent anti-tumor immunity and (3) distinct genomic differences between localized and metastatic PC. These results lend support that genomic profiling for advanced PC may identify actionable targets not routinely used in the current metastatic paradigm. Copyright ©2020, American Association for Cancer Research.Castration-resistant prostate cancer (CRPC) is a lethal disease with few treatment alternatives once patients become resistant to second-generation anti-androgens. In CRPC, BET proteins are key regulators of AR- and MYC-mediated transcription, while the PLK1 inhibitor potentially downregulates AR and MYC besides influencing the cell cycle. Therefore, synchronous inhibition of BET and PLK1 would be a promising approach for CRPC therapy. This study developed a dual BET and PLK1 inhibitor WNY0824 with nanomolar and equipotent inhibition of BRD4 and PLK1. In vitro, WNY0824 exhibited excellent anti-proliferation activity on AR-positive CRPC cells and induced apoptosis. These activities are attributable to its disruption of the AR-transcriptional program and the inhibition of the ETS pathway. Furthermore, WNY0824 downregulated MYC and induced mitotic abnormality. In vivo, oral WNY0824 administration suppressed tumor growth in the CRPC xenograft model of enzalutamide resistance. These findings suggest that WNY0824 is a selective dual BET and PLK1 inhibitor with potent anti-CRPC oncogenic activity and provides insights into the development of other novel dual BET- and PLK1-inhibiting drugs. Copyright ©2020, American Association for Cancer Research.Physical and chemical DNA-damaging agents are used widely in the treatment of cancer. Double-strand break (DSB) lesions in DNA are the most deleterious form of damage and, if left unrepaired, can effectively kill cancer cells. check details DNA-dependent protein kinase (DNA-PK) is a critical component of non-homologous end joining (NHEJ), one of the two major pathways for DSB repair. Whilst DNA-PK has been considered an attractive target for cancer therapy, the development of pharmacological DNA-PK inhibitors for clinical use has been lagging. Here, we report the discovery and characterization of a potent, selective, and orally bioavailable DNA-PK inhibitor, M3814, and provide in vivo proof of principle for DNA-PK inhibition as a novel approach to combination radiotherapy. M3814 potently inhibits DNA-PK catalytic activity and sensitizes multiple cancer cell lines to ionizing radiation (IR) and DSB-inducing agents. Inhibition of DNA-PK autophosphorylation in cancer cells or xenograft tumors led to an increased number of persistent DSBs. Oral administration of M3814 to two xenograft models of human cancer, using a clinically established 6-week fractionated radiation schedule, strongly potentiated the antitumor activity of IR and led to complete tumor regression at non-toxic doses. Our results strongly support DNA-PK inhibition as a novel approach for the combination radiotherapy of cancer. M3814 is currently under investigation in combination with radiotherapy in clinical trials. Copyright ©2020, American Association for Cancer Research.
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