Gederaas Odrun A, Søgaard Caroline D, Viset Trond, Bachke Siri, Bruheim Per, Arum Carl-Jørgen, Otterlei Marit
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
Department of Pathology and Medical Genetics, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
Transl Oncol. 2014 Dec;7(6):812-23. doi: 10.1016/j.tranon.2014.10.005.
Non-muscle-invasive bladder cancers (NMIBCs) are tumors confined to the mucosa or the mucosa/submucosa. An important challenge in treatment of NMIBC is both high recurrence and high progression rates. Consequently, more efficacious intravesical treatment regimes are in demand. Inhibition of the cell's DNA repair systems is a new promising strategy to improve cancer therapy, and proliferating cell nuclear antigen (PCNA) is a new promising target. PCNA is an essential scaffold protein in multiple cellular processes including DNA replication and repair. More than 200 proteins, many involved in stress responses, interact with PCNA through the AlkB homologue 2 PCNA-interacting motif (APIM), including several proteins directly or indirectly involved in repair of DNA interstrand crosslinks (ICLs). In this study, we targeted PCNA with a novel peptide drug containing the APIM sequence, ATX-101, to inhibit repair of the DNA damage introduced by the chemotherapeutics. A bladder cancer cell panel and two different orthotopic models of bladder cancer in rats, the AY-27 implantation model and the dietary BBN induction model, were applied. ATX-101 increased the anticancer efficacy of the ICL-inducing drug mitomycin C (MMC), as well as bleomycin and gemcitabine in all bladder cancer cell lines tested. Furthermore, we found that ATX-101 given intravesically in combination with MMC penetrated the bladder wall and further reduced the tumor growth in both the slow growing endogenously induced and the rapidly growing transplanted tumors. These results suggest that ATX-101 has the potential to improve the efficacy of current MMC treatment in NMIBC.
非肌层浸润性膀胱癌（NMIBC）是局限于黏膜或黏膜/黏膜下层的肿瘤。NMIBC治疗中的一个重要挑战是高复发率和高进展率。因此，需要更有效的膀胱内治疗方案。抑制细胞的DNA修复系统是改善癌症治疗的一种新的有前景的策略，而增殖细胞核抗原（PCNA）是一个新的有前景的靶点。PCNA是多种细胞过程（包括DNA复制和修复）中必不可少的支架蛋白。超过200种蛋白质（其中许多参与应激反应）通过AlkB同源物2 PCNA相互作用基序（APIM）与PCNA相互作用，包括几种直接或间接参与DNA链间交联（ICL）修复的蛋白质。在本研究中，我们用一种含有APIM序列的新型肽药物ATX-101靶向PCNA，以抑制化疗药物引起的DNA损伤的修复。应用了一组膀胱癌细胞系和两种不同的大鼠原位膀胱癌模型，即AY-27植入模型和饮食性BBN诱导模型。在所有测试的膀胱癌细胞系中，ATX-101提高了诱导ICL的药物丝裂霉素C（MMC）以及博来霉素和吉西他滨的抗癌疗效。此外，我们发现膀胱内给予ATX-101联合MMC可穿透膀胱壁，并进一步减少内源性缓慢生长和移植性快速生长肿瘤的肿瘤生长。这些结果表明，ATX-101有潜力提高当前MMC治疗NMIBC的疗效。
