Treatments for Gastrointestinal Stromal Tumors that are Resistant to Standard Therapies

Saponara, Maristella; Pantaleo, Maria Abbondanza; Nannini, Margherita; Biasco, Guido

doi:10.2217/fon.14.109

Cited by 9 publications

(7 citation statements)

References 64 publications

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“…Disulfiram, a drug for alcoholism, has also been reported to inhibit prostate cancer cell growth (Lin et al, 2011). Imatinib, developed to treat chronic myelogenous leukemia, is used to treat gastrointestinal stromal tumors (Saponara et al, 2014) and colorectal cancer (Kelley et al, 2013), which share a similar target.…”

Section: Introductionmentioning

confidence: 99%

Pimozide Inhibits the Human Prostate Cancer Cells Through the Generation of Reactive Oxygen Species

Kim

Lee

et al. 2020

Front. Pharmacol.

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The United States Food and Drug Administration-approved antipsychotic drug, pimozide, has anticancer activities. However, the role of reactive oxygen species (ROS) in its effect on prostate cancer is not well-known. We examined cell proliferation, colony formation, migration, ROS production, and the expression of antioxidant-related genes after treatment of human prostate cancer PC3 and DU145 cells with pimozide. In addition, histopathology, ROS production, and superoxide dismutase (SOD) activity were analyzed after administering pimozide to TRAMP, a transgenic mouse with prostate cancer. Pimozide increased the generation of ROS in both cell lines and inhibited cell proliferation, migration, and colony formation. Oxidative stress induced by pimozide caused changes in the expression of antioxidant enzymes (SOD1, peroxiredoxin 6, and glutathione peroxidase 2) and CISD2. Co-treatment with glutathione, an antioxidant, reduced pimozide-induced ROS levels, and counteracted the inhibition of cell proliferation. Administration of pimozide to TRAMP mice reduced the progression of prostate cancer with increased ROS generation and decreased SOD activity. These results suggest that the antipsychotic drug, pimozide, has beneficial effects in prostate cancer in vivo and in vitro. The mechanism of pimozide may be related to augmenting ROS generation. We recommend pimozide as a promising anticancer agent.

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Section: Introductionmentioning

confidence: 99%

Pimozide Inhibits the Human Prostate Cancer Cells Through the Generation of Reactive Oxygen Species

Kim

Lee

et al. 2020

Front. Pharmacol.

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“…Disulfiram, a drug that is widely used to control alcoholism, also suppresses the self-renewal of glioblastoma and overrides resistance to temozolomide [7]. Furthermore, the use of imatinib (Gleevec), a drug that was originally developed to treat chronic myelogenous leukaemia, has been expanded to treat several malignancies due to its targeting of similar signaling pathways [8], such as those in gastrointestinal stromal tumors [9] and colorectal cancers [10]. Consequently, finding new uses for existing drugs represents an effective strategy for developing novel pharmacotherapies to treat cancer cells.…”

Section: Introductionmentioning

confidence: 99%

The neuroleptic drug pimozide inhibits stem-like cell maintenance and tumorigenicity in hepatocellular carcinoma

et al. 2015

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Drug repurposing is currently an important approach for accelerating drug discovery and development for clinical use. Hepatocellular carcinoma (HCC) presents drug resistance to chemotherapy, and the prognosis is poor due to the existence of liver cancer stem-like cells. In this study, we investigated the effect of the neuroleptic agent pimozide to inhibit stem-like cell maintenance and tumorigenicity in HCC. Our results showed that pimozide functioned as an anti-cancer drug in HCC cells or stem-like cells. Pimozide inhibited cell proliferation and sphere formation capacities in HCC cells by inducing G0/G1 phase cell cycle arrest, as well as inhibited HCC cell migration. Surprisingly, pimozide inhibited the maintenance and tumorigenicity of HCC stem-like cells, particularly the side population (SP) or CD133-positive cells, as evaluated by colony formation, sphere formation and transwell migration assays. Furthermore, pimozide was found to suppress STAT3 activity in HCC cells by attenuating STAT3-dependent luciferase activity and down-regulating the transcription levels of downstream genes of STAT3 signaling. Moreover, pimozide reversed the stem-like cell tumorigenic phenotypes induced by IL-6 treatment in HCC cells. Further, the antitumor effect of pimozide was also proved in the nude mice HCC xenograft model. In short, the anti-psychotic agent pimozide may act as a novel potential anti-tumor agent in treating advanced HCC.

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“…To treat patients with acquired imatinib resistance, a second generation of TKIs, including sunitinib and regorafenib, has been developed; these TKIs also target the kinases involved in tumor-related angiogenesis [ 7 - 9 ]. The need of prolonging life expectancy of patients associated with the complex biology of progressive disease has led to a growing urgency and interest in the understanding the basic biology of GISTs and in the identification of new strategies to overcome resistance, including new molecules, drug-drug combinations, and the integration of loco-regional treatments [ 10 - 13 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of metastatic exon 11 mutant gastrointestinal stromal tumors (GIST) beyond KIT/PDGFRα genotype evaluated by next generation sequencing (NGS)

et al. 2015

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About 85% of GISTs are associated with KIT and PDGFRα gene mutations, which predict response to tyrosine kinase inhibitors. Although the outcomes in patients affected by GIST have dramatically improved, tumor progression control still remains a challenge. The aim of this study is the genomic characterization of individual metastatic KIT-exon 11-mutant GIST to identify additional aberrations and simultaneous molecular events representing potential therapeutic targets.Seven patients with metastatic GIST were studied with whole transcriptome sequencing and copy number analysis. Somatic single nucleotide variations were called; however, no shared mutated genes were detected except KIT. Almost all patients showed loss of genomic regions containing tumor suppressor genes, sometimes coupled with single nucleotide mutation of the other allele. Additionally, six fusion transcripts were found and three patients showed amplifications involving known oncogenes.Evaluating the concordance between CN status and mRNA expression levels, we detected overexpression of CCND2 and EGFR and silencing of CDKN2A, CDKN2C, SMARCB1, PTEN and DMD. Altered expression of these genes could be responsible for aberrant activation of signaling pathways that support tumor growth. In this work, we assessed the effect of Hedgehog pathway inhibition in GIST882 cells, which causes decrement of cell viability associated with reduction of KIT expression.Additional genomic alterations not previously reported in GIST were found even if not shared by all samples. This contributes to a more detailed molecular understanding of this disease, useful for identification of new targets and novel therapeutics and representing a possible point of departure for a truly individualized clinical approach.

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Treatments for Gastrointestinal Stromal Tumors that are Resistant to Standard Therapies

Cited by 9 publications

References 64 publications

Pimozide Inhibits the Human Prostate Cancer Cells Through the Generation of Reactive Oxygen Species

Pimozide Inhibits the Human Prostate Cancer Cells Through the Generation of Reactive Oxygen Species

The neuroleptic drug pimozide inhibits stem-like cell maintenance and tumorigenicity in hepatocellular carcinoma

Molecular characterization of metastatic exon 11 mutant gastrointestinal stromal tumors (GIST) beyond KIT/PDGFRα genotype evaluated by next generation sequencing (NGS)

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