Sustained antiproliferative mechanisms by RB24, a targeted precursor of multiple inhibitors of epidermal growth factor receptor and a DNA alkylating agent in the A431 epidermal carcinoma of the vulva cell line

Banerjee, Ranjita; Rachid, Zakaria; Qiu, Qiyu; McNamee, James P.; Tari, Ana M.; Jean‐Claude, Bertrand J.

doi:10.1038/sj.bjc.6602098

Cited by 17 publications

(12 citation statements)

References 38 publications

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“…Here, we describe a similar strategy based on the use of a small-molecule approach to target EGFR or Her2 TK-mediated signaling pathways while damaging DNA. This strategy, termed "combi-targeting," seeks to design a single molecule targeted to the TK function of Her2 or EGFR and programmed to be a latent DNA-damaging agent (Matheson et al, 2001(Matheson et al, , 2003(Matheson et al, , 2004aBrahimi et al, 2002Brahimi et al, , 2004Banerjee et al, 2003Banerjee et al, , 2004Rachid et al, 2003;Qiu et al, 2004).…”

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confidence: 99%

The Combi-Targeting Concept: Selective Targeting of the Epidermal Growth Factor Receptor- and Her2-Expressing Cancer Cells by the Complex Combi-Molecule RB24

Banerjee

Huang²,

McNamee³

et al. 2010

J Pharmacol Exp Ther

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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-(3Ј-bromophenylamino)-6-aminoquinazoline (RB10; another EGFR/Her2 inhibitor) plus a strong DNA-alkylating species. 6-(3-Acetoxymethyl-3-methyltriazenyl)-4-(3Ј-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.Members of the epidermal growth factor (EGF) family of receptors, including EGFR, Her2 (ErbB2), and EGFRvIII (truncated EGFR), are overexpressed in 20 to 40% of breast cancers (Tang et al., 2000). The Her2 receptor, the closest EGFR homolog, is overexpressed in 20 to 25% of overall breast cancers, 60 to 70% of ductal carcinoma in situ, and is often associated with highly aggressive tumor phenotypes and poor disease-free survival (Slamon et al., 1989;Arteaga, 2001). For example, the average survival of breast cancer patients with Her2-positive tumors is 2 to 3 years compared with 6 to 7 years of Her2-negative tumors (Slamon et al., 1987;Borg et al., 1990). More importantly, this dysfunction is also associated with resistance to endocrine therapy and chemotherapy (Slamon et al., 1987). The significant implication of the ErbB family members in tumor progression has made them important targets for breast cancer therapy. Indeed, blockade of EGFR or Her2 has proven highly effective in breast xenograft models and in the clinic (Ciardiello et al., 1999; Molder et al., 2001). Although gefitinib (Iressa, ZD1839) that targets the EGFR tyrosine kinase (TK) has shown moderate activity in breast cancer models, trastuzumab (Herceptin), a monoclonal antibody directed toward Her2, has demonstrated significant activity in advanced

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confidence: 99%

The Combi-Targeting Concept: Selective Targeting of the Epidermal Growth Factor Receptor- and Her2-Expressing Cancer Cells by the Complex Combi-Molecule RB24

Banerjee

Huang²,

McNamee³

et al. 2010

J Pharmacol Exp Ther

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“…Combi-molecules such as SMA41 and RB24 have been shown to block EGFR and to methylate DNA (7,27). Although numerous studies from our group have confirmed the dual actions of combi-molecules (7)(8)(9), little is known about the optimal condition under which they exhibit their optimal potency.…”

Section: Discussionmentioning

confidence: 99%

MGMT Is a Molecular Determinant for Potency of the DNA-EGFR–Combi-Molecule ZRS1

Huang¹,

Rachid²,

Jean‐Claude³

2011

Molecular Cancer Research

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To enhance the potency of current EGFR inhibitors, we developed a novel strategy that seeks to confer them an additional DNA damaging function, leading to the design of drugs termed combi-molecules. ZRS1 is a novel combi-molecule that contains an EGFR tyrosine kinase targeting quinazoline arm and a methyltriazenebased DNA damaging one. We examined its effect on human tumor cell lines with varied levels of EGFR and O6-methylguanine DNA methyltransferase (MGMT). ZRS1 was more potent than the clinical methylating agent temozolomide in all cell lines, regardless of their MGMT status. However, its potency was in the same range as or less than that of Iressa, an EGFR inhibitor, against MGMT-proficient cells. In the MGMTdeficient or in MGMT-proficient cells exposed to the MGMT inhibitor O6-benzylguanine, its potency was superior to that of Iressa and temozolomide or a temozolomideþIressa combination. Cell signaling analysis in A549 (MGMT þ ) and A427 (MGMT -) showed that ZRS1 strongly inhibited EGFR phosphorylation and related signaling pathways. In addition, the p53 pathway was activated by DNA damage in both cell lines, but apoptosis was significantly more pronounced in A427 cells. Using MGMT shRNA to block endogenous MGMT protein expression in A549 resulted in significant sensitization to ZRS1. Furthermore, transfection of MGMT into A427 greatly decreased the potency of ZRS1. These results conclusively show that MGMT is a critical molecular determinant for the full-blown potency of the dual EGFR-DNA targeting combi-molecule. Mol Cancer Res; 9(3); 320-31. Ó2011 AACR.

