Luhrs Keith A, Pink Desmond, Schulte Wendy, Zijlstra Andries, Lewis John D, Parseghian Missag H
Allergan Inc., Irvine, CA, USA.
Previous address: Peregrine Pharmaceuticals Inc., Tustin CA, USA.
Oncotarget. 2017 Mar 7;8(10):16275-16292. doi: 10.18632/oncotarget.15181.
Necrosis is induced by ischemic conditions within the core of many solid tumors. Using fluorescent fusion proteins, we provide in vivo evidence of histone trafficking among cancer cells in implanted tumors. In particular, the most abundant H1 isoform (H1.2) was found to be transported from necrotic tumor cells into surrounding viable cells where histones are selectively taken up by energy-dependent endocytosis. We propose that intercellular histone trafficking could function as a target for drug delivery. This concept was validated using an anti-histone antibody that was co-internalized with histones from dead cells into viable ones surrounding the necrotic regions of a tumor, where some of the most chemoresistant cells reside. These findings demonstrate that cellular translocation of conjugated drugs using anti-histone antibodies is a promising strategy for targeted drug delivery to chemoresistant tumors.
坏死是由许多实体瘤核心部位的缺血状况所引发的。利用荧光融合蛋白，我们提供了植入肿瘤中癌细胞间组蛋白转运的体内证据。特别地，发现最丰富的H1亚型（H1.2）从坏死肿瘤细胞转运至周围存活细胞，在那里组蛋白通过能量依赖的内吞作用被选择性摄取。我们提出细胞间组蛋白转运可作为药物递送的靶点。使用一种抗组蛋白抗体验证了这一概念，该抗体与来自死细胞的组蛋白共同内化到肿瘤坏死区域周围的存活细胞中，其中一些是最具化疗抗性的细胞。这些发现表明，利用抗组蛋白抗体进行共轭药物的细胞转运是一种有前景的策略，可将药物靶向递送至化疗抗性肿瘤。
