Strategy for reversing resistance to a single anticancer agent in human prostate and pancreatic carcinomas

Abstract

Effective therapies for most solid cancers, especially those that have progressed to metastasis, remain elusive because of inherent and acquired resistance of tumor cells to conventional treatments. Additionally, the effective therapeutic window for many protocols can be very narrow, frequently resulting in toxicity. The present study explores an anticancer strategy that effectively eliminates resistant cancer cells without exerting deleterious effects on normal cells. This approach employs melanoma differentiationinduced gene-7/interleukin-24 (mda-7/IL-24), a cancer-specific, apoptosis-inducing cytokine, in combination with nontoxic doses of a chemical compound from the endoperoxide class that decomposes in water generating singlet oxygen. This combinatorial regimen specifically induced in vitro apoptosis in prostate carcinoma cells, with innate resistance to chemotherapy or engineered resistance to mda-7/IL-24, as well as pancreatic carcinoma cells inherently resistant to any treatment modality, including mda-7/ IL-24. Apoptosis induction correlated with increased cellular reactive oxygen species production and was prevented by general antioxidants, such as N-acetyl-L-cysteine or Tiron. Induction of apoptosis in combination-treated cancer cells correlated with a reduction in the antiapoptotic protein BCL-x L. In contrast, both normal prostate and pancreatic epithelial cells were unaffected by the single or combination treatment. These provocative findings suggest that this combinatorial strategy might provide a platform for developing effective treatments for therapy-resistant cancers.

Therapeutic Applications of Interleukin 24 (IL24): A Review

“…IL24 is able to efficiently induce apoptosis in a wide variety of human cancers except pancreatic and ovarian cancer [21]. IL24 does not significantly alter growth or induce apoptosis in human pancreatic cancer cells due to the expression of oncogenic K-ras, which is a common genetic alteration in pancreatic cancers.…”

“…This resistance for IL24 can be overcome by combination treatment with an antisense K-ras expression vector. Another way to overcome the problem is to use IL24 in combination with non-toxic doses of a chemical compound from the endoperoxide class [21]. It has been reported that IL24 is able to induce apoptosis in ovarian cancer cells with a low efficiency.…”

Historical perspective and recent insights into our understanding of the molecular and biochemical basis of the antitumor properties of mda-7/IL-24

“…46 Apoptosis induction by mda-7/IL-24 also involves oxidative stress by generation of reactive oxygen species (ROS) specifically in cancer cells. 16,47,48 Initial studies in prostate cancer cells identified ROS as an active component in mda-7/IL-24 induced apoptosis. Antioxidants and mitochondrial permeability transition inhibitors hinder Ad.mda-7-mediated apoptosis and mitochondrial changes in prostate cancer cells.…”

Acquired and innate resistance to the cancer-specific apoptosis-inducing Cytokine, mda-7/IL-24: Not insurmountable therapeutic problems

“…[39][40][41] Interestingly, agents that induce ROS generation, such as arsenic trioxide or endoperoxides, can also overcome the translational inhibition without altering K-ras expression. 25,27 Ad.mda-7-mediated apoptosis induction involves downregulation of the anti-apoptotic proteins Bcl-2 and Bcl-xL and upregulation of the pro-apoptotic proteins Bax and Bak. Prostate cancer cells stably overexpressing Bcl-2 or Bcl-xL, a frequent event in patients, acquire resistance to Ad.mda-7.…”

“…Apoptosis induction by mda-7/IL-24 also involves oxidative stress by generation of reactive oxygen species (ROS) specifically in cancer cells. [25][26][27] The molecular mechanism of the cancer-selective apoptosis induction by mda-7/IL-24 remains to be unraveled. However, current studies highlight the ability of MDA-7/IL-24 to induce apoptosis selectively in cancer cells by altering diverse signaling pathways and processes in tumor and surrounding cells (Fig.…”