Noscapine inhibits tumor growth in TMZ-resistant gliomas

Jhaveri, Niyati; Cho, Heeyeon; Torres, Shering; Wang, Weijun; Schönthal, Axel H.; Petasis, Nicos A.; Louie, Stan G.; Hofman, Florence M.; Chen, Thomas C.

doi:10.1016/j.canlet.2011.08.015

Cited by 41 publications

(47 citation statements)

References 24 publications

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“…Glioma cell lines were originally purchased from ATCC; the cell lines have not been authenticated. Temozolomide-resistant cells were developed as described previously (5,25). Briefly, cell lines were incubated with increasing doses of NEO212 ranging from 10 to 100 mmol/L for approximately 6 months.…”

Section: Cells and Reagentsmentioning

confidence: 99%

NEO212, Temozolomide Conjugated to Perillyl Alcohol, Is a Novel Drug for Effective Treatment of a Broad Range of Temozolomide-Resistant Gliomas

Cho¹,

Wang²,

Jhaveri³

et al. 2014

Molecular Cancer Therapeutics

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Patients with glioblastoma multiforme (GBM), a malignant primary brain tumor, inevitably develop resistance to standard-of-care chemotherapy, temozolomide. This study explores the effects of the novel agent NEO212, a conjugate of temozolomide to perillyl alcohol, on temozolomide-resistant gliomas. NEO212 was tested for cytotoxic activity on three human temozolomide-resistant glioma cell lines, which were resistant to temozolomide based on overexpression of the base excision repair (BER) pathway, mismatch repair (MMR) deficiency, or overexpression of O 6 methyl-guanine-DNA methyltransferase (MGMT). BER expression was evaluated by Western blotting and PARP activity. MMR deficiency was determined by Western blotting and microsatellite instability. MGMT overexpression was evaluated by Western blotting and O 6 -benzylguanine (O 6 BG) inhibition. For in vivo evaluation of NEO212, temozolomide-resistant glioma cells were implanted into immune-incompetent mice, and NEO212 was administered. NEO212, at equimolar concentrations of temozolomide, was more cytotoxic for temozolomideresistant cells than temozolomide and not toxic to normal cells. NEO212-induced cell death in temozolomide-resistant glioma cells was independent of such mechanisms of resistance as high levels of MGMT, MMR deficiencies, or overexpression of BER proteins. NEO212 functions as a DNA alkylating agent, similar to temozolomide; however, this novel conjugate is unique for it may induce endoplasmic reticulum (ER) stress and inhibits autophagy. In vivo studies show that NEO212 reduces intracranial tumor growth and increases animal survival without significant toxicity. These results demonstrate that NEO212 is an effective drug against malignant gliomas that can be used for a broad range of newly diagnosed and temozolomide-resistant gliomas.

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Section: Cells and Reagentsmentioning

confidence: 99%

NEO212, Temozolomide Conjugated to Perillyl Alcohol, Is a Novel Drug for Effective Treatment of a Broad Range of Temozolomide-Resistant Gliomas

Cho¹,

Wang²,

Jhaveri³

et al. 2014

Molecular Cancer Therapeutics

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“…After 24 hours, POH and/or DMC and nelfinavir were added at different concentrations and cells were incubated for 48 hours. TMZ with or without POH was tested in the long-term MTT assay as previously described (8). The assay was conducted according to the manufacturer's protocol (EMD Chemical).…”

Section: Mtt Assaymentioning

confidence: 99%

“…Luciferase-labeled U251-TMZ-resistant glioma cells (2 Â 10 5 cells in 20 mL) were implanted intracranially, as previously described (8). Seven days after implantation, mice were randomly divided into groups of 5 each, and treatment was initiated as follows: vehicle (DMSO) control; POH (0.76 mg/kg); POH (1.9 mg/kg); and TMZ (5 mg/kg).…”

Section: In Vivo Experimentsmentioning

confidence: 99%

“…To determine whether the effects of POH observed in vitro were relevant to the in vivo environment, POH was tested on TMZ-resistant glioma cells in the orthotopic xenograft rodent model (8). Athymic nude mice were implanted intracranially with U251 TMZ-resistant glioma cells in the following groups (n ¼ 5): control-intranasal (IN) vehicle; IN 0.76 mg/kg POH; IN 1.9 mg/kg POH; and intragastric TMZ 5 mg/kg/d.…”

Section: Intranasal Delivery Of Poh Reduces Tumor Growthmentioning

confidence: 99%

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Perillyl Alcohol for the Treatment of Temozolomide-Resistant Gliomas

Cho

Wang

Jhaveri

et al. 2012

Molecular Cancer Therapeutics

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Perillyl alcohol (POH) is a monoterpene that has been used orally for the treatment of systemic cancer. However, when used orally significant gastrointestinal side effects and lack of overall efficacy were documented. Recently, in a phase II trial in Brazil for the treatment of temozolomide (TMZ)-resistant malignant gliomas, POH was well tolerated when administered intranasally. The present study explores the effects and mechanisms of POH on TMZ-sensitive and TMZ-resistant glioma cells. In vitro studies showed that POH was cytotoxic to TMZ-resistant as well as TMZ-sensitive glioma cells, and this effect was independent of O 6 -methylguanine-DNA methyltransferase expression. POH induced cytotoxicity, in part, through the endoplasmic reticulum (ER) stress pathway as shown by the increased expression of glucose-regulated protein-78 (GRP78), activating transcription factor 3, and C/EBP-homologous protein. In addition, POH impeded survival pathways, such as mTOR and Ras. As well, POH reduced the invasive capacity of sensitive and resistant glioma cells. POH alone and/or in combination with other ER stress-inducing cytotoxic drugs (i.e., 2, 5-dimethyl-celecoxib, nelfinavir) further induced apoptosis in TMZ-sensitive and TMZ-resistant glioma cells. To show whether intranasal delivery of POH was effective for the treatment of TMZ-resistant gliomas, animals bearing intracranial tumors were given POH intranasally. Animals treated through intranasal administration of POH exhibited a decrease in tumor growth and an increase in survival. Our data show that POH is an effective anti-glioma cytotoxic agent for TMZ-resistant gliomas when administered intranasally.

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“…Tumor tracing techniques are becoming more and more popular in recent years in the field of pursuing tumor microenvironment elements. The in vivo optical imaging system, which applied both green fluorescent protein (GFP) to trace the host cells and red fluorescent protein (RFP) to trace the tumor cells, offered great convenience for studying tumor invasion, spreading and metastasis [5][6][7][8]. The interactions between tumor cells and their microenvironmental host cells can be displayed quite directly and clearly in this dual-color model.…”

Section: Introductionmentioning

confidence: 99%