Potent Antitumour Effects of Novel Pentabromobenzylisothioureas Studied on Human Glial-derived Tumour Cell Lines

Pucko, Emanuela; Matyja, Ewa; Koronkiewicz, Mirosława; Ostrowski, Robert P.; Kazimierczuk, Zygmunt

doi:10.21873/anticanres.12511

Cited by 8 publications

(8 citation statements)

References 45 publications

(48 reference statements)

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“…However, their reports do not provide detailed information regarding the duration of incubation with ZKK-3, or whether the results are associated with the total kinase level or only to the level of its non-phosphorylated form. Other research performed in the T98G cell line indicates that a 48-h incubation with 10 µM ZKK-3 does not alter PKD1 expression, but significantly decreases the expression level of pPKD1 (Ser 916) (26). The present results indicated that ZKK-3 did not significantly change the expression of total PKD1 in GBM cells in vitro .…”

Section: Discussionmentioning

confidence: 91%

“…Therefore, intensive research is focused on developing novel treatment strategies. S-benzylisothiourea derivatives have been investigated, with in vitro results validating their proapoptotic and cytotoxic properties against various neoplastic cells, including several types of leukemia (20,21), prostate adenocarcinoma (22) and glioma (19,26). Furthermore, compounds from this group have demonstrated greater cytotoxicity against human glioblastoma cells in vitro compared with the clinically used compound temozolomide (26).…”

Section: Discussionmentioning

confidence: 99%

“…S-benzylisothiourea derivatives have been investigated, with in vitro results validating their proapoptotic and cytotoxic properties against various neoplastic cells, including several types of leukemia (20,21), prostate adenocarcinoma (22) and glioma (19,26). Furthermore, compounds from this group have demonstrated greater cytotoxicity against human glioblastoma cells in vitro compared with the clinically used compound temozolomide (26). However, ZKKs (including ZKK-3) also demonstrated cytotoxic activity against normal human astrocytes in vitro (26), and this effect should therefore be taken into account when considering anticancer therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, compounds from this group have demonstrated greater cytotoxicity against human glioblastoma cells in vitro compared with the clinically used compound temozolomide (26). However, ZKKs (including ZKK-3) also demonstrated cytotoxic activity against normal human astrocytes in vitro (26), and this effect should therefore be taken into account when considering anticancer therapy. The cytotoxic effect of ZKKs towards normal glial elements of brain tissue could be eliminated by modern methods of precise and direct delivery of compounds to the tumor tissue.…”

Section: Discussionmentioning

confidence: 99%

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Hyperbaric oxygen increases glioma cell sensitivity to antitumor treatment with a novel isothiourea derivative in�vitro

2019

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Glioblastoma (GBM) is the most common primary brain tumor. Tumor hypoxia is a pivotal factor responsible for the progression of this malignant glioma, and its resistance to radiation and chemotherapy. Thus, improved tumor tissue oxygenation may promote greater sensitivity to anticancer treatment. Protein kinase D1 (PKD1) protects cells from oxidative stress, and its abnormal activity serves an important role in multiple malignancies. The present study examined the effects of various oxygen conditions on the cytotoxic potential of the novel isothiourea derivate N,N′-dimethyl-S-(2,3,4,5,6-pentabromobenzyl)- isothiouronium bromide (ZKK-3) against the T98G GBM cell line. ZKK-3 was applied at concentrations of 10, 25 and 50 µM, and cells were maintained under conditions of normoxia, anoxia, hypoxia, hyperbaric oxygen (HBO), hypoxia/hypoxia and hypoxia/HBO. The proliferation and viability of neoplastic cells, and protein expression levels of hypoxia-inducible factor 1α (HIF-1α), PKD1, phosphorylated (p)PKD1 (Ser 916) and pPKD1 (Ser 744/748) kinases were evaluated. Oxygen deficiency, particularly regarding hypoxia, could diminish the cytotoxic effect of ZKK-3 at 25 and 50 µM and improve T98G cell survival compared with normoxia. HBO significantly reduced cell proliferation and increased T98G cell sensitivity to ZKK-3 when compared with normoxia. HIF-1α expression levels were increased under hypoxia compared with normoxia and decreased under HBO compared with hypoxia/hypoxia at 0, 10 and 50 µM ZKK-3, suggesting that HBO improved oxygenation of the cells. ZKK-3 exhibited inhibitory activity against pPKD1 (Ser 916) kinase; however, the examined oxygen conditions did not appear to significantly influence the expression of this phosphorylated form in cells treated with the tested compound. Regarding pPKD1 (Ser 744/748), a significant difference in expression was observed only for cells treated with 10 µM ZKK-3 and hypoxia/hypoxia compared with normoxia. However, there were significant differences in the expression levels of both phosphorylated forms of PKD1 under different oxygen conditions in the controls. In conclusion, the combination of isothiourea derivatives and hyperbaric oxygenation appears to be a promising therapeutic approach for malignant glioma treatment.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hyperbaric oxygen increases glioma cell sensitivity to antitumor treatment with a novel isothiourea derivative in�vitro

