The class I PI3K/Akt pathway is critical for cancer cell survival in dogs and offers an opportunity for therapeutic intervention.

Abstract

BACKGROUND:

Using novel small-molecular inhibitors, we explored the feasibility of the class I PI3K/Akt/mTORC1 signaling pathway as a therapeutic target in canine oncology either by using pathway inhibitors alone, in combination or combined with conventional chemotherapeutic drugs in vitro.

RESULTS:

We demonstrate that growth and survival of the cell lines tested are predominantly dependent on class I PI3K/Akt signaling rather than mTORC1 signaling. In addition, the newly developed inhibitors ZSTK474 and KP372-1 which selectively target pan-class I PI3K and Akt, respectively, and Rapamycin which has been well-established as highly specific mTOR inhibitor, decrease viability of canine cancer cell lines. All inhibitors demonstrated inhibition of phosphorylation of pathway members. Annexin V staining demonstrated that KP372-1 is a potent inducer of apoptosis whereas ZSTK474 and Rapamycin are weaker inducers of apoptosis. Simultaneous inhibition of class I PI3K and mTORC1 by ZSTK474 combined with Rapamycin additively or synergistically reduced cell viability whereas responses to the PI3K pathway inhibitors in combination with conventional drug Doxorubicin were cell line-dependent.

CONCLUSION:

This study highlighted the importance of class I PI3K/Akt axis signaling in canine tumour cells and identifies it as a promising therapeutic target.

• Authors: Yu-Ting Chen, Karen Al Tan, Lisa Y Pang, David J Argyle
• Journal: BMC veterinary research (BMC Vet Res) Vol. 8 Pg. 73 (May 30 2012) ISSN: 1746-6148 [Electronic] England
• PMID: 22647622 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Heterocyclic Compounds, 4 or More Rings
• KP372-1
• Phosphoinositide-3 Kinase Inhibitors
• Tetrazoles
• Triazines
• ZSTK474
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (physiology)
• Dog Diseases (metabolism)
• Dogs
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects, physiology)
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• Humans
• Neoplasms (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Sirolimus (administration & dosage, pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Tetrazoles (pharmacology)
• Triazines (administration & dosage, pharmacology)