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[Cancer Research 65, 10646-10650, December 1, 2005]
© 2005 American Association for Cancer Research

Priority Reports

Enhanced Targeting and Killing of Tumor Cells Expressing the CXC Chemokine Receptor 4 by Transducible Anticancer Peptides

Eric L. Snyder1, Cheryl C. Saenz1,2,3, Catherine Denicourt1,2, Bryan R. Meade1,2, Xian-Shu Cui1,2, Ian M. Kaplan1,2 and Steven F. Dowdy1,2

1 Howard Hughes Medical Institute and Departments of 2 Cellular and Molecular Medicine and 3 Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, California

Requests for reprints: Steven F. Dowdy, Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, 9600 Gilman Drive, La Jolla, CA 92037-0686. Phone: 858-534-7772; E-mail: sdowdy{at}ucsd.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Protein transduction domains (PTDs), such as the TAT PTD, have been shown to deliver a wide variety of cargo in cell culture and to treat preclinical models of cancer and cerebral ischemia. The TAT PTD enters cells by a lipid raft–dependent macropinocytosis mechanism that all cells perform. Consequently, PTDs resemble small-molecule therapeutics in their lack of pharmacologic tissue specificity in vivo. However, several human malignancies overexpress specific receptors, including HER2 in breast cancer, GnRH in ovarian carcinomas, and CXC chemokine receptor 4 (CXCR4) in multiple malignancies. To target tumor cells that overexpress the CXCR4 receptor, we linked the CXCR4 DV3 ligand to two transducible anticancer peptides: a p53-activating peptide (DV3-TATp53C') and a cyclin-dependent kinase 2 antagonist peptide (DV3-TAT-RxL). Treatment of tumor cells expressing the CXCR4 receptor with either the DV3-TATp53C' or DV3-TAT-RxL targeted peptides resulted in an enhancement of tumor cell killing compared with treatment with nontargeted parental peptides. In contrast, there was no difference between DV3 targeted peptide and nontargeted, parental peptide treatment of non-CXCR4-expressing tumor cells. These observations show that a multidomain approach can be used to further refine and enhance the tumor selectivity of biologically active, transducible macromolecules for treating cancer.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Protein transduction has emerged as a novel strategy for delivering biologically active macromolecules into the cellular interior in vivo (1, 2). Several small cationic peptide transduction domains (PTDs), including TAT, Antp, and poly-Arg, are capable of traversing the plasma membrane and entering the cytoplasm of cells in a concentration-dependent, receptor-independent manner that uses lipid raft–dependent macropinocytosis, a specialized form of endocytosis (3, 4). PTDs have been used to deliver a wide variety of cargo including biologically active proteins, peptides, and nucleic acids in vitro and to successfully treat a variety of preclinical models of human disease, including cancer and cerebral ischemia (5, 6). However, macropinocytosis is a nonselective form of endocytosis that all cells perform (3). Consequently, this nonselective aspect of protein transduction also results in the majority of the PTD cargo transducing into nontarget cells in vivo and thereby requires vastly more material. Therefore, pharmacologically speaking, PTDs resemble currently used small-molecule therapeutics in their lack of specific delivery to the cells and tissues for which they are intended in vivo. However, multiple cancer types overexpress a number of cell-surface receptors, including HER2 receptor in breast cancer, luteinizing hormone-releasing hormone receptor in most ovarian carcinomas, and CXC chemokine receptor 4 (CXCR4) receptor in multiple tumor types (7, 8). The CXCR4 chemokine receptor is overexpressed on >20 types of cancer, including breast cancer, ovarian cancer, glioma, pancreatic cancer, prostate cancer, acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), melanoma, cervical cancer, colon carcinoma, small-cell lung carcinoma, renal cancer, and non-Hodgkin's lymphoma (9–12). To test the hypothesis that delivery of PTDs could be selectively enhanced to tumor cells by targeting overexpressed receptors, we linked a CXCR4 receptor ligand, DV3 (13), to two proven transducible anticancer peptides, a p53-activating peptide (TATp53C'; ref. 14) and a cyclin-dependent kinase (cdk) 2 antagonist peptide (TAT-RxL; ref. 15). We evaluated the effect of these multidomain, biologically active, macromolecular peptides (termed DV3-TATp53 and DV3-TAT-RxL) on cancer cells that overexpress the CXCR4 receptor.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Cell culture and flow cytometry. TA3/St, H1299, and 293T cells were maintained in DMEM plus 10% fetal bovine serum (FBS) and penicillin/streptomycin. Namalwa B cells (American Type Culture Collection, Manassas, VA) were maintained in RPMI plus 10% FBS and penicillin/streptomycin. All cells were maintained at 37°C in 5% CO2. Short-term cell viability was assessed by a hemocytometer-based trypan blue exclusion. For cell cycle analysis, peptide-treated cells were analyzed by fluorescence-activated cell sorting (FACS) with 10 µg/mL propidium iodide in 0.5% NP40. DNA profiles were analyzed using a FACScan and CellQuest software (Becton Dickinson, San Jose, CA). Apoptosis was determined by nuclei condensation of 4',6-diamidino-2-phenylindole (DAPI)–stained cells and microscopy.

