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.