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Reply:

We appreciate that Dr. Xia et al. took an interest in our recent publication. We concur that our study did not address the individual contribution of H3/H4 histamine receptors on human cholangiocarcinoma growth. However, our study demonstrated that clobenpropit inhibits cholangiocarcinoma growth by way of H4HRs.1

We used clobenpropit, an H3HR antagonist / H4HR agonist, and found that stimulation of H4HR decreased cholangiocarcinoma growth both in vitro and in vivo.1 At resubmission, we determined if the effect was due to blocking H3HR or stimulating H4HR. After silencing H3HR, clobenpropit (interacting only with H4HR) decreased cholangiocarcinoma growth.

Although specific binding studies using cholangiocarcinoma cells would be better to define the role of H4HR, our study (where H3HR was silenced) provides strong evidence for the involvement of H4HR in cholangiocarcinoma management. Our conclusion that clobenpropit has a higher affinity for H4HR stems from the publications from a well-established group in this field and therefore cannot be dismissed.2, 3 In response to the reference cited by Dr. Xia regarding clobenpropit affinity for H3HR over H4HR, we feel this does not negate our findings. Studies have shown that there is not a biologically significant difference between the affinities of clobenpropit for H4HR and H3HR.4 The structure of clobenpropit, the cell type or tissue being evaluated and conditions impact the affinity of agonist to receptor. Therefore, we would contend that the affinities for clobenpropit and H3HR or H4HR are speculative.

Our intent here was to specify that clobenpropit inhibits cholangiocarcinoma growth by way of H4HR. We agree that treating athymic mice (injected with cholangiocarcinoma cells) with clobenpropit does not rule out effects on H3HR since clobenpropit may interact with both H3/H4HRs.5 In vivo clobenpropit reduces tumor growth, decreases mesenchymal characteristics, and blocks the activation of matrix metalloproteinases.1 We agree that our data are more specific to the studies in vitro instead of the data in vivo. Besides some expected limitations of the in vivo studies, we have clearly demonstrated that clobenpropit inhibits cholangiocarcinoma growth by way of H4HRs in vitro.

References

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  • 1
    Meng F, Han Y, Staloch D, Francis T, Stokes A, Francis H. The H4 histamine receptor agonist, clobenpropit, suppresses human cholangiocarcinoma progression by disruption of epithelial mesenchymal transition and tumor metastasis. HEPATOLOGY 2011; 54: 1718-1728.
  • 2
    Oda T, Matsumoto S. [Identification and characterization of histamine H4 receptor.] Nihon Yakurigaku Zasshi. Folia Pharmacol Jpn 2001; 118: 36-42.
  • 3
    Oda T, Morikawa N, Saito Y, Masuho Y, Matsumoto S. Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes. J Biol Chem 2000; 275: 36781-36786.
  • 4
    O'Reilly M, Alpert R, Jenkinson S, Gladue RP, Foo S, Trim S, et al. Identification of a histamine H4 receptor on human eosinophils—role in eosinophil chemotaxis. J Recept Signal Transduct Res 2002; 22: 431-448.
  • 5
    Francis H, Demorrow S, Venter J, Onori P, White M, Gaudio E, et al. Inhibition of histidine decarboxylase ablates the autocrine tumorigenic effects of histamine in human cholangiocarcinoma. Gut 2011 [Epub ahead of print].

Heather Francis Ph.D.*, * Scott & White Hospital, Temple, TX.