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“…1). This type of molecules RB24 [21,22] or RB107 [23] showed half-lives in the 45 minute range. With the purpose of enhancing the bioavailability of combi-molecules of the triazene class, we recently sought to further stabilize them by synthesizing a series of quinazoline-based 1,2,3-triazenes containing a hydrolabile carbamate at the 3-position of the triazene chain [24].…”

Section: Introductionmentioning

confidence: 95%

“…We recently developed a novel strategy termed "combitargeting" [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][26][27][28][29] that seeks to design molecules designated as "combi-molecules", capable of not only blocking the tyrosine kinase activity of EGFR, but also damaging the DNA of the cells, thereby conferring cytotoxic properties to these inhibitors. At the advanced stages, many solid tumours including breast, prostate and lung carcinomas overexpress EGFR, a receptor that in many cases activate the PI3K-Akt pathway, thereby leading to resistance to apoptosis [1,2].…”

Section: Introductionmentioning

confidence: 99%

“…The first prototypes of combi-molecules SMA41 and BJ2000 were 6-triazenoquinazolines, which in addition to poor water solubility were rather short-lived with t 1/2 in the 30 min range. Work by Banerjee et al [22,23] to mask the triazene moiety with an acetoxymethyl moiety led to molecules termed cascade released combi-molecules, which were designed to generate the monoalkyltriazene upon hydrolysis of the acetoxymethyl moiety (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the potency of epidermal growth factor (EGFR)-DNA targeting combi-molecules containing a hydrolabile carbamate at the 3-position of the triazene chain

et al. 2010

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Previous strategies for stabilizing combi-triazenes were based on masking the 1,2,3-triazene chain with a 3-acetoxymethylene group. The half-lives of the latter molecules were only ca 5 min longer than those of their parent 1,2,3-triazenes. The novel combi-molecules described herein contain a hydrolysable carbamate group that modulates their kinetics of degradation. Their half-lives were prolonged by ca 20-55 min when compared with their acetoxymethyltriazene counterparts. While they decomposed slowly in serum-containing medium, their intracellular decomposition was extremely rapid. They blocked EGFR tyrosine kinase in an isolated enzyme assay and in MDA-MB-468 breast cancer cells. Similarly, they all induced a dose-dependent DNA damage and G2/M cell cycle arrest in MDA-MB-468 cells, except the most stable compound ZRL2 (a 3-vinyl carbamate). ZRL4 (a chloromethyl carbamate) was the most potent and ZRL2 was the least active of the series against MDA-MB-468 cells. In selectivity assay with NIH-3T3 and NIH-3T3/HER-14, all compounds selectively blocked proliferation of NIH-3T3/HER-14. ZRS1 exerted the strongest growth inhibitory potency of the series. The results in toto suggest that ZRL2, despite being the most stable compound, could not hydrolyze at a rate that permitted the generation of DNA damaging species, thereby behaving primarily as an EGFR inhibitor. Thus the study permitted the definition of an optimized combi-molecule as one that decomposes at a rate that is slower than that of acetoxymethyltriazenes, but rapid enough to generate strong EGFR-DNA targeting potential and growth inhibition. Based on the latter criteria, ZRS1 and ZRL4 were tested in vivo and ZRS1 has proven the more effective.

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Sustained antiproliferative mechanisms by RB24, a targeted precursor of multiple inhibitors of epidermal growth factor receptor and a DNA alkylating agent in the A431 epidermal carcinoma of the vulva cell line

Cited by 17 publications

References 38 publications

The Combi-Targeting Concept: Selective Targeting of the Epidermal Growth Factor Receptor- and Her2-Expressing Cancer Cells by the Complex Combi-Molecule RB24

The Combi-Targeting Concept: Selective Targeting of the Epidermal Growth Factor Receptor- and Her2-Expressing Cancer Cells by the Complex Combi-Molecule RB24

MGMT Is a Molecular Determinant for Potency of the DNA-EGFR–Combi-Molecule ZRS1

Characterization of the potency of epidermal growth factor (EGFR)-DNA targeting combi-molecules containing a hydrolabile carbamate at the 3-position of the triazene chain

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