As one of the common malignancies that threaten human life,bladder cancer occurs frequently with a high mortality rate in the world,due to its invasion,recurrence and drug resistance.Natural products from marine micro...As one of the common malignancies that threaten human life,bladder cancer occurs frequently with a high mortality rate in the world,due to its invasion,recurrence and drug resistance.Natural products from marine microorganisms are becoming the hotspots in discovery of new candidate drug entities,especially in the area of cancer.Brefeldin A(BFA)is a natural Arf-GEFs inhibitor,but due to the low aqueous solubility,strong toxicity,and poor bioavailability,it is urgent to conduct structural optimization research.Herein,a new BFA pyridine acrylate derivative CHNQD-01281 with improved solubility was prepared and found to exert moderate to strong antiproliferative activity on a variety of human cancer cell lines.It was noteworthy that CHNQD-01281 was most sensitive to two bladder cancer cell lines T24 and J82(IC50=0.079 and 0.081μmol/L)with high selectivity index(SI=14.68 and 14.32),suggesting a superior safety to BFA.In vivo studies revealed that CHNQD-01281 remarkably suppressed tumor growth in a T24 nude mice xenograft model(TGI=52.63%)and prolonged the survival time(ILS=68.16%)in an MB49 allogeneic mouse model via inducing infiltration of cytotoxic T cells.Further mechanism exploration indicated that CHNQD-01281 regulated both EGFR/PI3K/AKT and EGFR/ERK pathways and mediated the chemotactic effect of chemokines on immune effector cells.Overall,CHNQD-01281 may serve as a potential therapeutic agent for bladder cancer through multiple mechanisms.展开更多
基金supported by the Special Funds of Shandong Province for Qingdao National Laboratory of Marine Sci-ence and Technology(No.2022QNLM030003)the open foundation of Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education(RDZH2024004)+4 种基金Natural Science Foundation of Shan-dong Province(No.ZR2020QH026)Shandong Province Special Fund“Frontier Technology and Free Exploration”from Laoshan Laboratory(No.8-01)the National Key Research and Development Program of China(No.2022YFC2601305)the Fundamental Research Funds for the Central Universities(No.202264001)the Innovation Center for Academicians of Hainan Province.
文摘As one of the common malignancies that threaten human life,bladder cancer occurs frequently with a high mortality rate in the world,due to its invasion,recurrence and drug resistance.Natural products from marine microorganisms are becoming the hotspots in discovery of new candidate drug entities,especially in the area of cancer.Brefeldin A(BFA)is a natural Arf-GEFs inhibitor,but due to the low aqueous solubility,strong toxicity,and poor bioavailability,it is urgent to conduct structural optimization research.Herein,a new BFA pyridine acrylate derivative CHNQD-01281 with improved solubility was prepared and found to exert moderate to strong antiproliferative activity on a variety of human cancer cell lines.It was noteworthy that CHNQD-01281 was most sensitive to two bladder cancer cell lines T24 and J82(IC50=0.079 and 0.081μmol/L)with high selectivity index(SI=14.68 and 14.32),suggesting a superior safety to BFA.In vivo studies revealed that CHNQD-01281 remarkably suppressed tumor growth in a T24 nude mice xenograft model(TGI=52.63%)and prolonged the survival time(ILS=68.16%)in an MB49 allogeneic mouse model via inducing infiltration of cytotoxic T cells.Further mechanism exploration indicated that CHNQD-01281 regulated both EGFR/PI3K/AKT and EGFR/ERK pathways and mediated the chemotactic effect of chemokines on immune effector cells.Overall,CHNQD-01281 may serve as a potential therapeutic agent for bladder cancer through multiple mechanisms.
