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Group I Paks as therapeutic targets in NF2-deficient meningioma.

Chow HY, Dong B, Duron SG, Campbell DA, Ong CC, Hoeflich KP, Chang LS, Welling DB, Yang ZJ, Chernoff J - Oncotarget (2015)

Bottom Line: In addition, we found a strong reduction in phosphorylation of Mek and S6, and decreased cyclin D1 expression in both cell lines after treatment with Pak inhibitors.Using intracranial xenografts of luciferase-expressing KT21-MG1 cells, we found that treated mice showed significant tumor suppression for all three Pak inhibitors.Similar effects were observed in Ben-Men1 cells.

View Article: PubMed Central - PubMed

Affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.

ABSTRACT
Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system, most notably schwannomas and meningiomas. Mutational inactivation of NF2 is found in 40-60% of sporadic meningiomas, but the molecular mechanisms underlying malignant changes of meningioma cells remain unclear. Because group I p21-activated kinases (Paks) bind to and are inhibited by the NF2-encoded protein Merlin, we assessed the signaling and anti-tumor effects of three group-I specific Pak inhibitors - Frax597, 716 and 1036 - in NF2-/- meningiomas in vitro and in an orthotopic mouse model. We found that these Pak inhibitors suppressed the proliferation and motility of both benign (Ben-Men1) and malignant (KT21-MG1) meningiomas cells. In addition, we found a strong reduction in phosphorylation of Mek and S6, and decreased cyclin D1 expression in both cell lines after treatment with Pak inhibitors. Using intracranial xenografts of luciferase-expressing KT21-MG1 cells, we found that treated mice showed significant tumor suppression for all three Pak inhibitors. Similar effects were observed in Ben-Men1 cells. Tumors dissected from treated animals exhibited an increase in apoptosis without notable change in proliferation. Collectively, these results suggest that Pak inhibitors might be useful agents in treating NF2-deficient meningiomas.

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Pak inhibitors suppressed tumor growth in an orthotopic meningioma modelMice bearing tumors were established as described in Materials and Methods and tumor growth was monitored by BLI. (A) A representative image showed the bioluminescent signal in the mice bearing KT21 cells, which treated with Pak inhibitors (Frax597, 716 and 1036) and mice treated with vehicle used as a control. Quantitation of bioluminescent signals detected in tumors was conducted from 5 animals per group imaged for 2 weeks. (B) A representative image showed the bioluminescent signal in the mice bearing Ben-Men cells, which treated with Pak inhibitors (Frax597, 716 and 1036) and mice treated with vehicle used as a control. Quantitation of bioluminescent signals detected in tumors was conducted from 5 animals per group imaged for 3 weeks. *P < 0.05, **P < 0.005, student's t-test.
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Figure 5: Pak inhibitors suppressed tumor growth in an orthotopic meningioma modelMice bearing tumors were established as described in Materials and Methods and tumor growth was monitored by BLI. (A) A representative image showed the bioluminescent signal in the mice bearing KT21 cells, which treated with Pak inhibitors (Frax597, 716 and 1036) and mice treated with vehicle used as a control. Quantitation of bioluminescent signals detected in tumors was conducted from 5 animals per group imaged for 2 weeks. (B) A representative image showed the bioluminescent signal in the mice bearing Ben-Men cells, which treated with Pak inhibitors (Frax597, 716 and 1036) and mice treated with vehicle used as a control. Quantitation of bioluminescent signals detected in tumors was conducted from 5 animals per group imaged for 3 weeks. *P < 0.05, **P < 0.005, student's t-test.

Mentions: Untreated mice bearing KT21 transplants displayed ventricular invasion (Fig. S5), whereas Ben-Men grew at the injection site only (not shown), consistent with a previous report [34]. Treatment with Frax597 impaired KT21 tumor growth by 50% compared to vehicle cohort (Fig. 5A). Larger effects were noted in Frax716-treated mice, with reduction on bioluminescence of 60% (P = 0.028). However, these animals also showed >10% loss of body weight compared with control littermates (Fig. S6A), an effect not seen in mice treated with Frax597 or Frax1036. Treatment with Frax1036 also resulted in slower tumor growth, with reduction in BMI signals of 37% (P = 0.042; Fig. 5A). It should be noted that, when tested in MDCK cells, FRAX1036 has low permeability and is subjected to extensive efflux, and is hence unlikely to have significant blood brain barrier permeability in mice (apparent permeability (Papp), apical to basolateral = 1 × 10−6 cm/s; basolateral to apical = 22.2 × 10−6 cm/s; Papp ratio = 22.6).


