Phase 1/2, Multi-center, Open Label, Dose Escalation, Safety, Efficacy and PK Study of PRLX 93936 Administered IV 3 Days a Week for 3 Weeks Followed by a 9 Day Rest Period in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma

To determine the maximum tolerated dose of, and response to, PRLX 93936 as treatment for patients with relapsed or relapsed/refractory multiple myeloma.

开始日期2012-03-01

申办/合作机构

Prolexys Pharmaceuticals, Inc.

NCT00528047 / Completed临床1期

A Phase I, Multi-center, Open-Label, Dose-Escalation, Safety, Pharmacodynamic and Pharmacokinetic Study of PRLX 93936 Administered Intravenously Daily for Five Days Followed by a 23-Day Rest Period in Patients With Advanced Solid Tumors

The purpose of this study is to test the safety of PRLX 93936 and see what kind of effect it has on patients and their cancer. This study will also determine the highest dose of PRLX 93936 that can be given without causing adverse side effects and the dose of PRLX 93936 that should be used in future studies.

开始日期2007-08-01

申办/合作机构

Prolexys Pharmaceuticals, Inc.

100 项与 PRLX-93936 相关的临床结果

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100 项与 PRLX-93936 相关的转化医学

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100 项与 PRLX-93936 相关的专利（医药）

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848

项与 PRLX-93936 相关的文献（医药）

2024-12-31·Animal Cells and Systems

Blocking SLC7A11 attenuates the proliferation of esophageal squamous cell carcinoma cells

Article

作者: Bai, Jie ; Jin, Xin ; Shi, Zhi-Zhou ; Li, Wen-Ting ; Song, Sheng-Jie ; Wang, Chong ; Fu, Chuang ; Jiang, Wen

The role of ferroptosis-associated gene SLC7A11 in esophageal cancer progression is largely unknown, therefore, the effects of blocking SLC7A11 on esophageal squamous cell carcinoma (ESCC) cells are evaluated. Results showed that SLC7A11 was overexpressed in ESCC tissues both in mRNA and protein levels. Blocking SLC7A11 using Erastin suppressed the proliferation and colony formation of ESCC cells, decreased cellular ATP levels, and improved ROS production. Sixty-three SLC7A11-binding proteins were identified using the IP-MS method, and these proteins were enriched in four signaling pathways, including spliceosome, ribosome, huntington disease, and diabetic cardiomyopathy. The deubiquitinase inhibitors PR-619, GRL0617, and P 22077 could reduce at least 40% protein expression level of SLC7A11 in ESCC cells, and PR-619 and GRL0617 exhibited suppressive effects on the cell viability and colony formation ability of KYSE30 cells, respectively. Erastin downregulated GPX4 and DHODH and also reduced the levels of β-catenin, p-STAT3, and IL-6 in ESCC cells. In conclusion, SLC7A11 was overexpressed in ESCC, and blocking SLC7A11 using Erastin mitigated malignant phenotypes of ESCC cells and downregulated key ferroptosis-associated molecules GPX4 and DHODH. The therapeutic potential of targeting SLC7A11 should be further evaluated in the future.

2024-12-31·Epigenetics

m6A reader YTHDC2 mediates NCOA4 mRNA stability affecting ferritinophagy to alleviate secondary injury after intracerebral haemorrhage

Article

作者: Feng, Lei ; Li, Yanan ; Li, Fengfeng ; Wang, Jianhua ; Wang, Fang ; Jiang, Pei ; Meng, Junjun ; Wei, Shanshan ; Wang, Lei

Oxidative stress and neuronal dysfunction caused by intracerebral haemorrhage (ICH) can lead to secondary injury. The m6A modification has been implicated in the progression of ICH. This study aimed to investigate the role of the m6A reader YTHDC2 in ICH-induced secondary injury. ICH models were established in rats using autologous blood injection, and neuronal cell models were induced with Hemin. Experiments were conducted to overexpress YTH domain containing 2 (YTHDC2) and examine its effects on neuronal dysfunction, brain injury, and neuronal ferritinophagy. RIP-qPCR and METTL3 silencing were performed to investigate the regulation of YTHDC2 on nuclear receptor coactivator 4 (NCOA4). Finally, NCOA4 overexpression was used to validate the regulatory mechanism of YTHDC2 in ICH. The study found that YTHDC2 expression was significantly downregulated in the brain tissues of ICH rats. However, YTHDC2 overexpression improved neuronal dysfunction and reduced brain water content and neuronal death after ICH. Additionally, it reduced levels of ROS, NCOA4, PTGS2, and ATG5 in the brain tissues of ICH rats, while increasing levels of FTH and FTL. YTHDC2 overexpression also decreased levels of MDA and Fe2+ in the serum, while promoting GSH synthesis. In neuronal cells, YTHDC2 overexpression alleviated Hemin-induced injury, which was reversed by Erastin. Mechanistically, YTHDC2-mediated m6A modification destabilized NCOA4 mRNA, thereby reducing ferritinophagy and alleviating secondary injury after ICH. However, the effects of YTHDC2 were counteracted by NCOA4 overexpression. Overall, YTHDC2 plays a protective role in ICH-induced secondary injury by regulating NCOA4-mediated ferritinophagy.

