Targeting Aurora Kinase A enhances radiation sensitivity of atypical teratoid rhabdoid tumor cells

Venkataraman, Sujatha; Alimova, Irina; Tello, Tiffany; Harris, Peter; Knipstein, Jeffrey; Donson, Andrew M.; Foreman, Nicholas K.; Liu, Arthur K.; Vibhakar, Rajeev

doi:10.1007/s11060-011-0795-y

Cited by 55 publications

(37 citation statements)

References 22 publications

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“…Similar additive potentiation or synergy with TMZ or radiation has been found with the selective (Aurora-A and Aurora-B) Aurora-B inhibitor ZM447439 against primary and standard glioblastoma monolayer cell lines [23]. MLN8237 has also been found to sensitize atypical teratoid rhabdoid tumor cells to radiation [24]. …”

Section: Discussionmentioning

confidence: 71%

The selective Aurora-A kinase inhibitor MLN8237 (alisertib) potently inhibits proliferation of glioblastoma neurosphere tumor stem-like cells and potentiates the effects of temozolomide and ionizing radiation

Xin

O'Donnell

Salazar

et al. 2014

Cancer Chemother Pharmacol

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The selective Aurora-A kinase inhibitor MLN8237 is in clinical trials for hematologic malignancies, ovarian cancer and other solid tumors. We previously showed that MLN8237 is potently antiproliferative toward standard monolayer cultured glioblastoma cells. We have now investigated the effect of MLN8237 with and without temozolomide or ionizing radiation on the proliferation of glioblastoma tumor stem-like cells (neurospheres) using soft agar colony formation assays and normal human astrocytes by MTT assay. Western blotting was utilized to compare MLN8237 IC50s to cellular Aurora-A and phospho-Thr288-Aurora-A levels. MLN8237 was more potently antiproliferative to neurosphere cells than to standard monolayer glioma cells, and was non-toxic to normal human astrocytes. Western blot analysis revealed that MLN8237 treatment inhibits phospho-Thr288-Aurora–A levels providing proof of drug target-hit in glioblastoma cells. Furthermore, phospho-Thr288-Aurora-A levels partially predicted the antiproliferative efficacy of MLN8237. We also found that Aurora-A inhibition by MLN8237 was synergistic with temozolomide and potentiated the effects of ionizing radiation on colony formation in neurosphere glioblastoma tumor stem-like cells. These results further support the potential of Aurora-A inhibitors as primary chemotherapy agents or biological response modifiers in glioblastoma patients.

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Section: Discussionmentioning

confidence: 71%

The selective Aurora-A kinase inhibitor MLN8237 (alisertib) potently inhibits proliferation of glioblastoma neurosphere tumor stem-like cells and potentiates the effects of temozolomide and ionizing radiation

Xin

O'Donnell

Salazar

et al. 2014

Cancer Chemother Pharmacol

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“…Consistent with this notion, inhibition of Aurora kinases can enhance radiation sensitivity of cancer cells [25,26]. For example, inhibition of Aurora B sensitizes mesothelioma cells by enhancing mitotic arrests [27] and also potently suppresses repopulation during fractionated irradiation of human lung cancer cell lines [28].…”

Section: Introductionmentioning

confidence: 96%

Inhibition of Aurora B by CCT137690 sensitizes colorectal cells to radiotherapy

Cao

et al. 2014

J Exp Clin Cancer Res

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Colorectal cancer is the third most commonly diagnosed cancer worldwide. Although surgery remains the best treatment for this disease, adjuvant chemotherapy and radiotherapy are also very important in clinical practice. However, the notorious refractory lack of responses to radiochemotherapy greatly limits the application of radiochemotherapy in the context of colorectal cancer.There is a growing interest in the role that Aurora B may play in colorectal cancer cell survival as well as other cancer subtypes. In the current study, we sought to ascertain whether blocking of Aurora B signaling machinery by a small molecule inhibitor, CCT137690, could synergize radiation-induced colorectal cancer cell death. Results showed that CCT137690 increases the sensitivity of SW620 cells to radiation. Mechanistic studies revealed that Aurora B-Survivin pathway may be involved in this synergistic effect.Taken together, our results for the first time show that Aurora B inhibition and radiation exert a synergistic effect, resulting in enhanced colorectal cancer cell death. This synergistic effect is clinically relevant as lower doses of radiation could be used for cancer treatment, and could provide significant clinical benefits in terms of colorectal cancer management, while reducing unwanted side-effects.

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“…Clinical trials of MLN8237 in progressive solid cancer, acute myelogenous leukemia and hematopoietic organ tumors such as non-Hodgkin's lymphoma are ongoing and a phase III trial in refractory peripheral T-cell lymphoma has recently been initiated. MLN8237 also increases cisplatin-induced apoptosis in esophageal adenocarcinoma cells (24) and enhances radiosensitivity in teratoid tumor cells (25).…”

Section: Clinical Applications Of Aurora Kinase Inhibitorsmentioning

confidence: 99%

Aurora kinase inhibitors: Potential molecular-targeted drugs for gynecologic malignant tumors

et al. 2013

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Abstract. Chemotherapy and surgery are important treatment strategies for gynecologic malignant tumors such as ovarian, cervical and endometrial cancer. However, many anticancer drugs currently available are cytotoxic and cause strong adverse reactions in patients. Aurora kinases have attracted increasing attention in recent years as serine/threonine kinases with various roles in cell division, including chromosomal agglutination and segregation, functions of centromeres, centrosomal maturation, spindle formation and cytokinesis. Aurora kinases are overexpressed in a number of cancers and recent studies have shown that they are involved in onco genesis and cause an aberrant increase in centrosome number, emergence of polykaryocytes and failure of cancer inhibition mechanisms. Thus, drugs that inhibit Aurora kinases are likely to exert anticancer effects in various fields, including the gynecologic field. Aurora kinase inhibitors exert antitumor effects in monotherapy and synergistic effects in combination therapy with taxane-based anticancer agents for gynecologic tumors and are likely to increase the efficacy of existing anticancer drugs. Current Aurora kinase inhibitors include ZM447439, Hesperadin, VX-680/MK-0457, AT9283 and Barasertib, and clinical trials are ongoing to verify the effects of these inhibitors.

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Targeting Aurora Kinase A enhances radiation sensitivity of atypical teratoid rhabdoid tumor cells

Cited by 55 publications

References 22 publications

The selective Aurora-A kinase inhibitor MLN8237 (alisertib) potently inhibits proliferation of glioblastoma neurosphere tumor stem-like cells and potentiates the effects of temozolomide and ionizing radiation

The selective Aurora-A kinase inhibitor MLN8237 (alisertib) potently inhibits proliferation of glioblastoma neurosphere tumor stem-like cells and potentiates the effects of temozolomide and ionizing radiation

Inhibition of Aurora B by CCT137690 sensitizes colorectal cells to radiotherapy

Aurora kinase inhibitors: Potential molecular-targeted drugs for gynecologic malignant tumors

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