The combi-targeting concept: selective targeting of the epidermal growth factor receptor- and Her2-expressing cancer cells by the complex combi-molecule RB24.

Abstract

Within the context of a new tumor-targeting strategy termed "combi-targeting," we designed RB24 to inhibit epidermal growth factor receptor (EGFR) or Her2 phosphorylation and to further degrade upon hydrolysis to 4-(3'-bromophenylamino)-6-aminoquinazoline (RB10; another EGFR/Her2 inhibitor) plus a strong DNA-alkylating species. 6-(3-Acetoxymethyl-3-methyltriazenyl)-4-(3'-bromophenylamino)quinazoline (RB24) showed significant antiproliferative activity against human breast cancer cells, and transfection of one such cell line, MDA-MB-435, with ErbB1 or ErbB2 (Her2) dramatically enhanced cell death by apoptosis. RB24 was capable of releasing 2- to 3-fold higher levels of RB10 in the transfectants than in their wild-type counterparts. More importantly, RB10 was abundantly distributed in the perinuclear region of the cells, and its elevated levels in the ErbB transfectants were concomitant with increased levels of DNA lesions in the latter cells. This selectivity could be abolished by coincubation of the cells with exogenous RB10, suggesting that the entire combi-molecule may bind primarily to its cognate perinuclear sites before degradation. This localization may exert a bystander effect, allowing the alkylating species to be abundantly propagated into the nucleus. Cell response to this novel targeting mechanism was mediated by 1) activation of c-Jun NH(2)-terminal kinase in response to DNA damage and 2) down-regulation of Bad through blockade of EGFR tyrosine kinase activity: two events that cooperatively converged into enhancement of apoptosis in the oncogene-transfected cells.

• Authors: Ranjita Banerjee, Ying Huang, James P McNamee, Margarita Todorova, Bertrand J Jean-Claude
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 334 Issue 1 Pg. 9-20 (Jul 2010) ISSN: 1521-0103 [Electronic] United States
• PMID: 20348204 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 6-(3-acetoxymethyl-3-methyltriazenyl)-4-(3'-bromophenylamino)quinazoline
• Antineoplastic Agents
• BAD protein, human
• Quinazolines
• Triazenes
• bcl-Associated Death Protein
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• Oncogene Protein v-akt
• JNK Mitogen-Activated Protein Kinases
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Antineoplastic Agents (chemistry, metabolism, pharmacology)
• Cell Culture Techniques
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Comet Assay
• DNA Damage
• ErbB Receptors (antagonists & inhibitors, biosynthesis)
• Flow Cytometry
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Microscopy, Fluorescence
• Molecular Structure
• Oncogene Protein v-akt (metabolism)
• PTEN Phosphohydrolase (metabolism)
• Phosphorylation
• Quinazolines (chemistry, metabolism, pharmacology)
• Receptor, ErbB-2 (antagonists & inhibitors, biosynthesis)
• Transfection
• Triazenes (chemistry, metabolism, pharmacology)
• bcl-Associated Death Protein (metabolism)