Lebedeva Irina V, Su Zao-Zhong, Sarkar Devanand, Gopalkrishnan Rahul V, Waxman Samuel, Yacoub Adly, Dent Paul, Fisher Paul B
Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY 10032, USA.
Oncogene. 2005 Jan 20;24(4):585-96. doi: 10.1038/sj.onc.1208183.
Pancreatic cancer is exceptionally aggressive with no long-term effective therapy. Current interventional approaches, including surgery, radiation and/or chemotherapy, have done little to quell the mortality associated with this malignancy. Subtraction hybridization identified a cancer-specific apoptosis-inducing cytokine gene, melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), with a broad range of selective antitumor activity in diverse cancers both in vitro and in vivo in nude mice and recently in patients with advanced carcinomas and melanomas. Unlike most neoplasms, pancreatic cancers display innate resistance to mda-7/IL-24-induced apoptosis, which correlates with a diminished capacity to convert mda-7/IL-24 mRNA into protein. We presently demonstrate that this translational block can be reversed by treatment with agents that elevate reactive oxygen species (ROS). Induction of apoptosis in vitro and suppression of tumorigenesis in vivo in nude mice are induced in pancreatic cancers, irrespective of the status of their K-ras gene, only when tumor cells simultaneously express mda-7/IL-24 and are treated with a ROS-inducer, such as arsenic trioxide (ARS), N-(4-hydroxyphenyl) retinamide (HPR) or dithiophene (NSC656240 (NSC)). In pancreatic cancer cells constitutively expressing mda-7/IL-24 mRNA, a single treatment with arsenic trioxide, HPR or NSC656240 induces apoptosis, which correlates with production of MDA-7/IL-24 protein. The specificity of this action is documented by the ability of ROS inhibitors, including N-acetyl-L-cysteine and Tiron, to block this killing effect. Of potential clinical significance, similar treatment of normal cells does not elicit significant changes in growth nor does it induce apoptosis. Analysis of signal transduction changes in pancreatic carcinoma cells infected with Ad.mda-7 in combination with a ROS-inducer indicate that cell death correlates with modulation of discrete cassettes of multiple signaling pathways in a pancreatic cancer cell-specific manner, supporting global signaling dysregulation as a potential mediator of apoptosis induction. These findings suggest a promising combinatorial approach for safely promoting cell death in pancreatic tumors that provides a rational framework for developing a selective and effective therapy for this invariably fatal cancer.
胰腺癌极具侵袭性，目前尚无长期有效的治疗方法。包括手术、放疗和/或化疗在内的现有介入治疗方法，对降低这种恶性肿瘤相关的死亡率收效甚微。消减杂交技术鉴定出一种癌症特异性凋亡诱导细胞因子基因，即黑色素瘤分化相关基因-7/白细胞介素-24（mda-7/IL-24），该基因在体外、裸鼠体内以及最近在晚期癌症和黑色素瘤患者体内的多种癌症中均具有广泛的选择性抗肿瘤活性。与大多数肿瘤不同，胰腺癌对mda-7/IL-24诱导的凋亡具有天然抗性，这与将mda-7/IL-24 mRNA转化为蛋白质的能力降低有关。我们目前证明，用能提高活性氧（ROS）的药物治疗可逆转这种翻译障碍。仅当肿瘤细胞同时表达mda-7/IL-24并接受ROS诱导剂（如三氧化二砷（ARS）、N-（4-羟基苯基）视黄酸（HPR）或二噻吩（NSC656240（NSC）））治疗时，无论其K-ras基因状态如何，胰腺癌在体外均可诱导凋亡，在裸鼠体内可抑制肿瘤发生。在组成性表达mda-7/IL-24 mRNA的胰腺癌细胞中，单次使用三氧化二砷、HPR或NSC656240可诱导凋亡，这与MDA-7/IL-24蛋白的产生相关。ROS抑制剂（包括N-乙酰-L-半胱氨酸和钛铁试剂）能够阻断这种杀伤作用，证明了这种作用的特异性。具有潜在临床意义的是，对正常细胞进行类似处理不会引起生长的显著变化，也不会诱导凋亡。对感染Ad.mda-7并联合ROS诱导剂的胰腺癌细胞信号转导变化的分析表明，细胞死亡与以胰腺癌细胞特异性方式调节多个信号通路的离散模块相关，支持全局信号失调作为凋亡诱导的潜在介质。这些发现提示了一种有前景的联合方法，可安全地促进胰腺肿瘤细胞死亡，为开发针对这种必死性癌症的选择性有效治疗方法提供了合理框架。
