作者: Chen, Thomas C ; Wang, Weijun ; Cho, Hee-Yeon ; Swenson, Stephen D ; Ou, Mengting ; Fu, Jie ; Schönthal, Axel H ; Thein, Thu Zan ; Stathopoulos, Apostolos ; Tang, Liling ; Minea, Radu O ; Hofman, Florence M

Glioblastoma (GBM) is the most aggressive primary brain tumor, exhibiting a high rate of recurrence and poor prognosis. Surgery and chemoradiation with temozolomide (TMZ) represent the standard of care, but, in most cases, the tumor develops resistance to further treatment and the patients succumb to disease. Therefore, there is a great need for the development of well-tolerated, effective drugs that specifically target chemoresistant gliomas. NEO214 was generated by covalently conjugating rolipram, a PDE4 (phosphodiesterase 4) inhibitor, to perillyl alcohol, a naturally occurring monoterpene related to limonene. Our previous studies in preclinical models showed that NEO214 harbors anticancer activity, is able to cross the blood-brain barrier (BBB), and is remarkably well tolerated. In the present study, we investigated its mechanism of action and discovered inhibition of macroautophagy/autophagy as a key component of its anticancer effect in glioblastoma cells. We show that NEO214 prevents autophagy-lysosome fusion, thereby blocking autophagic flux and triggering glioma cell death. This process involves activation of MTOR (mechanistic target of rapamycin kinase) activity, which leads to cytoplasmic accumulation of TFEB (transcription factor EB), a critical regulator of genes involved in the autophagy-lysosomal pathway, and consequently reduced expression of autophagy-lysosome genes. When combined with chloroquine and TMZ, the anticancer impact of NEO214 is further potentiated and unfolds against TMZ-resistant cells as well. Taken together, our findings characterize NEO214 as a novel autophagy inhibitor that could become useful for overcoming chemoresistance in glioblastoma.Abbreviations: ATG: autophagy related; BAFA1: bafilomycin A₁; BBB: blood brain barrier; CQ: chloroquine; GBM: glioblastoma; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MGMT: O-6-methylguanine-DNA methyltransferase; MTOR: mechanistic target of rapamycin kinase; MTORC: MTOR complex; POH: perillyl alcohol; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TMZ: temozolomide.

2019-03-01·Molecular Cancer Therapeutics2区 · 医学

The Rolipram–Perillyl Alcohol Conjugate (NEO214) Is A Mediator of Cell Death through the Death Receptor Pathway

2区 · 医学

Article

作者: Wang, Weijun ; Ou, Mengting ; Cho, Hee-Yeon ; Schönthal, Axel H. ; Thein, Thu Zan ; Marín-Ramos, Nagore I. ; Chen, Thomas C. ; Swenson, Stephen D. ; Hofman, Florence M. ; Fayngor, Rochelle A.

AbstractGlioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. Treatment with temozolomide, standard of care for gliomas, usually results in drug resistance and tumor recurrence. Therefore, there is a great need for drugs that target GBM. NEO214 was generated by covalently linking rolipram to perillyl alcohol (POH) via a carbamate bond to form the rolipram–perillyl alcohol conjugate. We show here that NEO214 is effective against both temozolomide-sensitive and temozolomide-resistant glioma cells. Furthermore, NEO214 is effective for different mechanisms of temozolomide resistance: overexpression of MGMT (O6-methylguanine methyl-transferase); deficiency in specific mismatch repair proteins; and overexpression of base excision repair (BER) proteins. NEO214-induced cytotoxicity involves apoptosis triggered by endoplasmic reticulum (ER) stress, as well as activating the Death Receptor 5 (DR5)/TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) pathway. In vitro studies show that glioma cells treated with NEO214 express DR5 and exhibit cell death in the presence of recombinant TRAIL, a growth factor constitutively produced by astrocytes. Our in vitro 3D coculture data show that induction of DR5 in glioma cells with NEO214 and TRAIL cause tumor cell death very effectively and specifically for glioma cells. In vivo studies show that NEO214 has antitumor efficacy in orthotropic syngeneic rodent tumor models. Furthermore, NEO214 has therapeutic potential especially for brain tumors because this drug can cross the blood–brain barrier (BBB), and is effective in the TRAIL-rich astrocyte microenvironment. NEO214 is a strong candidate for use in the treatment of GBMs.

2004-01-01·Drugs in R & D4区 · 医学

RIGScan CR

4区 · 医学

ReviewOA

作者: &NA;

RIGScan CR49, a 125I-labelled CR monoclonal antibody directed against the tumour-associated antigen TAG-72, is undergoing development with Neoprobe for the intraoperative detection of metastatic colorectal cancer. The Neoprobe's proprietary RIGS (radioimmunoguided surgery) technology combines an injectable radiolabelled cancer-targeting agent and hand-held radiation detection probe that emits an audible tone when located tissue has accumulated a significant amount of the radioactive agent. Neoprobe's RIGS technology also includes a patented surgical method providing surgeons with real-time information to locate tumour deposits that can not be detected by other conventional methods. The RIGS technology has been evaluated in late clinical studies for the detection of adenocarcinomas including primary colorectal, gastrointestinal, breast, ovarian, pancreatic, prostate and neuroendocrine/endocrine. Neoprobe signed an option agreement for its first-generation RIGScan compound, RIGScan CR, with OncoSurg Inc. (formerly NuRigs Ltd). The second-generation humanised RIGScan CR agent was also optionally licensed to OncoSurg Inc. In 1997, Neoprobe filed for approval with the US FDA and the EMEA for RIGScan CR for the intraoperative detection of metastatic colorectal cancer. Both regulatory agencies have requested additional clinical data. On 19 April 2004, Neoprobe announced that it had met with the US FDA to discuss its position on submitting additional clinical information in response to the FDA's questions regarding the Biologic Licence Application (BLA) for RIGScan CR49. The company provided the FDA with new information related to a survival differential for patients whose colorectal cancer was evaluated with RIGScan CR49. The information was not available at the time of the BLA's submission in 1997. The agency indicated that it would consider accepting survival data from one of the two phase III trials, NEO2-14, but not from another trial NEO2-13, as supportive data for a prognostic indication for colorectal cancer. The FDA also clarified that two well controlled studies were required for approval, and indicated that Neoprobe needed to complete an additional confirmatory phase III study for a prognostic indication in colorectal cancer. In its Annual Report 2002, Neoprobe stated that it had been working to secure a partner for further development of its proprietary RIGS technology. The company intends either to find a development partner or sell or licence out their RIGS assets if the partner is not found.

100 项与 NEO-214 相关的药物交易

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