Group I Paks as therapeutic targets in NF2-deficient meningioma.

Chow HY, Dong B, Duron SG, Campbell DA, Ong CC, Hoeflich KP, Chang LS, Welling DB, Yang ZJ, Chernoff J - Oncotarget (2015)

Pak inhibitors suppressed tumor growth in an orthotopic meningioma modelMice bearing tumors were established as described in Materials and Methods and tumor growth was monitored by BLI. (A) A representative image showed the bioluminescent signal in the mice bearing KT21 cells, which treated with Pak inhibitors (Frax597, 716 and 1036) and mice treated with vehicle used as a control. Quantitation of bioluminescent signals detected in tumors was conducted from 5 animals per group imaged for 2 weeks. (B) A representative image showed the bioluminescent signal in the mice bearing Ben-Men cells, which treated with Pak inhibitors (Frax597, 716 and 1036) and mice treated with vehicle used as a control. Quantitation of bioluminescent signals detected in tumors was conducted from 5 animals per group imaged for 3 weeks. *P < 0.05, **P < 0.005, student's t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385830&req=5

Figure 5: Pak inhibitors suppressed tumor growth in an orthotopic meningioma modelMice bearing tumors were established as described in Materials and Methods and tumor growth was monitored by BLI. (A) A representative image showed the bioluminescent signal in the mice bearing KT21 cells, which treated with Pak inhibitors (Frax597, 716 and 1036) and mice treated with vehicle used as a control. Quantitation of bioluminescent signals detected in tumors was conducted from 5 animals per group imaged for 2 weeks. (B) A representative image showed the bioluminescent signal in the mice bearing Ben-Men cells, which treated with Pak inhibitors (Frax597, 716 and 1036) and mice treated with vehicle used as a control. Quantitation of bioluminescent signals detected in tumors was conducted from 5 animals per group imaged for 3 weeks. *P < 0.05, **P < 0.005, student's t-test.
Mentions: Untreated mice bearing KT21 transplants displayed ventricular invasion (Fig. S5), whereas Ben-Men grew at the injection site only (not shown), consistent with a previous report [34]. Treatment with Frax597 impaired KT21 tumor growth by 50% compared to vehicle cohort (Fig. 5A). Larger effects were noted in Frax716-treated mice, with reduction on bioluminescence of 60% (P = 0.028). However, these animals also showed >10% loss of body weight compared with control littermates (Fig. S6A), an effect not seen in mice treated with Frax597 or Frax1036. Treatment with Frax1036 also resulted in slower tumor growth, with reduction in BMI signals of 37% (P = 0.042; Fig. 5A). It should be noted that, when tested in MDCK cells, FRAX1036 has low permeability and is subjected to extensive efflux, and is hence unlikely to have significant blood brain barrier permeability in mice (apparent permeability (Papp), apical to basolateral = 1 × 10−6 cm/s; basolateral to apical = 22.2 × 10−6 cm/s; Papp ratio = 22.6).

Bottom Line: In addition, we found a strong reduction in phosphorylation of Mek and S6, and decreased cyclin D1 expression in both cell lines after treatment with Pak inhibitors.Using intracranial xenografts of luciferase-expressing KT21-MG1 cells, we found that treated mice showed significant tumor suppression for all three Pak inhibitors.Similar effects were observed in Ben-Men1 cells.

View Article: PubMed Central - PubMed

Affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.

ABSTRACT
Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system, most notably schwannomas and meningiomas. Mutational inactivation of NF2 is found in 40-60% of sporadic meningiomas, but the molecular mechanisms underlying malignant changes of meningioma cells remain unclear. Because group I p21-activated kinases (Paks) bind to and are inhibited by the NF2-encoded protein Merlin, we assessed the signaling and anti-tumor effects of three group-I specific Pak inhibitors - Frax597, 716 and 1036 - in NF2-/- meningiomas in vitro and in an orthotopic mouse model. We found that these Pak inhibitors suppressed the proliferation and motility of both benign (Ben-Men1) and malignant (KT21-MG1) meningiomas cells. In addition, we found a strong reduction in phosphorylation of Mek and S6, and decreased cyclin D1 expression in both cell lines after treatment with Pak inhibitors. Using intracranial xenografts of luciferase-expressing KT21-MG1 cells, we found that treated mice showed significant tumor suppression for all three Pak inhibitors. Similar effects were observed in Ben-Men1 cells. Tumors dissected from treated animals exhibited an increase in apoptosis without notable change in proliferation. Collectively, these results suggest that Pak inhibitors might be useful agents in treating NF2-deficient meningiomas.

Show MeSH
Related in: MedlinePlus