© The Author 2006. Published by Oxford University Press.
ARTICLE |
Effect of Cromolyn on S100P Interactions With RAGE and Pancreatic Cancer Growth and Invasion in Mouse Models
Affiliations of authors: Departments of Cancer Biology (TA, VR, CDL) and Medical Oncology (CDL), The University of Texas M. D. Anderson Cancer Center, Houston, TX
Correspondence to: Craig D. Logsdon, PhD, Departments of Cancer Biology and Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: clogsdon{at}mdanderson.org).
Background: We previously found that S100P, a member of the S100 protein family, is expressed in more than 90% of pancreatic tumors and is associated with tumor growth and invasion. In the current study, we investigated the ability of the antiallergy drug, cromolyn, to block S100P function. Methods: Interactions between cromolyn and S100P were investigated using a drug affinity column and by examining cromolyn's effects on coimmunoprecipitation of S100P and receptor for advanced glycation end-products (RAGE). The effects of cromolyn on cell growth, invasion, and nuclear factor-
B (NFB) activity of pancreatic cancer cells with (BxPC-3 and MPanc-96) and without (Panc-1) endogenous S100P were investigated by cell proliferation assay, by cell invasion assay, and by luciferase reporter gene assay, respectively. The effects of cromolyn on tumor growth in vivo were investigated in three orthotopic models (n = 20 mice per model) by administration of cromolyn (5 mg/kg body weight, daily) with and without gemcitabine (125 mg/kg body weight, biweekly), the drug currently used to treat pancreatic cancer. Tumor growth was assayed by reporter gene expression. All statistical tests were two-sided. Results: S100P was retained on a cromolyn affinity column. Cromolyn blocked the coimmunoprecipitation of S100P and RAGE. In vitro, cromolyn (100 µM) inhibited S100P-stimulated Panc-1 cell proliferation (S100P, mean = 0.93 U, versus S100P + cromolyn, mean = 0.56 U, difference = 0.37 U; 95% confidence interval [CI] = 0.24 to 0.49 U; P = .001, n = 3), invasion (S100P, mean = 58.0%, versus S100P + cromolyn, mean = 9.4%, difference = 48.6%; 95% CI = 38.8% to 58.8%; P<.001, n = 3), and NFB activity (S100P, mean = 14 460, versus S100P + cromolyn, mean = 7360 photons/s, difference = 7100 photons/s; 95% CI = 3689 to 10 510 photons/s; P = .005, n = 3). In vivo, cromolyn inhibited tumor growth in mice bearing tumor with endogenous S100P (BxPC-3: control, mean = 1.6 x 109 photons/s, versus cromolyn, mean = 4.4 x 108 photons/s, difference = 1.2 x 109 photons/s; 95% CI = 6.2 x 108 to 1.6 x 109 photons/s; P<.001, n = 5; MPanc-96: control, mean = 1.1 x 1010 photons/s, versus cromolyn, mean = 4.8 x 109 photons/s, difference = 6.2 x 109 photons/s; 95% CI = 1.9 x 109 to 1.0 x 1010 photons/s; P = .009, n = 5) and increased the effectiveness of gemcitabine (BxPC-3: gemcitabine, mean = 9.2 x 108 photons/s, versus combination, mean = 1.8 x 108 photons/s, difference = 7.4 x 108 photons/s; 95% CI = 4.5 x 108 to 1.0 x 109 photons/s; P<.001; MPanc-96: gemcitabine, mean = 4.1 x 109 photons/s, versus combination, mean = 2.0 x 109 photons/s, difference = 2.1 x 109 photons/s; 95% CI = 4.4 x 108 to 3.8 x 109 photons/s; P<.001). However, cromolyn had no effect on growth of tumors lacking S100P (Panc-1). Conclusion: Cromolyn binds S100P, prevents activation of RAGE, inhibits tumor growth, and increases the effectiveness of gemcitabine in experimental models.
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