Torti S V, Lemler E, Mueller B K, Popp A, Torti F M
Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, Connecticut, USA.
Abbvie Deutschland GmbH and Co. KG, Knollstrasse 67061, Ludwigshafen, Germany.
Clin Exp Pharmacol. 2016 Nov;6(6). doi: 10.4172/2161-1459.1000223. Epub 2016 Nov 17.
Hepcidin is a peptide hormone produced by the liver that regulates systemic iron homeostasis. Hepcidin is also synthesized by tumors, where it contributes to tumor growth by increasing the tumoral retention of iron. Targeted reduction of hepcidin may therefore be useful in reducing tumor growth. H5F9-AM8 is an antibody in preclinical development for the anemia of chronic disease that reduces hepcidin synthesis by binding to RGMc, a co-receptor involved in the transcriptional induction of hepcidin by BMP6. We explored the ability of H5F9-AM8 to act as an anti-tumor agent.
Effects of anti-hemojuvelin antibody on hepcidin synthesis were assessed by qRTPCR in tissue culture and in tumor xenografts and livers of mice treated with H5F9-AM8 or saline. Tumor growth was assessed using caliper measurements. Serum iron was measured colorimetrically and tissue iron was measured using western blotting and inductively coupled mass spectrometry.
In tissue culture, the anti-hemojuvelin antibody H5F9-AM8 significantly reduced BMP6-stimulated hepcidin synthesis in HepG2 and other cancer cells. In mice, H5F9-AM8 reduced hepcidin in the liver and increased serum iron, total liver iron, and liver ferritin. Although hepcidin in tumors was also significantly decreased, H5F9-AM8 did not reduce tumor iron content, ferritin, or tumor growth.
Anti-hemojuvelin antibody successfully reduces hepcidin in both tumors and livers but has different effects in these target organs: it reduces iron content and ferritin in the liver, but does not reduce iron content or ferritin in tumors, and does not inhibit tumor growth. These results suggest that despite their ability to induce hepcidin in tumors, the anti-tumor efficacy of systemic, non-targeted hepcidin antagonists may be limited by their ability to simultaneously elevate plasma iron. Tumor-specific hepcidin inhibitors may be required to overcome the limitations of drugs that target the synthesis of both systemic and tumor hepcidin.
铁调素是一种由肝脏产生的肽类激素，可调节全身铁稳态。肿瘤也能合成铁调素，它通过增加肿瘤对铁的潴留来促进肿瘤生长。因此，靶向降低铁调素可能有助于抑制肿瘤生长。H5F9-AM8是一种处于临床前研发阶段的用于治疗慢性病贫血的抗体，它通过与RGMc结合来减少铁调素的合成，RGMc是一种参与骨形态发生蛋白6（BMP6）转录诱导铁调素的共受体。我们探究了H5F9-AM8作为抗肿瘤药物的能力。
在组织培养以及用H5F9-AM8或生理盐水处理的小鼠的肿瘤异种移植物和肝脏中，通过定量逆转录聚合酶链反应（qRTPCR）评估抗血色素沉着症相关蛋白抗体对铁调素合成的影响。使用卡尺测量评估肿瘤生长情况。采用比色法测定血清铁，使用蛋白质免疫印迹法和电感耦合质谱法测定组织铁。
在组织培养中，抗血色素沉着症相关蛋白抗体H5F9-AM8显著降低了BMP6刺激的HepG2细胞和其他癌细胞中铁调素的合成。在小鼠中，H5F9-AM8降低了肝脏中的铁调素水平，并增加了血清铁、肝脏总铁含量和肝脏铁蛋白。尽管肿瘤中的铁调素也显著降低，但H5F9-AM8并未降低肿瘤铁含量铁蛋白或肿瘤生长。
抗血色素沉着症相关蛋白抗体成功降低了肿瘤和肝脏中的铁调素，但在这些靶器官中具有不同的作用：它降低了肝脏中的铁含量和铁蛋白，但未降低肿瘤中的铁含量或铁蛋白，也未抑制肿瘤生长。这些结果表明，尽管全身性、非靶向性铁调素拮抗剂能够在肿瘤中诱导铁调素的产生，但其抗肿瘤疗效可能受到同时升高血浆铁能力的限制。可能需要肿瘤特异性铁调素抑制剂来克服靶向全身和肿瘤铁调素合成的药物的局限性。