2024-12-01·Molecular Biology Reports

LncRNA MEG3 suppresses erastin-induced ferroptosis of chondrocytes via regulating miR-885-5p/SLC7A11 axis

Article

作者: Wang, Shengyu ; Zhu, Chongtao ; Chen, Bin ; Zhu, Xun ; Li, Yan ; Li, Xiaolu ; Li, Weiyuan ; He, Xu ; Wan, Ping

BACKGROUNDFerroptosis is involved in osteoarthritis development; however, the roles of long noncoding RNAs (lncRNAs), including lncRNA MEG3, in the regulation of ferroptosis in osteoarthritis are still unclear.METHODSIn this study, qRT‒PCR and Western blotting assays were used to detect the expression of lncRNA MEG3, miR-885-5p, SLC7A11 and GPX4; MDA and CCK-8 assays were applied to analyse cellular MDA levels and cell viability, respectively.RESULTErastin elevated cellular MDA levels and decreased the viability of chondrocytes and the erastin-induced decline in cell viability was reversed by a ferroptosis inhibitor (ferrostatin-1). Erastin downregulated lncRNA MEG3, SLC7A11 and GPX4 and upregulated miR-885-5p. Silencing of lncRNA MEG3 increased miR-885-5p and downregulated SLC7A11 and GPX4 and further sensitized chondrocytes to erastin-induced ferroptosis. In contrast, overexpression of lncRNA MEG3 had opposite effects. Dual luciferase assays confirmed binding between lncRNA MEG3 and miR-885-5p and between miR-885-5p and the 3'UTR of SLC7A11. In the synovial fluids from patients with osteoarthritis compared with synovial fluids from normal controls, the RNA levels of lncRNA MEG3 and SLC7A11 were decreased and the miR-885-5p expression level was increased.CONCLUSIONOur findings indicated that lncRNA MEG3 overexpression alleviated ferroptosis in chondrocytes by affecting the miR-885-5p/SLC7A11 signalling pathway.

项与 PRLX-93936 相关的新闻（医药）

2022-03-21

·生物谷

英国药理学: 盐酸益母草碱通过激活Nrf2信号通路减轻顺铂所致急性肾损伤中的铁死亡

越来越多的证据表明，铁死亡在顺铂所致急性肾损伤(AKI)的病理生理机制中起着关键作用。Nrf2信号通路调节氧化应激和脂质过氧化，并正向调节顺铂诱导的AKI(CI-AKI)。然而，其对CI-AKI后铁死亡的作用以及一种生物碱化合物盐酸益母草碱(LH)的作用尚不清楚。图片来源: https://pubmed.ncbi.nlm.nih.gov/35303762/ 近日，吉林大学第一医院的研究者们在Br J Pharmacol杂志上发表了题为“Leonurine hydrochloride alleviates ferroptosis in cisplatin-induced acute kidney injury by activating the Nrf2 signaling pathway”的文章，该研究表明，Nrf2激活对CI-AKI的肾保护作用至少部分是通过抑制脂质过氧化物介导的铁死亡来实现的，并突出了LH作为CI-AKI治疗的潜力。在本研究中，研究者用小鼠顺铂诱导的AKI模型评价Nrf2和LH的抗铁死亡作用。体外观察LH对Erastin(铁死亡诱导剂)和RSL3(铁死亡激动剂)诱导的HK-2人PTEC铁死亡的影响。正如预期的那样，Nrf2缺失诱导了铁死亡相关蛋白的表达和体内铁的积累，进一步加重了CI-AKI。在体外，LH能激活Nrf2，防止铁蓄积、脂质过氧化和铁死亡，而siNrf2处理的细胞中这些作用被取消。此外，LH有效地改善了顺铂引起的肾损害。重要的是，LH激活了Nrf2抗氧化信号通路，抑制了与铁下垂相关的形态和生化指标的变化，如丙二醛水平、超氧化物歧化酶和谷胱甘肽的耗竭以及Gpx4和XCT的下调。此外，Nrf2敲除小鼠在CI-AKI后发生铁死亡的敏感性高于对照组，而LH对Nrf2敲除小鼠AKI和铁死亡的保护作用在Nrf2敲除小鼠中被基本消除。 LH减轻顺铂诱导的体内铁死亡的作用依赖于Nrf2基因的表达图片来源: https://pubmed.ncbi.nlm.nih.gov/35303762/ 总之，该研究揭示了上调Nrf2对预防铁死亡从而缓解CI-AKI的重要意义。这一结论源于三个关键发现。首先，Nrf2 敲除小鼠更容易受到顺铂引起的肾损伤和铁死亡的影响。第二，LH通过激活抗氧化信号分子Nrf2，抑制铁死亡相关的形态和生化改变，对顺铂诱导的AKI具有保护作用。最后，用LH处理Nrf2敲除小鼠和Nrf2 siRNA HK-2细胞，在体内和体外几乎不能挽救顺铂和RSL3诱导的铁死亡和肾脏损伤。本研究进一步理解了Nrf2抑制铁离子腐蚀的机制，并为研究Nrf2激活剂在顺铂诱导的AKI中的抗铁离子腐蚀活性提供了策略。仍需临床试验进一步的研究LH治疗顺铂所致急性肾损伤的安全性和有效性。参考文献 Jianqiang Hu et al. Leonurine hydrochloride alleviates ferroptosis in cisplatin-induced acute kidney injury by activating the Nrf2 signaling pathway. Br J Pharmacol. 2022 Mar 18. doi: 10.1111/bph.15834. 内容来源于网络，如有侵权，请联系删除，谢谢