Hazlehurst Lori A, Enkemann Steven A, Beam Craig A, Argilagos Raul F, Painter Jeffrey, Shain Kenneth H, Saporta Sara, Boulware David, Moscinski Lynn, Alsina Melissa, Dalton William S
Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, at The University of South Florida, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Cancer Res. 2003 Nov 15;63(22):7900-6.
Cancer cell adhesion confers a transient, de novo drug-resistant phenotype referred to as cell adhesion-mediated drug resistance (CAM-DR). In this report, we extend the CAM-DR phenotype to primary specimens from patients with myeloma, providing further evidence that CAM-DR is a viable clinical form of drug resistance. To examine mechanisms of cellular resistance to melphalan, we compared genotypic and phenotypic profiles of acquired and de novo melphalan resistance in an isogenic human myeloma cell line. Acquired melphalan resistance (8226/LR5) was associated with decreased drug-induced DNA damage and a complex gene expression profile showing that genes involved in the Fanconi anemia DNA repair pathway are increased in the LR5 cells compared with drug-sensitive or adherent cells. In contrast, cells adhered to fibronectin accumulate similar amounts of DNA damage compared with drug-sensitive cells but are protected from melphalan-induced mitochondrial perturbations and caspase activation. Levels of the proapoptotic protein Bim were significantly reduced in adherent cells. Gene expression changes associated with de novo resistance were significantly less complex compared with acquired resistance, but a significant overlap in gene expression was noted involving cholesterol synthesis. We propose that myeloma cell adhesion promotes a form of de novo drug resistance by protecting cells from melphalan-induced cytotoxic damage and that this transient protection allows cells to acquire a more permanent and complex drug resistance phenotype associated with a reduction in drug induced DNA damage.
癌细胞黏附赋予一种短暂的、新出现的耐药表型，称为细胞黏附介导的耐药性（CAM-DR）。在本报告中，我们将CAM-DR表型扩展至骨髓瘤患者的原发性标本，进一步证明CAM-DR是一种可行的临床耐药形式。为了研究细胞对美法仑耐药的机制，我们比较了同基因人骨髓瘤细胞系中获得性和美法仑原发耐药的基因型和表型特征。获得性美法仑耐药（8226/LR5）与药物诱导的DNA损伤减少以及复杂的基因表达谱相关，表明与范可尼贫血DNA修复途径相关的基因在LR5细胞中比药物敏感或贴壁细胞中有所增加。相比之下，与药物敏感细胞相比，黏附于纤连蛋白的细胞积累的DNA损伤量相似，但可免受美法仑诱导的线粒体扰动和半胱天冬酶激活的影响。贴壁细胞中促凋亡蛋白Bim的水平显著降低。与原发耐药相关的基因表达变化与获得性耐药相比明显不那么复杂，但在基因表达方面存在显著重叠，涉及胆固醇合成。我们提出，骨髓瘤细胞黏附通过保护细胞免受美法仑诱导的细胞毒性损伤来促进一种原发耐药形式，并且这种短暂的保护使细胞获得与药物诱导的DNA损伤减少相关的更持久和复杂的耐药表型。