2019

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“…Modification of a biologically active molecule by introducing various substituents may result in an unexpected effect. For example, the addition of chlorine in the structure of a compound may result in its low or no cytotoxic activity, as in the case of BEN compound, which showed very little or no cytotoxicity towards low-(G1) and high-grade (G4) glioma cells [97]. TBB, TBI, and DMAT compounds show strong CK2 inhibitory properties, while S-pentabromobenzylisothiourea derivatives, which are structurally similar to polybrominated compounds (TBB, TBI, DMAT), show a distinct protein kinase inhibition profile.…”

Section: Cx-4945mentioning

confidence: 99%

Inhibiting CK2 among Promising Therapeutic Strategies for Gliomas and Several Other Neoplasms

Pucko

Ostrowski

2022

Pharmaceutics

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In gliomas, casein kinase 2 (CK2) plays a dominant role in cell survival and tumour invasiveness and is upregulated in many brain tumours. Among CK2 inhibitors, benzimidazole and isothiourea derivatives hold a dominant position. While targeting glioma tumour cells, they show limited toxicity towards normal cells. Research in recent years has shown that these compounds can be suitable as components of combined therapies with hyperbaric oxygenation. Such a combination increases the susceptibility of glioma tumour cells to cell death via apoptosis. Moreover, researchers planning on using any other antiglioma investigational pharmaceutics may want to consider using these agents in combination with CK2 inhibitors. However, different compounds are not equally effective when in such combination. More research is needed to elucidate the mechanism of treatment and optimize the treatment regimen. In addition, the role of CK2 in gliomagenesis and maintenance seems to have been challenged recently, as some compounds structurally similar to CK2 inhibitors do not inhibit CK2 while still being effective at reducing glioma viability and invasion. Furthermore, some newly developed inhibitors specific for CK2 do not appear to have strong anticancer properties. Further experimental and clinical studies of these inhibitors and combined therapies are warranted.

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The mesoionic compound MI-D changes energy metabolism and induces apoptosis in T98G glioma cells

et al. 2022

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Potent Antitumour Effects of Novel Pentabromobenzylisothioureas Studied on Human Glial-derived Tumour Cell Lines

Abstract: Our findings indicated that modified ZKKs show promise for the treatment of glioma-derived brain tumours.

Cited by 8 publications

References 45 publications

Hyperbaric oxygen increases glioma cell sensitivity to antitumor treatment with a novel isothiourea derivative in�vitro

Hyperbaric oxygen increases glioma cell sensitivity to antitumor treatment with a novel isothiourea derivative in�vitro

Inhibiting CK2 among Promising Therapeutic Strategies for Gliomas and Several Other Neoplasms

The mesoionic compound MI-D changes energy metabolism and induces apoptosis in T98G glioma cells

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