Peptide synthesis. D- and L-isomer peptides were synthesized by standard Fmoc chemistry on an ABI 433A Peptide Synthesizer (Applied Biosystems, Foster City, CA; ref. 14). Crude peptides were purified over a C18 high-performance liquid chromatography preparatory column (Varian, Palo Alto, CA) and confirmed by mass spectrometry. DV3-TATp53C', TATp53C', DV3-TAT, DV3-p53c', p53C', and DV3 peptides were synthesized with D-isomer residues whereas the DV3 domain of DV3-TAT-RxL was D-isomer residues and the TAT-RxL domain was L-isomer residues.

CXC chemokine receptor 4 binding assay. CXCR4-expressing Namalwa cells were washed thrice with PBS/0.5% bovine serum albumin (BSA) and incubated on ice with phycoerythrin-labeled anti-CXCR4 monoclonal antibody (12G5-phycoerythrin, R&D Systems, Minneapolis, MN) and peptide. Phycoerythrin-labeled isotype matched antibody was used to control for nonspecific cell-surface binding. After 45 minutes on ice, cells were washed twice, fixed for 5 minutes in 2% paraformaldehyde, and resuspended in PBS/0.5% BSA, analyzed by FACS and the FL2 geometric mean was used to quantitate inhibition of CXCR4 binding by 12G5-phycoerythrin antibody.

Transient transfection. 293T cells were transiently transfected with the CXCR4 expression vector (kindly provided by Dr. David Looney, Center for AIDS Research, University of California, San Diego; ref. 16) or control vector by Lipofectamine (Invitrogen, Carlsbad, CA), then treated with DV3-TAT-RxL or TAT-RxL peptide at 18 hours, and the number of viable cells was counted 24 hours later. CXCR4 expression was quantified by 12G5-phycoerythrin antibody treatment and FACS.

Statistical analysis. Student's t test was used to determine statistical significance (P < 0.05).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
DV3 enhances the affinity of TAT peptides for CXC chemokine receptor 4–expressing cells. To test the hypothesis that linkage of a receptor ligand to transducible anticancer peptides could selectively enhance delivery to tumor cells overexpressing cognate receptors, we added the CXCR4 receptor DV3 ligand to the NH2 terminus of a retroinverso, D-isomer transducible TATp53-activating peptide, yielding DV3-TATp53C' and mutant non-p53-activating, DV3-TATp53MUT peptide (Fig. 1A; refs. 13, 14). In addition, we synthesized a previously characterized cdk2 antagonist peptide (TAT-RxL; ref. 15) and a DV3-TAT-RxL peptide version as well as multiple control peptides (Fig. 1A).



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  		Figure 1. CXCR4 receptor binding DV3 peptide domain increases the affinity of TAT peptides for CXCR4-expressing lymphoma cells. A, sequences of peptides used in this study. All peptides were synthesized using D-isomer residues, except for the TAT-RxL peptides. B, human Namalwa lymphoma cells that overexpress CXCR4 receptor were incubated with increasing concentrations of peptide, followed by fluorescent phycoerythrin-conjugated anti-CXCR4 monoclonal antibody incubation, then analyzed for antibody binding to CXCR4 receptor (mean fluorescence) by flow cytometry. Graph plots relative fluorescence of cells with respect to cells treated with antibody only. Points, mean of three independent experiments; bars, SE.

