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IPA-3 inhibits the growth of liver cancer cells by suppressing PAK1 and NF-κB activation.

Wong LL, Lam IP, Wong TY, Lai WL, Liu HF, Yeung LL, Ching YP - PLoS ONE (2013)

Bottom Line: Furthermore, our data suggested that IPA-3 not only inhibits the HCC cell growth, but also suppresses the metastatic potential of HCC cells.Nude mouse xenograft assay demonstrated that IPA-3 treatment significantly reduced the tumor growth rate and decreased tumor volume, indicating that IPA-3 can suppress the in vivo tumor growth of HCC cells.Taken together, our demonstration of the potential preclinical efficacy of IPA-3 in HCC provides the rationale for cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

ABSTRACT
Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide and is associated with poor prognosis due to the high incidences of metastasis and tumor recurrence. Our previous study showed that overexpression of p21-activated protein kinase 1 (PAK1) is frequently observed in HCC and is associated with a more aggressive tumor behavior, suggesting that PAK1 is a potential therapeutic target in HCC. In the current study, an allosteric small molecule PAK1 inhibitor, IPA-3, was evaluated for the potential in suppressing hepatocarcinogenesis. Consistent with other reports, inhibition of PAK1 activity was observed in several human HCC cell lines treated with various dosages of IPA-3. Using cell proliferation, colony formation and BrdU incorporation assays, we demonstrated that IPA-3 treatment significantly inhibited the growth of HCC cells. The mechanisms through which IPA-3 treatment suppresses HCC cell growth are enhancement of apoptosis and blockage of activation of NF-κB. Furthermore, our data suggested that IPA-3 not only inhibits the HCC cell growth, but also suppresses the metastatic potential of HCC cells. Nude mouse xenograft assay demonstrated that IPA-3 treatment significantly reduced the tumor growth rate and decreased tumor volume, indicating that IPA-3 can suppress the in vivo tumor growth of HCC cells. Taken together, our demonstration of the potential preclinical efficacy of IPA-3 in HCC provides the rationale for cancer therapy.

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The suppressive effect of IPA-3 in nude mouse xenograft model.(A) MHCC97L cells were used for the xenograft model. Mice were treated three times weekly either with DMSO or IPA-3 (2 mg/kg or 4 mg/kg, i.p.). *P<0.001 (ANOVA) compared with the DMSO control group. (B) Tumor weights were measured at the end of study. *P<0.001, **P<0.01, (ANOVA) compared with the DMSO control group. (C) Representative results of Western blotting analysis. P-PAK1 (T423), total PAK1, P-JNK and total JNK were detected. ***P<0.05 (ANOVA) compared with the DMSO control. Error bars, mean ± SD of 5 animals per group.
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pone-0068843-g006: The suppressive effect of IPA-3 in nude mouse xenograft model.(A) MHCC97L cells were used for the xenograft model. Mice were treated three times weekly either with DMSO or IPA-3 (2 mg/kg or 4 mg/kg, i.p.). *P<0.001 (ANOVA) compared with the DMSO control group. (B) Tumor weights were measured at the end of study. *P<0.001, **P<0.01, (ANOVA) compared with the DMSO control group. (C) Representative results of Western blotting analysis. P-PAK1 (T423), total PAK1, P-JNK and total JNK were detected. ***P<0.05 (ANOVA) compared with the DMSO control. Error bars, mean ± SD of 5 animals per group.

Mentions: The breadth of IPA-3 antitumor activity in vivo was evaluated using a nude mouse xenograft model. Since the H2M cell line was unable to develop solid tumors in nude mice, another human HCC line MHCC97L with similar PAK1 level was used (Fig. 1A). Following tumor establishment (100 mm3), five mice per groups were treated with either DMSO or various doses of IPA-3 (2 mg/kg and 4 mg/kg) TIW by i.p. injection. While the treatment was well tolerated as proved by no significant weight loss, IPA-3 significantly suppressed tumor growth (Fig. 6A) and resulted in lower tumor weights (Fig. 6B). In addition, Western blotting analysis showed that IPA-3 reduced the phosphorylation of PAK1 and its downstream target JNK (Fig. 6C). Taken together, these results indicated that IPA-3 can suppress tumorigenesis in vivo by reducing the PAK1 activity.


