Fluorine Scanning by Nonselective Fluorination: Enhancing Raf/MEK Inhibition while Keeping Physicochemical Properties

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Overcoming resistance to BRAF inhibition in BRAF-mutated metastatic melanoma

Almost 50% of metastatic melanoma patients harbor a BRAF^V600 mutation andthe introduction of BRAF inhibitors has improved their treatment options. BRAF inhibitors vemurafenib and dabrafenib achieved improved overall survival over chemotherapy and have been approved for the treatment of BRAF-mutated metastatic melanoma. However, most patients develop mechanisms of acquired resistance and about 15% of them do not achieve tumor regression at all, due to intrinsic resistance to therapy. Moreover, early adaptive responses limit the initial efficacy of BRAF inhibition, leading mostly to incomplete responses that may favor the selection of a sub-population of resistant clones and the acquisition of alterations that cause tumor regrowth and progressive disease.The purpose of this paper is to review the mechanisms of resistance to therapy with BRAF inhibitors and to discuss the strategies to overcome them based on pre-clinical and clinical evidences.     

Driving GDNF expression: the green and the red traffic lights

Glial cell line-derived neurotrophic factor (GDNF) is widely recognized as a potent survival factor for dopaminergic neurons of the nigrostriatal pathway that degenerate in Parkinson's disease (PD). In animal models of PD, GDNF delivery to the striatum or the substantia nigra protects dopaminergic neurons against subsequent toxin-induced injury and rescues previously damaged neurons, promoting recovery of the motor function. Thus, GDNF was proposed as a potential therapy to PD aimed at slowing down, halting or reversing neurodegeneration, an issue addressed in previous reviews. However, the use of GDNF as a therapeutic agent for PD is hampered by the difficulty in delivering it to the brain. Another potential strategy is to stimulate the endogenous expression of GDNF, but in order to do that we need to understand how GDNF expression is regulated. The aim of this review is to do a comprehensive analysis of the state of the art on the control of endogenous GDNF expression in the nervous system, focusing mainly on the nigrostriatal pathway. We address the control of GDNF expression during development, in the adult brain and after injury, and how damaged neurons signal glial cells to up-regulate GDNF. Pharmacological agents or natural molecules that increase GDNF expression and show neuroprotective activity in animal models of PD are reviewed. We also provide an integrated overview of the signalling pathways linking receptors for these molecules to the induction of GDNF gene, which might also become targets for neuroprotective therapies in PD.     

MEK–ERK signaling in adult newt retinal pigment epithelium cells is strengthened immediately after surgical induction of retinal regeneration

Adult newt retinal pigment epithelium (RPE) cells are mitotically quiescent in the physiological condition, but upon a traumatic injury of the neural retina (NR) they re-enter the cell-cycle and eventually regenerate the missing NR. Here, to understand the mechanism underlying the cell-cycle re-entry of RPE cells following NR injury, we first investigated changes in MEK–ERK signaling activity in RPE cells upon removal of the NR (retinectomy) from the eye of living animals, and found that ERK-mediated signaling activity is elevated quickly (in 30 min) upon retinectomy. In addition, we found, in in vitro analyses, that immediate early activation of MEK–ERK signaling may occur in RPE cells upon NR injury, intensifying the MEK–ERK signaling itself through up-regulation of the expression of constituent molecules in the pathway, and that 1-h blockade of such early MEK–ERK signaling interferes with the cell-cycle re-entry, which occurs 5–10 days later. Together, these results provide us with insight that elevation of MEK–ERK signaling activity upon NR injury may be a key process for mitotically quiescent RPE cells to re-enter the cell-cycle, leading to retinal regeneration.     