 
To determine if the addition of the DV3 ligand enhances the affinity of TAT peptides for CXCR4-expressing cancer cells, we first carried out CXCR4 binding assays. Human Namalwa Burkitt's lymphoma cells overexpress the CXCR4 receptor (17) and were treated with various peptides to block the CXCR4 receptor, then incubated with phycoerythrin-conjugated anti-CXCR4 antibody and analyzed by flow cytometry. Chemokines use two contact domains to bind their receptors: the first is represented by the DV3 peptide ligand and the second is a basic patch mimicked by the TAT basic domain that facilitates the initial interaction with negatively charged chemokine receptors (18). Control DV3-only peptide displayed an IC50 of ~1 µmol/L (Fig. 1B), a value that is within 2-fold of the published value (13). Consistent with the chemokine two-domain binding to CXCR4, the TAT basic peptide displayed a similar affinity as DV3 for CXCR4. However, linkage of DV3 and TAT basic domains resulted in a synergistic ~100-fold increased affinity (IC50 <0.01 µmol/L) for the CXCR4 receptor (Fig. 1B). Importantly, addition of the p53C' cargo domain to the DV3-TAT peptide did not alter the affinity (IC50 <0.01 µmol/L) for the CXCR4 receptor.

DV3-TATp53C' and DV3-TAT-RxL peptides have enhanced cell killing in CXC chemokine receptor 4–expressing tumor cells. We compared the abilities of DV3-TATp53C', DV3-TATp53MUT, and parental TATp53C' peptides to induce apoptosis in Namalwa lymphoma cells that overexpress the CXCR4 receptor. TATp53C' peptide treatment of Namalwa cells induced a dose-dependent decrease in cell number and a concomitant increase in apoptotic cells (Fig. 2A and E; data not shown). However, treatment with targeted DV3-TATp53C' peptide resulted in an enhanced cell killing. This was particularly apparent at 40 µmol/L where DV3-TATp53C' peptide reduced cell number by >80% whereas TATp53C' peptide only reduced the cell number by 55% (Fig. 2A). In contrast, the functionally inactive, but transducible, DV3-TATp53Mut peptide showed background levels of activity on Namalwa cells (Fig. 2A). TA3/St mammary adenocarcinoma cells have undetectable CXCR4 surface expression (data not shown; ref. 19) and treatment of TA3/St cells with TATp53C' peptide induced a G1 arrest (Fig. 2B; ref. 14). Consistent with the absence of CXCR4 receptors, treatment of TA3/St cells with the targeted DV3-TATp53C' peptide induced a G1 arrest that was indistinguishable from treatment with parental TATp53C' peptide (Fig. 2B). In addition, targeted DV3-TATp53C', parental TATp53C', and control DV3 peptide had little to no effect on control, p53-deficient human H1299 lung adenocarcinoma cells (Fig. 2C).



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  		Figure 2. Targeted DV3-TATp53C' and DV3-TAT-RxL peptides kill CXCR4-expressing lymphoma cells with increased efficacy. A, Namalwa lymphoma cells were treated with 40 µmol/L TATp53MUT, TATp53C', or DV3-TATp53C' peptide for 48 hours. Cell viability was assessed by trypan blue exclusion. Columns, mean of three independent experiments; bars, SE. B, TATp53C' and DV3-TATp53C' peptides induce similar level of p53-dependent G1 cell cycle arrest in CXCR4-nonexpressing TA3/St mammary carcinoma cells. Cells were treated with 5 µmol/L peptide for 24 hours and analyzed for DNA content by flow cytometry. C, DV3-TATp53C', TATp53C', and control DV3 peptide (30 µmol/L) have no effect on CXCR4-nonexpressing, p53-deficient H1299 lung adenocarcinoma cells. D, DV3-TAT-RxL is more potent than TAT-RxL in killing CXCR4-expressing Namalwa lymphoma cells. Cells were treated with indicated concentrations of cdk2 antagonist TAT-RxL or DV3-TAT-RxL peptides for 48 hours. Cell viability was assessed by trypan blue exclusion. Points, mean of three independent experiments; bars, SE. E, Namalwa lymphoma (CXCR4+) cells were treated with DV3-TATp53C', TATp53C', or DV3-TATp53MUT peptides for 24 hours. Apoptosis was determined by <2N DNA content as measured by flow cytometry and DNA staining.

 
To test if the DV3 domain could enhance the activity of another proven anticancer peptide, we synthesized a TAT-fusion peptide containing a domain that antagonizes Cdk2 activity (15), termed TAT-RxL. Treatment of CXCR4-expressing Namalwa lymphoma cells with parental TAT-RxL reduced viable cell number in a dose-dependent fashion (Fig. 2D). However, treatment of Namalwa cells with the CXCR4-targeted, DV3-TAT-RxL peptide resulted in a significant increase in peptide potency at all concentrations tested. In contrast, TAT-RxL and DV3-TAT-RxL peptide treatment of non-CXCR4-expressing 293T cells and non-CXCR4-expressing TA3/St cells (data not shown) showed no differences between the two peptides. Taken together, these observations are consistent with the hypothesis that the DV3 domain enhances peptide delivery to CXCR4-overexpressing tumor cells.

