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Efficacy of perifosine alone and in combination with sorafenib in an HrasG12V plus shp53 transgenic mouse model of hepatocellular carcinoma

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Abstract

Purpose

Perifosine has shown antitumor activity via inhibition of Akt phosphorylation in many advanced solid tumors. This study investigated the efficacy of perifosine alone and in combination with sorafenib in a transgenic mouse model of HCC.

Methods

The mouse model of HCC was generated by hydrodynamic injection of transposons encoding HrasG12V and short-hairpin RNA downregulating p53. The transgenic mice were treated with perifosine alone and in combination with sorafenib to evaluate efficacy of drugs on tumor growth and survival.

Results

Treatment with perifosine for 5 weeks, alone and in combination with sorafenib, strongly inhibited tumor growth and increased survival. Perifosine inhibited HCC cell proliferation, induced apoptosis, and decreased tumor angiogenesis. Furthermore, its combination with sorafenib enhanced these effects. In addition, Akt phosphorylation was decreased by perifosine and further decreased by combination treatment. Although perifosine alone did not appear to activate the caspase pathway, combination treatment increased the cleavage of caspase-3, caspase-9, and poly (ADP-ribose) polymerase.

Conclusions

The preclinical effect that current study showed represents a strong rationale for clinical trials using perifosine alone and in combination with sorafenib in the treatment of HCC patients.

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Abbreviations

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

ALP:

Alkaline phosphatase

ERK:

Extracellular signal-regulated kinase

HCC:

Hepatocellular carcinoma

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GEM:

Genetically engineered mouse

MAPK:

Mitogen-activated protein kinase

MEK:

MAPK kinase

PARP:

Poly (ADP-ribose) polymerase

PI3K:

Phosphatidylinositol 3-kinase

SD:

Standard deviation

Shp53:

Short-hairpin RNA downregulating p53

TUNEL:

Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling

VEGF:

Vascular endothelial growth factor

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Acknowledgments

This research was supported by grants from the Korean Association for the Study of Liver and was supported by a faculty research grant of Yonsei University College of Medicine for 2013 (6-2013-0004). The authors are grateful to Dong-Su Jang (Medical Illustrator, Medical Research Support Section, Yonsei University College of Medicine, Seoul, Korea) for his help with the figure.

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Authors and Affiliations

  1. Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, Korea

    Mi Na Kim, Do Young Kim & Kwang-Hyub Han

  2. Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea

    Simon Weonsang Ro, Do Young Kim, Da Young Kim, Kyung-Ju Cho & Kwang-Hyub Han

  3. Department of Microbiology, Yonsei University College of Medicine, Seoul, Korea

    Jeon Han Park

  4. Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Ho Yeong Lim

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  1. Mi Na Kim
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Correspondence to Do Young Kim or Kwang-Hyub Han.

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Kim, M.N., Ro, S.W., Kim, D.Y. et al. Efficacy of perifosine alone and in combination with sorafenib in an HrasG12V plus shp53 transgenic mouse model of hepatocellular carcinoma. Cancer Chemother Pharmacol 76, 257–267 (2015). https://doi.org/10.1007/s00280-015-2787-7

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