Podar Klaus, Raab Marc S, Zhang Jing, McMillin Douglas, Breitkreutz Iris, Tai Yu-Tzu, Lin Boris K, Munshi Nikhil, Hideshima Teru, Chauhan Dharminder, Anderson Kenneth C
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Blood. 2007 Feb 15;109(4):1669-77. doi: 10.1182/blood-2006-08-042747. Epub 2006 Oct 5.
In multiple myeloma (MM) protein kinase C (PKC) signaling pathways have been implicated in cell proliferation, survival, and migration. Here we investigated the novel, orally available PKC-inhibitor enzastaurin for its anti-MM activity. Enzastaurin specifically inhibits phorbol ester-induced activation of PKC isoforms, as well as phosphorylation of downstream signaling molecules MARCKS and PKCmu. Importantly, it also inhibits PKC activation triggered by growth factors and cytokines secreted by bone marrow stromal cells (BMSCs), costimulation with fibronectin, vascular endothelial growth factor (VEGF), or interleukin-6 (IL-6), as well as MM patient serum. Consequently, enzastaurin inhibits proliferation, survival, and migration of MM cell lines and MM cells isolated from multidrug-resistant patients and overcomes MM-cell growth triggered by binding to BMSCs and endothelial cells. Importantly, strong synergistic cytotoxicity is observed when enzastaurin is combined with bortezomib and moderate synergistic or additive effects when combined with melphalan or lenalidomide. Finally, tumor growth, survival, and angiogenesis are abrogated by enzastaurin in an in vivo xenograft model of human MM. Our results therefore demonstrate in vitro and in vivo efficacy of the orally available PKC inhibitor enzastaurin in MM and strongly support its clinical evaluation, alone or in combination therapies, to improve outcome in patients with MM.
在多发性骨髓瘤（MM）中，蛋白激酶C（PKC）信号通路与细胞增殖、存活及迁移有关。在此，我们研究了新型口服可用的PKC抑制剂恩杂他滨的抗MM活性。恩杂他滨特异性抑制佛波酯诱导的PKC亚型激活，以及下游信号分子MARCKS和PKCμ的磷酸化。重要的是，它还抑制骨髓基质细胞（BMSC）分泌的生长因子和细胞因子、纤连蛋白、血管内皮生长因子（VEGF）或白细胞介素-6（IL-6）以及MM患者血清引发的PKC激活。因此，恩杂他滨抑制MM细胞系以及从多药耐药患者中分离出的MM细胞的增殖、存活和迁移，并克服与BMSC和内皮细胞结合引发的MM细胞生长。重要的是，恩杂他滨与硼替佐米联合使用时观察到强烈的协同细胞毒性，与美法仑或来那度胺联合使用时观察到中度协同或相加效应。最后，在人MM的体内异种移植模型中，恩杂他滨消除了肿瘤生长、存活和血管生成。因此，我们的结果证明了口服可用的PKC抑制剂恩杂他滨在MM中的体外和体内疗效，并有力地支持其单独或联合治疗的临床评估，以改善MM患者的预后。