DV3 domain enhanced killing of CXC chemokine receptor 4–expressing cells requires covalent linkage to TATp53C'peptide. To rule out the possibility that the enhanced potency of DV3-TATp53C' was a consequence of CXCR4 blockade, we synthesized a variety of control peptides (Fig. 1A) and tested their ability to alter Namalwa lymphoma cell viability. Consistent with the observations above, targeted DV3-TATp53C' peptide treatment of CXCR4-expressing Namalwa cells decreased viability to a significantly greater extent than treatment with parental TATp53C' peptide (Fig. 3A). In contrast, treatment with control DV3-only peptide, DV3-p53 peptide, or DV3-TAT peptide had minimal effects on cell number (Fig. 3A; data not shown). Because the affinities of DV3-TAT and DV3-TATp53C' for CXCR4 are nearly identical (Fig. 1B), these results suggest that the increased DV3-TATp53C' activity cannot be explained purely by CXCR4 binding and antagonism.



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  		Figure 3. DV3 domain enhanced effect requires covalent linkage to TATp53C' peptide. A, addition of DV3-TATp53C' constituent domains in trans does not recapitulate the effect of DV3-TATp53C' peptide in cis on lymphoma cells, as indicated. Namalwa lymphoma cells were treated with 30 µmol/L peptide for 48 hours. Cell viability was assessed by trypan blue exclusion. Columns, mean of three independent experiments; bars, SE. B, blockade of CXCR4 receptors by excess DV3 peptide reduces the ability of DV3-TATp53C' to kill Namalwa lymphoma cells to TATp53C' level. Cells were treated with 30 µmol/L DV3-TATp53C' or parental TATp53C' peptide for 48 hours in the presence or absence of a 200 µmol/L excess of DV3 peptide. Cell viability was assessed by trypan blue exclusion. Columns, mean of three independent experiments; bars, SE.

 
We next assayed whether enhanced DV3-TATp53C' peptide activity could be reconstituted by adding its constituent domains to Namalwa cells in trans. Treatment of Namalwa cells with DV3 and TATp53C' peptides in trans led to a similar reduction in cell viability as treatment with TATp53C' peptide alone (Fig. 3A). Furthermore, coadministration of control DV3-TAT and p53C' peptides (Fig. 3A) or control DV3-p53C' and TAT peptide (data not shown) in trans also caused minimal to no cell death and failed to reconstitute DV3-TATp53C' in cis peptide activity. Finally, simultaneous treatment of lymphoma cells with DV3-TAT and TATp53C' peptide reduced the cell number to the same extent as treatment with parental TATp53C' peptide alone (Fig. 3A). Thus, regardless of the configuration, none of the DV3, TAT, or p53C' constituent domains, either alone or in trans, were as effective at killing CXCR4-expressing lymphoma cells as cis-linked DV3-TATp53C' peptide.

Enhanced DV3-TAT-RxL peptide killing of tumor cells requires CXC receptor 4. If the increased potency of DV3-TATp53C' peptide was a direct result of the interaction between DV3-TATp53C' peptide and the CXCR4 receptor, then elimination of this peptide/receptor interaction should reduce DV3-TATp53C' peptide potency. To test this prediction, CXCR4-expressing Namalwa cells were incubated with DV3-TATp53C' in the presence or absence of excess competing DV3 peptide. Addition of 200 µmol/L excess DV3 peptide alone had no effect on Namalwa cell viability. However, coadministration of 200 µmol/L DV3 peptide with 30 µmol/L DV3-TATp53C' peptide reduced the potency of DV3-TATp53C' peptide to levels similar to that of parental TATp53C' peptide (Fig. 3B). In contrast, excess DV3-only peptide had no effect on parental TATp53C' peptide killing. These results suggest that DV3-TATp53C' peptide interaction with CXCR4 is essential for increased potency, independent of disrupting CXCR4 signaling.

