Kudva Avinash K, Kaushal Naveen, Mohinta Sonia, Kennett Mary J, August Avery, Paulson Robert F, Prabhu K Sandeep
Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
PLoS One. 2013 Dec 2;8(12):e80622. doi: 10.1371/journal.pone.0080622. eCollection 2013.
Previous studies have demonstrated the ability of an eicosapentaenoic acid (EPA)-derived endogenous cyclopentenone prostaglandin (CyPG) metabolite, Δ(12)-PGJ3, to selectively target leukemic stem cells, but not the normal hematopoietic stems cells, in in vitro and in vivo models of chronic myelogenous leukemia (CML). Here we evaluated the stability, bioavailability, and hypersensitivity of Δ(12)-PGJ3. The stability of Δ(12)-PGJ3 was evaluated under simulated conditions using artificial gastric and intestinal juice. The bioavailability of Δ(12)-PGJ3 in systemic circulation was demonstrated upon intraperitoneal injection into mice by LC-MS/MS. Δ(12)-PGJ3 being a downstream metabolite of PGD3 was tested in vitro using primary mouse bone marrow-derived mast cells (BMMCs) and in vivo mouse models for airway hypersensitivity. ZK118182, a synthetic PG analog with potent PGD2 receptor (DP)-agonist activity and a drug candidate in current clinical trials, was used for toxicological comparison. Δ(12)-PGJ3 was relatively more stable in simulated gastric juice than in simulated intestinal juice that followed first-order kinetics of degradation. Intraperitoneal injection into mice revealed that Δ(12)-PGJ3 was bioavailable and well absorbed into systemic circulation with a Cmax of 263 µg/L at 12 h. Treatment of BMMCs with ZK118182 for 12 h resulted in increased production of histamine, while Δ(12)-PGJ3 did not induce degranulation in BMMCs nor increase histamine. In addition, in vivo testing for hypersensitivity in mice showed that ZK118182 induces higher airways hyperresponsiveness when compared Δ(12)-PGJ3 and/or PBS control. Based on the stability studies, our data indicates that intraperitoneal route of administration of Δ(12)-PGJ3 was favorable than oral administration to achieve effective pharmacological levels in the plasma against leukemia. Δ(12)-PGJ3 failed to increase histamine and IL-4 in BMMCs, which is in agreement with reduced airway hyperresponsiveness in mice. In summary, our studies suggest Δ(12)-PGJ3 to be a promising bioactive metabolite for further evaluation as a potential drug candidate for treating CML.
先前的研究已证明，在慢性髓性白血病（CML）的体外和体内模型中，一种源自二十碳五烯酸（EPA）的内源性环戊烯酮前列腺素（CyPG）代谢物Δ(12)-PGJ3能够选择性地靶向白血病干细胞，而不是正常造血干细胞。在此，我们评估了Δ(12)-PGJ3的稳定性、生物利用度和超敏反应。使用人工胃液和肠液在模拟条件下评估Δ(12)-PGJ3的稳定性。通过液相色谱-串联质谱法（LC-MS/MS）对小鼠腹腔注射后，证明了Δ(12)-PGJ3在体循环中的生物利用度。Δ(12)-PGJ3作为PGD3的下游代谢物，在体外使用原代小鼠骨髓来源的肥大细胞（BMMCs）进行了测试，并在体内小鼠模型中测试了气道超敏反应。ZK118182是一种具有强效PGD2受体（DP）激动剂活性的合成PG类似物，也是当前临床试验中的候选药物，用于毒理学比较。Δ(12)-PGJ3在模拟胃液中比在模拟肠液中相对更稳定，模拟肠液中其降解遵循一级动力学。对小鼠腹腔注射显示，Δ(12)-PGJ3具有生物利用度，能很好地吸收进入体循环，12小时时的Cmax为263μg/L。用ZK118182处理BMMCs 12小时会导致组胺产生增加，而Δ(12)-PGJ3不会诱导BMMCs脱颗粒，也不会增加组胺。此外，小鼠体内超敏反应测试表明，与Δ(12)-PGJ3和/或PBS对照相比，ZK118182诱导更高的气道高反应性。基于稳定性研究，我们的数据表明，腹腔注射Δ(12)-PGJ3比口服给药更有利于在血浆中达到针对白血病的有效药理水平。Δ(12)-PGJ3未能增加BMMCs中的组胺和IL-4，这与小鼠气道高反应性降低一致。总之，我们的研究表明，Δ(12)-PGJ3作为一种有前景的生物活性代谢物，有望作为治疗CML的潜在候选药物进行进一步评估。
