Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Given the poor prognosis of glioblastoma, we have been investigating treatments adjunctive to the current standard of resection, irradiation and temozolomide. Our focus has been on exploring already-marketed medicines that have evidence of inhibiting growth factors previously identified as active and important in glioblastoma. In this short note we describe how previous research has demonstrated that the common angiotensin-converting enzyme (ACE) inhibitor captopril used to treat hypertension and for renal protection inhibits 72-kDa matrix metalloproteinase-2 and 92-kDa matrix metalloproteinase-9, which a separate body of research shows are used by glioblastoma cells to grow and invade. We review these bodies of data and combine them to conclude that captopril may slow glioblastoma progression. Two other drugs, the aldehyde dehydrogenase inhibitor disulfiram used to treat alcoholism and the anti-HIV protease inhibitor nelfinavir also have a database supporting their incidental inhibition of matrix metalloproteinases. Given the importance of matrix metalloproteinases in helping glioblastomas grow and invade, we suggest that this trio-captopril, disulfiram, and nelfinavir-be tested for antiglioblastoma activity.
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PMID:Matrix metalloproteinase-2 and -9 in glioblastoma: a trio of old drugs-captopril, disulfiram and nelfinavir-are inhibitors with potential as adjunctive treatments in glioblastoma. 2256 23

Glioblastomas (GBM) are associated with high rates of relapse. These brain tumors are often resistant to chemotherapies like temozolomide (TMZ) and there are very few treatment options available to patients. We recently reported that polo-like kinase-1 (PLK1) is associated with the proliferative subtype of GBM; which has the worst prognosis. In this study, we addressed the potential of repurposing disulfiram (DSF), a drug widely used to control alcoholism for the past six decades. DSF has good safety profiles and penetrates the blood-brain barrier. Here we report that DSF inhibited the growth of TMZ resistant GBM cells, (IC90=100 nM), but did not affect normal human astrocytes. At similar DSF concentrations, self-renewal was blocked by ~100% using neurosphere growth assays. Likewise the drug completely inhibited the self-renewal of the BT74 and GBM4 primary cell lines. Additionally, DSF suppressed growth and self-renewal of primary cells from two GBM tumors.These cells were resistant to TMZ, had unmethylated MGMT, and expressed high levels of PLK1. Consistent with its role in suppressing GBM growth, DSF inhibited the expression of PLK1 in GBM cells. Likewise, PLK1 inhibition with siRNA, or small molecules (BI-2536 or BI-6727) blocked growth of TMZ resistant cells. Our studies suggest that DSF has the potential to be repurposed for treatment of refractory GBM.
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PMID:Disulfiram, a drug widely used to control alcoholism, suppresses the self-renewal of glioblastoma and over-rides resistance to temozolomide. 2304 41

The concept of a stem cell subpopulation as understood from normal epithelial tissue or bone marrow function has been extended to our understanding of cancer tissue and is now the target of treatment efforts specifically directed to this subpopulation. In glioblastoma, as well as in other cancers, increased expression of aldehyde dehydrogenase (ALDH) has been found localized within a minority sub-population of tumor cells which demonstrate stem cell properties. A separate body of research associated increased expression of heat-shock protein-90 (HSP90) with stem cell attributes. We present here results from our initial immunohistochemistry study of human glioblastoma biopsy tissue where both ALDH and HSP90 tended to be co-expressed in high amounts in the same minority of cells. Since 12% of all cells in the six biopsies studied were ALDH positive and 17% were HSP90 positive, by chance alone 2% would have been expected to be positive for both. In fact 7% of all cells simultaneously expressed both markers-a significant difference (p = 0.037). That two previously identified proteins associated with stem cell attributes tend to be co-expressed in the same individual glioblastoma cells might have clinical utility. Disulfiram, used to treat alcoholism for half-a century now, is a potent ALDH inhibitor and the old anti-viral drug ritonavir inhibits HSP90. These should be explored for the potential to retard aspects of glioblastoma stem cells' function subserved by ALDH and HSP90.
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PMID:Aldehyde dehydrogenase and HSP90 co-localize in human glioblastoma biopsy cells. 2320 60

Based on reporting in the last several years, an impressive but dismal list of cytotoxic chemotherapies that fail to prolong the median overall survival of patients with glioblastoma has prompted the development of treatment protocols designed to interfere with growth-facilitating signaling systems by using non-cytotoxic, non-oncology drugs. Recent recognition of the pro-mobility stimulus, interleukin-18, as a driver of centrifugal glioblastoma cell migration allows potential treatment adjuncts with disulfiram and ritonavir. Disulfiram and ritonavir are well-tolerated, non-cytotoxic, non-oncology chemotherapeutic drugs that are marketed for the treatment of alcoholism and human immunodeficiency virus (HIV) infection, respectively. Both drugs exhibit an interleukin-18-inhibiting function. Given the favorable tolerability profile of disulfiram and ritonavir, the unlikely drug-drug interaction with temozolomide, and the poor prognosis of glioblastoma, trials of addition of disulfiram and ritonavir to current standard initial treatment of glioblastoma would be warranted.
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PMID:The role of interleukin-18 in glioblastoma pathology implies therapeutic potential of two old drugs-disulfiram and ritonavir. 2596 12

Background: Disulfiram (DSF) is a well-tolerated, inexpensive, generic drug that has been in use to treat alcoholism since the 1950s. There is now independent preclinical data that supports DSF as an anticancer agent, and experimental data suggest that copper may increase its anti-neoplastic properties. There is also some clinical evidence that DSF is a promising anticancer agent in extracranial cancers. In glioblastoma, DSF induced O 6-methylguanine methyltransferase (MGMT) inhibition may increase response to alkylating chemotherapy. A recent phase I study demonstrated the safety of DSF in glioblastoma patients when DSF was administered at doses below 500 mg/day together with chemotherapy. We plan to assess the effects of DSF combined with nutritional copper supplement (DSF-Cu) as an adjuvant to alkylating chemotherapy in glioblastoma treatment. Methods: In an academic, industry independent, multicenter, open label randomized controlled phase II/III trial with parallel group design (1:1) we will assess the efficacy and safety of DSF-Cu in glioblastoma treatment. The study will include 142 patients at the time of first recurrence of glioblastoma where salvage therapy with alkylating chemotherapy is planned. Patients will be randomized to treatment with or without DSF-Cu. Primary end-point is survival at 6 months. Secondary end-points are overall survival, progression free survival, quality of life, contrast enhancing tumor volume and safety. Discussion: There is a need to improve the treatment of recurrent glioblastoma. Results from this randomized controlled trial with DSF-Cu in glioblastoma will serve as preliminary evidence of the future role of DSF-Cu in glioblastoma treatment and a basis for design and power estimations of future studies. In this publication we provide rationale for our choices and discuss methodological issues. Trial registration: The study underwent registration in EudraCT 2016-000167-16 (Date: 30.03.2016,) and Clinicaltrials.gov NCT02678975 (Date: 31.01.2016) before initiating the study.
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PMID:Disulfiram repurposing combined with nutritional copper supplement as add-on to chemotherapy in recurrent glioblastoma (DIRECT): Study protocol for a randomized controlled trial. 3064 12