IPA-3 inhibits the growth of liver cancer cells by suppressing PAK1 and NF-κB activation.

Wong LL, Lam IP, Wong TY, Lai WL, Liu HF, Yeung LL, Ching YP - PLoS ONE (2013)

The suppressive effect of IPA-3 in nude mouse xenograft model.(A) MHCC97L cells were used for the xenograft model. Mice were treated three times weekly either with DMSO or IPA-3 (2 mg/kg or 4 mg/kg, i.p.). *P<0.001 (ANOVA) compared with the DMSO control group. (B) Tumor weights were measured at the end of study. *P<0.001, **P<0.01, (ANOVA) compared with the DMSO control group. (C) Representative results of Western blotting analysis. P-PAK1 (T423), total PAK1, P-JNK and total JNK were detected. ***P<0.05 (ANOVA) compared with the DMSO control. Error bars, mean ± SD of 5 animals per group.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3716906&req=5

pone-0068843-g006: The suppressive effect of IPA-3 in nude mouse xenograft model.(A) MHCC97L cells were used for the xenograft model. Mice were treated three times weekly either with DMSO or IPA-3 (2 mg/kg or 4 mg/kg, i.p.). *P<0.001 (ANOVA) compared with the DMSO control group. (B) Tumor weights were measured at the end of study. *P<0.001, **P<0.01, (ANOVA) compared with the DMSO control group. (C) Representative results of Western blotting analysis. P-PAK1 (T423), total PAK1, P-JNK and total JNK were detected. ***P<0.05 (ANOVA) compared with the DMSO control. Error bars, mean ± SD of 5 animals per group.
Mentions: The breadth of IPA-3 antitumor activity in vivo was evaluated using a nude mouse xenograft model. Since the H2M cell line was unable to develop solid tumors in nude mice, another human HCC line MHCC97L with similar PAK1 level was used (Fig. 1A). Following tumor establishment (100 mm3), five mice per groups were treated with either DMSO or various doses of IPA-3 (2 mg/kg and 4 mg/kg) TIW by i.p. injection. While the treatment was well tolerated as proved by no significant weight loss, IPA-3 significantly suppressed tumor growth (Fig. 6A) and resulted in lower tumor weights (Fig. 6B). In addition, Western blotting analysis showed that IPA-3 reduced the phosphorylation of PAK1 and its downstream target JNK (Fig. 6C). Taken together, these results indicated that IPA-3 can suppress tumorigenesis in vivo by reducing the PAK1 activity.

Bottom Line: Furthermore, our data suggested that IPA-3 not only inhibits the HCC cell growth, but also suppresses the metastatic potential of HCC cells.Nude mouse xenograft assay demonstrated that IPA-3 treatment significantly reduced the tumor growth rate and decreased tumor volume, indicating that IPA-3 can suppress the in vivo tumor growth of HCC cells.Taken together, our demonstration of the potential preclinical efficacy of IPA-3 in HCC provides the rationale for cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

ABSTRACT
Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide and is associated with poor prognosis due to the high incidences of metastasis and tumor recurrence. Our previous study showed that overexpression of p21-activated protein kinase 1 (PAK1) is frequently observed in HCC and is associated with a more aggressive tumor behavior, suggesting that PAK1 is a potential therapeutic target in HCC. In the current study, an allosteric small molecule PAK1 inhibitor, IPA-3, was evaluated for the potential in suppressing hepatocarcinogenesis. Consistent with other reports, inhibition of PAK1 activity was observed in several human HCC cell lines treated with various dosages of IPA-3. Using cell proliferation, colony formation and BrdU incorporation assays, we demonstrated that IPA-3 treatment significantly inhibited the growth of HCC cells. The mechanisms through which IPA-3 treatment suppresses HCC cell growth are enhancement of apoptosis and blockage of activation of NF-κB. Furthermore, our data suggested that IPA-3 not only inhibits the HCC cell growth, but also suppresses the metastatic potential of HCC cells. Nude mouse xenograft assay demonstrated that IPA-3 treatment significantly reduced the tumor growth rate and decreased tumor volume, indicating that IPA-3 can suppress the in vivo tumor growth of HCC cells. Taken together, our demonstration of the potential preclinical efficacy of IPA-3 in HCC provides the rationale for cancer therapy.

Show MeSH
Related in: MedlinePlus