Inhibition of Aurora kinases enhances chemosensitivity to temozolomide and causes radiosensitization in glioblastoma cells

Borges, Kleiton Silva; Castro‐Gamero, Angel Mauricio; Moreno, Daniel Antunes; Silveira, Vanessa da Silva; Brassesco, María Sol; Queiróz, Rosane Gomes de Paula; Oliveira, Harley Francisco de; Carlotti, Carlos Gilberto; Scrideli, Carlos Alberto; Tone, Luíz Gonzaga

doi:10.1007/s00432-011-1111-0

Cited by 45 publications

(33 citation statements)

References 41 publications

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“…Recent research has indicated that Aurora kinase inhibitors could be used as a new strategy for GBM [40]. Diaz et al [41] reported that the inhibition of Aurora-B/C can promote apoptosis in GBM cells, and Borges et al [42] reported that inhibition of Aurora kinases enhances chemosensitivity to TMZ and causes radiosensitization in GBM, suggesting Aurora kinase inhibitors play a role for combination therapy with standard treatment for GBM, such as radiation and TMZ.…”

Section: Discussionmentioning

confidence: 99%

The Aurora Kinases Inhibitor VE-465 is a Novel Treatment for Glioblastoma Multiforme

et al. 2013

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Glioblastoma multiforme (GBM) is one of the most common and aggressive types of primary brain tumor. After complete surgical resection combined with radiation and chemotherapy, approximately 10% of patients survive for more than 5 years. Therefore, a novel therapy for GBM is needed. Aurora-A (AURKA) plays important roles in cell cycle regulation, such as centrosome maturation, chromatic separation, bipolar spindle assembly, and mitotic entry. To investigate the effects of AURKA inhibition, three GBM cell lines, including GBM 8401, GBM 8901, and U87-MG cells, were treated with the AURKA inhibitor VE-465. Sensitivities to VE-465, as indicated by 50% inhibitory concentration values for GBM 8401, GBM 8901, and U87-MG cells, were 6, 25, and 19 nM, respectively. Additionally, colony formation of GBM 8401 and GBM 8901 cells was decreased after treatment with the VE-465. VE-465 treatment increased polyploidy and p53 protein expression, and inhibited cell growth in a caspase-independent manner. Taken together, these results suggest that the inhibition of AURKA by a small-molecule inhibitor may have potential to serve as a novel therapeutic approach for GBM.

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Section: Discussionmentioning

confidence: 99%

The Aurora Kinases Inhibitor VE-465 is a Novel Treatment for Glioblastoma Multiforme

et al. 2013

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“…Currently, new kinase inhibitors are being tested in combination with Temozolomide and radiation for cancer treatment; among them, it has been reported that Aurora kinase inhibitors could be suitable for use as chemoadjuvant treatment in GBM. 42 Most interestingly, different studies have shown a certain overlap between Aurora kinases and PLK1 coregulating several processes in mitosis, and the inhibition of either of them has been shown to cause similar phenotypes. 43 In conclusion, PLK1 inhibition causes a decrease in proliferation and clonogenic formation, and an increase in apoptosis and sensitization to radiation.…”

Section: Pezuk Et Almentioning

confidence: 99%

Inhibition of Polo-Like Kinase 1 Induces Cell Cycle Arrest and Sensitizes Glioblastoma Cells to Ionizing Radiation

Pezuk

Brassesco

Morales

et al. 2013

Cancer Biotherapy and Radiopharmaceuticals

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Despite efforts to improve surgical, radiologic, and chemotherapeutic strategies, the outcome of patients with glioblastoma (GBM) is still poor. Polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays key roles in cell cycle control and has been associated with tumor growth and prognosis. Here, we aimed at testing the radiosensitizing effects of the PLK1 inhibitor BI 2536 on eight GBM cell lines. For cell cycle analysis, T98G, U251, U343 MG-a, LN319, SF188, U138 MG, and U87 MG cell lines were treated with 10, 50, or 100 nM of BI 2536 for 24 hours. In addition, cell cultures exposed to BI 2536 50 nM for 24 hours were irradiated with c-rays from 60 Cobalt source at final doses of 2, 4, and 6 Gy. Combinatorial effects were evaluated through proliferation and clonogenic capacity assays. Treatment with BI 2536 caused mitotic arrest after 24 hours, and increased apoptosis in GBM cells. Moreover, our results demonstrate that pretreatment with this drug sensitized six out of seven GBM cell lines to different doses of c-irradiation as shown by decreased growth and abrogation of colony-formation capacity. Our data suggest that PLK1 blockage has a radiosensitizing effect on GBM, which could improve treatment strategies for this devastating tumor.

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“…Therefore, it remains unclear whether Aurora kinase inhibitors will be effective as single agent or whether they will need to be combined with other agents. Several studies have reported on the benefits of combining Aurora kinase inhibitors with other anti-cancer agents such as cisplatin [18], temozolomide [19], taxanes [20], vorinostat [21] and nilotinib [22]. One notable example is the Aurora A inhibitor MLN8237, which overcomes resistance to BCR-ABL kinase inhibitors, in chronic myeloid leukemia (CML) [22].…”

Section: Introductionmentioning

confidence: 99%

Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation

et al. 2014

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Aurora A and JAK2 kinases are involved in cell division and tumor cell survival, respectively. Here we demonstrate that ectopic expression of Aurora A and JAK2 together is more effective than each alone at inducing non-transformed cells to grow in an anchorage-independent manner and to invade. Furthermore, siRNA silencing or pharmacological inhibition of Aurora A and JAK2 with Alisertib and Ruxolitinib, respectively, is more effective than blocking each kinase alone at suppressing anchorage-dependent and –independent growth and invasion as well as at inducing apoptosis. Importantly, we have developed dual Aurora and JAK inhibitors, AJI-214 and AJI-100, which potently inhibit Aurora A, Aurora B and JAK2 in vitro. In human cancer cells, these dual inhibitors block the auto-phosphorylation of Aurora A (Thr-288) and the phosphorylation of the Aurora B substrate histone H3 (Ser-10) and the JAK2 substrate STAT3 (Tyr-705). Furthermore, AJI-214 and AJI-100 inhibit anchorage dependent and independent cell growth and invasion and induce G2/M cell cycle accumulation and apoptosis. Finally, AJI-100 caused regression of human tumor xenografts in mice. Taken together, our genetic and pharmacological studies indicate that targeting Aurora A and JAK2 together is a more effective approach than each kinase alone at inhibiting malignant transformation and warrant further advanced pre clinical investigations of dual Aurora A/JAK2 inhibitors as potential anti tumor agents.

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Inhibition of Aurora kinases enhances chemosensitivity to temozolomide and causes radiosensitization in glioblastoma cells

Abstract: These data suggest that Aurora kinase inhibition may be a target for glioblastoma treatment and could be used as adjuvant to chemo- and radiotherapy.

Cited by 45 publications

References 41 publications

The Aurora Kinases Inhibitor VE-465 is a Novel Treatment for Glioblastoma Multiforme

The Aurora Kinases Inhibitor VE-465 is a Novel Treatment for Glioblastoma Multiforme

Inhibition of Polo-Like Kinase 1 Induces Cell Cycle Arrest and Sensitizes Glioblastoma Cells to Ionizing Radiation

Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation

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