Combined Targeted Inhibition of bcl-2, bcl-XL, Epidermal Growth Factor Receptor, and Protein Kinase A Type I Causes Potent Antitumor, Apoptotic, and Antiangiogenic Activity

• Published in: Clinical cancer research Vol. 9; no. 2; pp. 866 - 871
• Main Authors: TORTORA, Giampaolo, CAPUTO, Rosa, DAMIANO, Vincenzo, CAPUTO, Roberta, TROIANI, Teresa, VENEZIANI, Bianca Maria, DE PLACIDO, Sabino, BIANCO, Angelo Raffaele, ZANGEMEISTER-WITTKE, Uwe, CIARDIELLO, Fortunato
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.02.2003
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - physiology; bcl-X Protein; Biological and medical sciences; Breast Neoplasms - blood supply; Breast Neoplasms - pathology; Cell Death; Cell Division - drug effects; Cell Division - physiology; Chemotherapy; Colonic Neoplasms - blood supply; Colonic Neoplasms - pathology; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Endothelial Growth Factors - secretion; Female; Humans; Intercellular Signaling Peptides and Proteins - secretion; Lymphokines - secretion; Medical sciences; Mice; Mice, Nude; Neovascularization, Pathologic - prevention & control; Oligonucleotides; Oligonucleotides, Antisense - pharmacology; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Quinazolines - toxicity; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Transfection; Transplantation, Heterologous; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Antineoplastic agent; Protein kinase A; Epidermal growth factor receptor; Angiogenesis; Epidermal growth factor; Established cell line; Intestinal disease; Colon; Mammary gland; Antiangiogenic agent; Protein-tyrosine kinase; Tumor cell; Protooncogene; Human; Drug combination; Enzyme; Transferases; Rodentia; Enzyme inhibitor; Malignant tumor; Antisense oligonucleotide; In vitro; Biological activity; Colonic disease; Mammary gland diseases; In vivo; Vertebrata; Chemotherapy; Growth factor receptor; Mammalia; Treatment; Mouse; Cell death; Protein kinase; Animal; C-Onc gene; Digestive diseases; Apoptosis
• ISSN: 1078-0432; 1557-3265

Purpose: This study investigated whether the functional and structural interactions between epidermal growth factor receptor (EGFR), protein kinase AI (PKAI), and bcl -2/ bcl -xL could be exploited to obtain cooperative antitumor effects against models of human colon and breast cancer. Experimental design: Antisense bcl -2/ bcl -xL (4625), antisense PKAI (AS-PKAI), and ZD1839 (“Iressa”), a selective EGFR tyrosine kinase inhibitor, were administered as single agents and in combination against GEO colon and ZR-75-1 breast cancer cell lines in vitro and to mice bearing s.c. GEO human tumor xenografts in vivo . Effects on growth inhibition, vascular endothelial growth factor secretion, and induction of apoptosis were assessed. Results: Antisense bcl -2/ bcl -xL inhibited the growth of GEO and ZR-75-1 cells in vitro , reducing bcl -2 and bcl -xL expression and vascular endothelial growth factor secretion. Supra-additive growth inhibition and apoptosis induction were observed when 4625 was combined with ZD1839 or AS-PKAI. Combining all three agents resulted in a complete growth inhibitory effect in vitro . Antisense bcl -2/ bcl -xL, AS-PKAI, and ZD1839 administered in vivo as single agents caused growth inhibition of GEO xenografts. Combining all three agents caused a marked and sustained effect, with 50% growth inhibition and 50% of mice tumor free 5 weeks after treatment withdrawal. The combination was well tolerated. Conclusions: The combination of 4625, AS-PKAI, and ZD1839 resulted in a strong antiproliferative, proapoptotic, and antiangiogenic response, suggestive of a functional interaction between EGFR, PKAI, and bcl -2/ bcl -xL and providing a rationale for the selection of specific molecular treatments for the development of therapeutic strategies. Iressa is a trademark of the AstraZeneca group of companies.