PTPIP51、p-Raf-1及ERK1/2在口腔鳞状细胞癌中的表达

目的探讨PTPIP51和p-Raf-1及ERK1/2在口腔鳞状细胞癌中的表达及对口腔鳞癌侵袭、转移的影响。方法收集32例口腔鳞状细胞癌及其配对癌旁正常口腔黏膜组织。用免疫荧光组织化学染色激光共聚焦显微镜检测PTPIP51与p-Raf-1蛋白在组织切片内表达及定位;PBS冲洗后对标本进行苏木精-伊红染色,普通光镜对比观察组织结构及细胞形态,同时用免疫组织化学方法(SP法)检测PTPIP51蛋白在组织和细胞内的定位;Rea-ltime PCR检测PT-PIP51与ERK1/2基因mRNA在肿瘤组织及癌旁正常口腔黏膜组织的表达情况。结果 PTPIP51与p-Raf-1蛋白在癌巢周围增殖旺盛的肿瘤细胞、间质免疫细胞及部分脉管壁内皮细胞表达阳性且2种蛋白在细胞中共定位表达。同时发现PTPIP51与ERK1/2基因mRNA在口腔鳞癌组织表达高于配对癌旁正常口腔黏膜组织,差异具有统计学意义(P<0.05);ERK1/2及PTPIP51基因mRNA表达呈正相关(r=0.641,P<0.05);两者的表达水平与患者的性别、年龄,病理分级无关,与肿瘤的TNM分级及有无淋巴结转移有关(P<0.05)。结论 PTPIP51与Raf-1可能通过Ras/Raf/MEK/ERK信号通路参与口腔鳞状细胞癌的发生、发展过程,且2种蛋白与肿瘤的侵袭、转移有密切关系。     

Targeting autophagy in colorectal cancer: An update on pharmacological small-molecule compounds

Autophagy, an evolutionarily highly conserved cellular degradation process, plays the Janus role (either cytoprotective or death-promoting) in colorectal cancer, so the targeting of several key autophagic pathways with small-molecule compounds may be a new therapeutic strategy. In this review, we discuss autophagy-associated cell death pathways and key cytoprotective autophagy pathways in colorectal cancer. Moreover, we summarize a series of small-molecule compounds that have the potential to modulate autophagy-associated cell death or cytoprotective autophagy for therapeutic purposes. Taken together, these findings demonstrate the Janus role of autophagy in colorectal cancer, and shed new light on the exploitation of a growing number of small-molecule compounds to target autophagy in future cancer drug discovery.     

Fentanyl inhibits acute myeloid leukemia differentiated cells and committed progenitors via opioid receptor‐independent suppression of Ras and STAT5 pathways

Fentanyl is a common sedative/analgesic used for intrathecal chemotherapy injection in children with acute leukemia. Given the contradictory findings that fentanyl has both inhibitory and stimulatory activities in cancer cells, we investigated the biological effects of fentanyl alone and its combination with standard of care in acute myeloid leukemia (AML) cells at all stages of development. We showed that fentanyl at clinically relevant concentration inhibited growth and colony formation of AML differentiated cells and committed progenitors without affecting their survival. Compared to AML cells without FLT3 mutation, cells harboring FLT3‐ITD mutation are likely to be more sensitive to fentanyl. However, fentanyl did not affect the most primitive AML stem cells. Fentanyl significantly augmented the efficacy of cytarabine but not midostaurin in AML differentiated cells and committed progenitors. We further demonstrated that fentanyl inhibited AML cells via suppressing Ras/Raf/MEK/ERK and STAT5 pathway, and this was not dependent on opioid receptor system. Our findings demonstrate the anti‐leukemia activity of fentanyl and synergistic effects between fentanyl and cytarabine in AML, via opioid receptor‐independent suppression of Ras and STAT5 pathways. Our work is the first to suggest the beneficial effects of fentanyl in children with leukemia.     

Ras/Raf/MEK/ERK信号通路参与自噬调控作用的研究进展

自噬是机体保守的自我防御机制,是将细胞内变形坏死的细胞器和多余蛋白降解为小分子,以供循环利用。自噬在生理和病理状态下均发挥重要作用,可通过多条信号通路影响胞内物质的表达。目前已知Ras/Raf/MEK/ERK信号通路不仅广泛参与调控细胞生长、增殖、分化、凋亡等多个生理病理过程,并且参与调控自噬,并具有促进肿瘤细胞发生自噬性死亡的作用,但是其具体参与调控自噬的作用机制尚未完全阐明。本文就Ras/Raf/MEK/ERK信号通路参与调控自噬的作用的研究进展进行详细阐述,以期为研究Ras/Raf/MEK/ERK信号通路调控自噬的作用机制提供参考。     

对INT-FAK信号通路调控脑缺血后神经细胞凋亡的思考

脑缺血性疾病是人类健康的主要杀手之一,相关研究表明,神经细胞的凋亡是造成脑缺血疾病中神经系统损害的主要机制之一,而以整合素-黏着斑激酶（INT-FAK）控制调节的PI3K/PDK/Akt以及Raf/MEK/ERK两条主要信号途径引起的细胞凋亡是其主要作用机制。凋亡过程出现的诸多能加以调控的信号分子,都可以作为治疗脑缺血性损伤的潜在靶点。随着对脑缺血损伤与神经细胞凋亡关联的深入研究,抗凋亡治疗已经成为治疗脑缺血性疾病的重要途径。