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Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-κB impairs this drug-induced senescence.

Liu Y, Hawkins OE, Su Y, Vilgelm AE, Sobolik T, Thu YM, Kantrow S, Splittgerber RC, Short S, Amiri KI, Ecsedy JA, Sosman JA, Kelley MC, Richmond A - EMBO Mol Med (2012)

Bottom Line: Mechanistic analyses revealed that inhibition of aurora kinases induced polyploidy and the ATM/Chk2 DNA damage response, which mediated senescence and a NF-κB-related, senescence-associated secretory phenotype (SASP).Blockade of IKKβ/NF-κB led to reversal of MLN8237-induced senescence and SASP.Altogether, these data demonstrate that induction of senescence, coupled with immune surveillance, can limit melanoma growth.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.

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Combination of IKKβ/NF-κB inhibitor (BMS345541) and AURKA inhibitor (MLN8237) does not produce a synergistic inhibitory effect on tumour growthA. Patient tumour tissues (V32) were implanted subcutaneously into nude mice. After 1 week, tumour-bearing mice received daily oral doses of BMS-345541 (100 mg/kg) or MLN8237 (30 mg/kg) or both. Mean tumour volumes ± SEM are shown (n = 5).B. H&E staining of the V32 patient tumours from mice treated with vehicle, BMS345541, MLN8237, or both BMS345541 and MLN8237.C,D. Hs294T melanoma cells were injected subcutaneously into nude mice (2 × 106 cells per mouse). After 1 week, tumour-bearing mice received daily oral doses of BMS-345541 [100 mg/kg (C) or 75 mg/kg (D)] or MLN8237 (30 mg/kg) or 30 mg/kg MLN8237 combined with 100 mg/kg BMS345541 (C) or 75 mg/kg BMS345541 (D). Mean tumour volumes ± SEM are shown. (n = 5).E. Diagrammatic representation of the proposed model of MLN8237-induced senescence and senescence surveillance by immune cells.
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fig09: Combination of IKKβ/NF-κB inhibitor (BMS345541) and AURKA inhibitor (MLN8237) does not produce a synergistic inhibitory effect on tumour growthA. Patient tumour tissues (V32) were implanted subcutaneously into nude mice. After 1 week, tumour-bearing mice received daily oral doses of BMS-345541 (100 mg/kg) or MLN8237 (30 mg/kg) or both. Mean tumour volumes ± SEM are shown (n = 5).B. H&E staining of the V32 patient tumours from mice treated with vehicle, BMS345541, MLN8237, or both BMS345541 and MLN8237.C,D. Hs294T melanoma cells were injected subcutaneously into nude mice (2 × 106 cells per mouse). After 1 week, tumour-bearing mice received daily oral doses of BMS-345541 [100 mg/kg (C) or 75 mg/kg (D)] or MLN8237 (30 mg/kg) or 30 mg/kg MLN8237 combined with 100 mg/kg BMS345541 (C) or 75 mg/kg BMS345541 (D). Mean tumour volumes ± SEM are shown. (n = 5).E. Diagrammatic representation of the proposed model of MLN8237-induced senescence and senescence surveillance by immune cells.

Mentions: To extend our findings in vivo, we treated patient tumour-bearing mice with vehicle, IKKβ inhibitor (BMS345541 100 mg/kg daily), aurora kinase inhibitor (MLN8237 30 mg/kg daily), or both. After treatment, we observed no synergistic effects with combined treatment (Fig 9A). H&E staining demonstrated that disruption of IKKβ/NF-κB bypasses aurora kinase inhibitor-induced senescence (Fig 9B). Similar results were obtained in Hs294T-bearing mice with the same treatment (Fig 9C). Since BMS345541 treatment induces cell death, we reduced the dose of BMS345541 from 100 to 75 mg/kg once daily. When 75 mg/kg of BMS345541 was administered, we found that combined treatment impaired the growth inhibitory response compared to treatment with either single agent alone (Fig 9D).


Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-κB impairs this drug-induced senescence.