CXCR4-targeted and parental nontargeted peptides have indistinguishable activities in non-CXCR4-expressing cells. Therefore, to directly test the requirement for CXCR4 overexpression for DV3-TAT domain enhancement, we ectopically expressed CXCR4 in non-CXCR4-expressing human 293T cells and assayed for altered peptide efficacies (Fig. 4A). Treatment of non-CXCR4-expressing 293T cells with parental TAT-RxL or targeted DV3-TAT-RxL peptides showed a near identical dose-dependent decrease in cell viability and induction of apoptosis (Fig. 4B and C). However, treatment of CXCR4-transfected 293T cells with the targeted DV3-TAT-RxL peptide resulted in an enhanced cell killing activity compared with treatment with parental TAT-RxL peptide at all concentrations tested (Fig. 4B). Taken together, these observations show that the cargo-independent, enhanced DV3-TATp53C' and DV3-TAT-RxL activities derive from the increased targeting of the peptide via the DV3 domain to CXCR4-overexpressing cancer cells.



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  		Figure 4. Enhanced effect by DV3 targeted peptide requires CXCR4 receptor expression. A, flow cytometric analysis of control, CXCR4-nonexpressing 293T cells and CXCR4-transfected 293T cells incubated with phycoerythrin-labeled anti-CXCR4 antibody. B and C, ectopic expression of CXCR4 in 293T cells enhances efficacy of DV3-TAT-RxL peptide–induced cell death. 293T cells were transiently transfected with a CXCR4 expression plasmid for 18 hours, followed by peptide treatment for 24 hours. Cell viability was assessed by trypan blue exclusion (B). Apoptosis was measured by DAPI staining for nuclear condensation (C). Columns and points, mean of two independent experiments; bars, SE.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Tumor cells overexpress a variety of receptors on their cell surface, including HER2 receptor in breast cancer, GnRH receptor in ovarian carcinomas, and CXCR4 receptor in multiple tumor types (7, 8, 10). Due to genetic alterations in protein degradation pathways and hypoxic regions of tumors, the CXCR4 chemokine receptor is overexpressed in over 20 different types of tumors, including breast cancer, ovarian cancer, glioma, pancreatic cancer, prostate cancer, AML, B-CLL, melanoma, cervical cancer, colon carcinoma, rhabdomyosarcoma, astrocytoma, small-cell lung carcinoma, CLL, renal cancer, and non-Hodgkin's lymphoma (10–12, 20). Therefore, therapeutics that target CXCR4-overexpressing tumor cells may be applicable to malignancies at the earliest stages of oncogenesis. We hypothesized that a multidomain approach could be used to enhance tumor targeting of nonselective TAT-mediated protein transduction delivery. Addition of the CXCR4 targeting domain (DV3) resulted in an enhanced cell killing in lymphoma cells overexpressing CXCR4 in a cargo-independent fashion but had no enhanced effect on non-CXCR4-expressing cancer cells. Importantly, the increased potency was dependent on cis linkage of the DV3 targeting domain to the TAT anticancer cargo and was not merely due to a blockade of CXCR4 signaling.

Finally, the enhanced cell killing observed here by targeting CXCR4-overexpressing tumor cells shows a proof-of-concept that potentially has broad implications for treating malignant disease by PTD-mediated protein transduction. Similar to chemotherapy, it is likely that most tissues receive only a small fraction of the total nontargeted, TAT molecules administered (1, 4, 14). Therefore, even a small increase in the total amount of peptide delivered to target tumor cells could lead to a substantial increase in potency, a decrease in the minimally effective dose, and/or a decrease in potential side effects. Taken together, these observations show that a multidomain approach can be used to modulate transducible anticancer peptides to selectively target and kill tumor cells based on receptor overexpression common to many malignancies. Due to the inherent absence of a size limitation on transduction domains to deliver therapeutic cargo into cells, this type of approach could be applied reiteratively to refine both the tumor selectivity and killing abilities of multidomain transducible macromolecules to further enhance therapeutic efficacy.


   Acknowledgments
 
Grant support: NIH Women's Reproductive Health Research (C. Saenz), National Cancer Institute of Canada (C. Denicourt), Moores University of California, San Diego Cancer Center (C. Saenz), Gynecologic Cancer Foundation (C. Saenz), NIH grant CA96098 (S. Dowdy), and the Howard Hughes Medical Institute (S. Dowdy).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We thank Dr. David Looney for reagents.


   Footnotes
 
Note: E.L. Snyder and C.C. Saenz contributed equally to this work.

Received 1/14/05. Revised 6/24/05. Accepted 10/ 6/05.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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