Gefitinib induction of in vivo detectable signals by Bcl-2/Bcl-xL modulation of inositol trisphosphate receptor type 3.

Abstract

PURPOSE:

To test whether epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) induce detectable signals in tumor cells and whether such signals may reveal alterations of the apoptotic program.

EXPERIMENTAL DESIGN:

Tumor cells were treated with gefitinib or erlotinib and tested for their ability to accumulate 99mTc-Sestamibi, a radiolabeled lipophilic cation that localizes in mitochondria. Then we tested whether Bcl-2 and Bcl-xL alter the pattern of drug-dependent tracer accumulation while reducing tumor cell sensitivity to EGFR TKIs. The mechanism underlying the pattern of tracer accumulation was elucidated. Finally, imaging studies were done in animal models and lung cancer patients before and after treatment with EGFR TKIs using single-photon emission computed tomography and 99mTc-Sestamibi.

RESULTS:

Gefitinib increases accumulation of 99mTc-Sestamibi in Bcl-2-overexpressing cells and enhances the physical interaction of phosphorylated Bcl-2 with inositol trisphosphate receptor type 3 (IP3R3). Consequently, a relative increase of cytosolic and mitochondrial calcium levels occurs. Similarly, lung cancer cells showed an increase of tracer uptake and an enhanced interaction of Bcl-xL with IP3R3 on exposure to erlotinib concentrations achievable in plasma. The occurrence of these interactions was associated with an enhanced EGFR TKI-induced apoptosis resistance. Posttreatment imaging studies in nude mice bearing control and Bcl-2-overexpressing breast carcinomas showed a high tumor uptake of the tracer whereas baseline studies failed to visualize tumors. Similarly, an enhancement of tracer uptake could be detected in patients with lung cancer treated with erlotinib.

CONCLUSION:

EGFR TKIs generate detectable signals by Bcl-2/Bcl-xL modulation of IP3R3 in tumor cells.

• Authors: Antonella Zannetti, Francesca Iommelli, Rosa Fonti, Angela Papaccioli, Jvana Sommella, Anna Lettieri, Giuseppe Pirozzi, Roberto Bianco, Giampaolo Tortora, Marco Salvatore, Silvana Del Vecchio
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 16 Pg. 5209-19 (Aug 15 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18698039 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Inositol 1,4,5-Trisphosphate Receptors
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Quinazolines
• Radiopharmaceuticals
• bcl-X Protein
• Technetium Tc 99m Sestamibi
• Erlotinib Hydrochloride
• ErbB Receptors
• Gefitinib

Topics

• Aged
• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism)
• Cell Line, Tumor
• ErbB Receptors (drug effects, metabolism)
• Erlotinib Hydrochloride
• Female
• Gefitinib
• Humans
• Immunoprecipitation
• Inositol 1,4,5-Trisphosphate Receptors (metabolism)
• Lung Neoplasms (drug therapy, metabolism)
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mice, Nude
• Middle Aged
• Mitochondria (drug effects)
• Neoplasms (drug therapy, metabolism)
• Positron-Emission Tomography
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Quinazolines (pharmacology)
• Radiopharmaceuticals
• Signal Transduction (drug effects, physiology)
• Technetium Tc 99m Sestamibi
• bcl-X Protein (metabolism)