Rational Incorporation of Selenium into Temozolomide Elicits Superior Antitumor Activity Associated with Both Apoptotic and Autophagic Cell Death

Cheng, Yan; Sk, Ugir Hossain; Zhang, Yi; Ren, Xingcong; Zhang, Li; Huber-Keener, Kathryn J.; Sun, Yuan; Liao, Jason; Amin, Shantu; Sharma, Arun; Yang, Jin Ming

doi:10.1371/journal.pone.0035104

Cited by 31 publications

(31 citation statements)

References 25 publications

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“…Thus, the dynamics of these structures are essential in normal cell physiology [37–39]. For this reason, a variety of antitumor agents with action on microtubules have been developed [20].…”

Section: Discussionmentioning

confidence: 99%

Human Lung Cancer Cell Line A-549 ATCC Is Differentially Affected by Supranutritional Organic and Inorganic Selenium

Villavicencio

Cruz-Jiménez

Barbosa‐Sabanero

et al. 2014

Bioinorganic Chemistry and Applications

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The effects of organic and inorganic forms of selenium (Se) on human cells have been extensively studied for nutritional concentrations; however, to date, little is known about the potential toxicity at supranutritional levels. In the present study we determined the effects of sodium selenite (SSe) and selenomethionine (SeMet) on cell growth and intracellular structures in lung cancer cells exposed at Se concentrations between 0 and 3 mM. Our results showed that SSe affected cell growth more rapidly than SeMet (24 h and 48 h, resp.). After 24 h of cells exposure to 0.5, 1.5, and 3 mM SSe, cell growth was reduced by 10, 50, and 60%, as compared to controls. After 48 h, nuclear fragmentation was evident in cells exposed to SSe, suggesting an induction to cell death. In contrast, SeMet did not affect cell proliferation, and the cells were phenotypically similar to controls. Microtubules and microfilaments structures were also affected by both Se compounds, again SSe being more toxic than SeMet. To our knowledge, this is the first report on the differential effects of organic and inorganic Se in supranutritional levels in lung cancer cells.

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Section: Discussionmentioning

confidence: 99%

Human Lung Cancer Cell Line A-549 ATCC Is Differentially Affected by Supranutritional Organic and Inorganic Selenium

Villavicencio

Cruz-Jiménez

Barbosa‐Sabanero

et al. 2014

Bioinorganic Chemistry and Applications

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“…42,51,52 To our knowledge, only one derivative has outperformed TMZ in an intracranial murine model of GBM, bestowing a modest 10% increase in median survival. 53 Clearly, the interplay between retaining the favorable properties that have kept TMZ as frontline treatment for GBM and modulating its structure is not trivial.…”

Section: Resultsmentioning

confidence: 88%

Tunable Stability of Imidazotetrazines Leads to a Potent Compound for Glioblastoma

et al. 2018

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Even in the era of personalized medicine and immunotherapy, temozolomide (TMZ), a small molecule DNA alkylating agent, remains the standard-of-care for glioblastoma (GBM). TMZ has an unusual mode-of-action, spontaneously converting to its active component via hydrolysis in vivo. While TMZ has been FDA approved for two decades, it provides little benefit to patients whose tumors express the resistance enzyme MGMT and gives rise to systemic toxicity through myelosuppression. TMZ was first synthesized in 1984, but certain key derivatives have been inaccessible due to the chemical sensitivity of TMZ, precluding broad exploration of the link between imidazotetrazine structure and biological activity. Here, we sought to discern the relationship between the hydrolytic stability and anticancer activity of imidazotetrazines, with the objectives of identifying optimal timing for prodrug activation and developing suitable compounds with enhanced efficacy via increased blood-brain barrier penetrance. This work necessitated the development of new synthetic methods to provide access to previously unexplored functionality (such as aliphatic, ketone, halogen, and aryl groups) at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 h), we derive a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM. This work points a clear path forward for the development of novel and effective anticancer imidazotetrazines.

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“…TMZ, the first-line chemotherapeutic drug for GBM treatment, causes cancer cell death by inducing DNA double strand breaks [36, 37], but the human glioblastoma cell line LN229 has a high degree of resistance to TMZ [38, 39]. In the orthotopic xenograft mouse model, compared with the TMZ and siPSMB4 groups, the combination of TMZ-siPSMB4 group inhibited the progression of GBM tumors.…”

Section: Discussionmentioning

confidence: 99%

Interference with PSMB4 Expression Exerts an Anti-Tumor Effect by Decreasing the Invasion and Proliferation of Human Glioblastoma Cells

Cheng

Tsai

Sung

et al. 2018

Cell Physiol Biochem

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Background/Aims: Glioblastoma (GBM) is a malignant brain tumor with a poor prognosis. Proteasome subunit beta type-4 (PSMB4) is an essential subunit that contributes to the assembly of the 20S proteasome complex. However, the role of PSMB4 in glioblastomas remains to be clarified. The aim of this study was to investigate the role of PSMB4 in GBM tumor progression. Methods: We first analyzed the PSMB4 protein and mRNA expression in 80 clinical brain specimens and 77 datasets from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. Next, we inhibited the PSMB4 expression by siRNA in cellular and animal models to explore PSMB4’s underlying mechanisms. The cell survival after siPSMB4 transfection was assayed by MTT assay. Annexin V and propidium iodide staining was used to monitor the apoptosis by flow cytometric analysis. Moreover, the migration and invasion were evaluated by wound healing and Transwell assays. The expression of migration-related and invasion-related proteins after PSMB4 inhibition was detected by Western blotting. In addition, an orthotropic xenograft mouse model was used to assay the effect of PSMB4 knockdown in the in vivo study. Results: Basis on the results of bioinformatics study, glioma patients with higher PSMB4 expression had a shorter survival time than those with lower PSMB4 expression. The staining of clinical brain tissues showed elevated PSMB4 expression in GBM tissues compared with normal brain tissues. The PSMB4 inhibition decreased proliferation, migration and invasion abilities in human GBM cells. Downregulated PSMB4 resulted in cell cycle arrest and apoptosis in vitro. In an orthotropic xenograft mouse model, the glioma tumors progression was reduced when PSMB4 was down-regulated. The decreased PSMB4 enhanced the anti-tumor effect of temozolomide (TMZ) on tumor growth. In addition, the absence of PSMB4 decreased the expression of phosphorylated focal adhesion kinase and matrix metallopeptidase 9 in vivo. Conclusion: PSMB4 inhibition in combination with TMZ may exert an anti-tumor effect by decreasing cell proliferation and invasion as well as by promoting apoptosis in human glioblastoma cells. This research may improve the therapeutic efficacy of glioblastoma treatment.

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Rational Incorporation of Selenium into Temozolomide Elicits Superior Antitumor Activity Associated with Both Apoptotic and Autophagic Cell Death

Cited by 31 publications

References 25 publications

Human Lung Cancer Cell Line A-549 ATCC Is Differentially Affected by Supranutritional Organic and Inorganic Selenium

Human Lung Cancer Cell Line A-549 ATCC Is Differentially Affected by Supranutritional Organic and Inorganic Selenium

Tunable Stability of Imidazotetrazines Leads to a Potent Compound for Glioblastoma

Interference with PSMB4 Expression Exerts an Anti-Tumor Effect by Decreasing the Invasion and Proliferation of Human Glioblastoma Cells

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