Liu Y, Hawkins OE, Su Y, Vilgelm AE, Sobolik T, Thu YM, Kantrow S, Splittgerber RC, Short S, Amiri KI, Ecsedy JA, Sosman JA, Kelley MC, Richmond A - EMBO Mol Med (2012)

Combination of IKKβ/NF-κB inhibitor (BMS345541) and AURKA inhibitor (MLN8237) does not produce a synergistic inhibitory effect on tumour growthA. Patient tumour tissues (V32) were implanted subcutaneously into nude mice. After 1 week, tumour-bearing mice received daily oral doses of BMS-345541 (100 mg/kg) or MLN8237 (30 mg/kg) or both. Mean tumour volumes ± SEM are shown (n = 5).B. H&E staining of the V32 patient tumours from mice treated with vehicle, BMS345541, MLN8237, or both BMS345541 and MLN8237.C,D. Hs294T melanoma cells were injected subcutaneously into nude mice (2 × 106 cells per mouse). After 1 week, tumour-bearing mice received daily oral doses of BMS-345541 [100 mg/kg (C) or 75 mg/kg (D)] or MLN8237 (30 mg/kg) or 30 mg/kg MLN8237 combined with 100 mg/kg BMS345541 (C) or 75 mg/kg BMS345541 (D). Mean tumour volumes ± SEM are shown. (n = 5).E. Diagrammatic representation of the proposed model of MLN8237-induced senescence and senescence surveillance by immune cells.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3569660&req=5

fig09: Combination of IKKβ/NF-κB inhibitor (BMS345541) and AURKA inhibitor (MLN8237) does not produce a synergistic inhibitory effect on tumour growthA. Patient tumour tissues (V32) were implanted subcutaneously into nude mice. After 1 week, tumour-bearing mice received daily oral doses of BMS-345541 (100 mg/kg) or MLN8237 (30 mg/kg) or both. Mean tumour volumes ± SEM are shown (n = 5).B. H&E staining of the V32 patient tumours from mice treated with vehicle, BMS345541, MLN8237, or both BMS345541 and MLN8237.C,D. Hs294T melanoma cells were injected subcutaneously into nude mice (2 × 106 cells per mouse). After 1 week, tumour-bearing mice received daily oral doses of BMS-345541 [100 mg/kg (C) or 75 mg/kg (D)] or MLN8237 (30 mg/kg) or 30 mg/kg MLN8237 combined with 100 mg/kg BMS345541 (C) or 75 mg/kg BMS345541 (D). Mean tumour volumes ± SEM are shown. (n = 5).E. Diagrammatic representation of the proposed model of MLN8237-induced senescence and senescence surveillance by immune cells.
Mentions: To extend our findings in vivo, we treated patient tumour-bearing mice with vehicle, IKKβ inhibitor (BMS345541 100 mg/kg daily), aurora kinase inhibitor (MLN8237 30 mg/kg daily), or both. After treatment, we observed no synergistic effects with combined treatment (Fig 9A). H&E staining demonstrated that disruption of IKKβ/NF-κB bypasses aurora kinase inhibitor-induced senescence (Fig 9B). Similar results were obtained in Hs294T-bearing mice with the same treatment (Fig 9C). Since BMS345541 treatment induces cell death, we reduced the dose of BMS345541 from 100 to 75 mg/kg once daily. When 75 mg/kg of BMS345541 was administered, we found that combined treatment impaired the growth inhibitory response compared to treatment with either single agent alone (Fig 9D).

Bottom Line: Mechanistic analyses revealed that inhibition of aurora kinases induced polyploidy and the ATM/Chk2 DNA damage response, which mediated senescence and a NF-κB-related, senescence-associated secretory phenotype (SASP).Blockade of IKKβ/NF-κB led to reversal of MLN8237-induced senescence and SASP.Altogether, these data demonstrate that induction of senescence, coupled with immune surveillance, can limit melanoma growth.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.

Show MeSH
Related in: MedlinePlus