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

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.

• Authors: Mi Na Kim, Simon Weonsang Ro, Do Young Kim, Da Young Kim, Kyung-Ju Cho, Jeon Han Park, Ho Yeong Lim, Kwang-Hyub Han
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 76 Issue 2 Pg. 257-67 (Aug 2015) ISSN: 1432-0843 [Electronic] Germany
• PMID: 26037205 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• DNA Transposable Elements
• Phenylurea Compounds
• RNA, Small Interfering
• Tumor Suppressor Protein p53
• Phosphorylcholine
• Niacinamide
• perifosine
• Sorafenib
• Poly(ADP-ribose) Polymerases
• Caspase 3
• Caspase 9
• HRAS protein, human
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (blood supply, drug therapy, pathology)
• Caspase 3 (metabolism)
• Caspase 9 (metabolism)
• Cell Proliferation (drug effects)
• DNA Transposable Elements
• Drug Synergism
• Liver Neoplasms, Experimental (blood supply, drug therapy, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neovascularization, Pathologic (drug therapy)
• Niacinamide (analogs & derivatives, therapeutic use)
• Phenylurea Compounds (therapeutic use)
• Phosphorylcholine (analogs & derivatives, therapeutic use)
• Poly(ADP-ribose) Polymerases (metabolism)
• Proto-Oncogene Proteins p21(ras) (genetics)
• RNA, Small Interfering (genetics)
• Sorafenib
• Tumor Suppressor Protein p53 (genetics)