Therapeutic Applications of Interleukin 24 (IL24): A Review

Fisher’s group identified melanoma differentiation-associated protein-7 (MDA-7) upon discovery of cell surface receptor MDA-7 renamed Interleukin 24 (IL24).It has three N-glycosylation sites. IL24 signals through receptors. Binding of IL24 to receptors leads to the activation of STAT-3 and STAT-1. IL 24 induces the secretion of high level of Interferon Gamma (IFN- γ ) ,IL6 and tumor necrosis factor alpha (TNF- α ) and low levels of IL1,IL12 and granulocyte macrophage colony stimulating factor (GM-CSF) from human peripheral blood mononuclear cells(PBMC). IL24 has growth suppressive properties in a wide variety of human cancer cell lines without inducing harmful effects in normal cells. This review is focused on the role of IL 24 on tumor cell biology and its potential therapeutic applications.


INTRODUCTION
In the mid-1990s, Paul Fisher's group at Colombia University identified a gene by substraction hybridization, MDA-7 (melanoma differentiation-associated protein-7). In 2002 MDA-7 was renamed interleukin 24 (IL24) upon discovery of cell surface receptors [

Melanoma differentiation associated gene-7/IL24 and melanoma
Melanoma represents an aggressive cancer that most frequently metastasizes the lymph node region and to distant sites as the disease progress. In the United States the incidence of melanoma is increasing at a faster rate than any other cancer [10]. Surgery is an option for treating metastases as chemotherapy and radiotherapy do not achieve cure in majority of the patients and less than 5% of melanoma patients with systemic metastases survive 5 years or more [10]. Treatment with inclusion of a high level of Interferon alpha has shown significant increase in patient life time but not act towards the cure [11]. The metastases treatment focus on expression of skin cell protein as IL24 mRNA and protein are expressed in melanocytes and the only skin cell expressing IL24 protein constitutively [12]. Gupta et al [10] reported the expression of IL24 during melanoma progression. The immune-histochemical analysis of IL24 expression during tissue section of melanoma indicated abundant expression of IL24 protein in human nevi and in primary melanoma tumors.IL24 has growth suppressive properties in wide variety of human cancer cell lines without inducing harmful effects in normal cells [10].

Apoptosis Inducing Properties of IL24
IL24 has growth inhibiting and apoptosis inducing properties in human tumors [13]. IL24 role in inducing apoptosis has been extensively studied since it was identified. The exact mechanism for this protein to act as a tumor suppressor is still unknown. The secreted intracellular IL24 is able to induce apoptosis and inhibit tumor cell invasion [13]. The apoptosis inducing properties of IL24 was first tested using replication incompetent adenoviral vector (Ad.IL24) in breast cancer cell lines (Table 2). Ad.IL24 inhibited growth and decreased the survival of the tumor cells invitro and invivo without having the same effects on normal cells [4]. This apoptosis inducing ability of Ad.IL24 was demonstrated to be independent of the p53 or retinobla-  [14]. In prostate cancer cells free radicals are involved in IL24-induced apoptosis. Ad.IL24 selectively induces apoptosis by mitochondrial dysfunction and production of reactive oxygen species (ROS). IL24 increases the reactive oxygen species (ROS) production by 3-5 fold in cancer cells without having the same effect on normal cells [15]. A number of molecules involved in apoptotic signaling of IL24 in tumor cells have been identified. However identities of the critical molecules or signaling pathways for tumor cell apoptosis have not been assortmend [6,16].

Antitumor bystander activity of IL24
The secreted form of IL24 has antitumor bystander activity. The exact mechanism of this activity is not yet known but it is thought to involve direct cytotoxicity, anti-angiogenic activity or it can be result of immunoregulatory activities [17].
IL24 is secreted from both normal and cancer cells after administration of Ad.IL24.These secreted proteins possess the antitumor bystander activity and are able to suppress growth, induce apoptosis and enhance radiation lethality in human cancer cells [18].

Anti-angiogenic activity of IL24
Angiogenesis is complex process that involves the formation of new blood vessels [19]. It is a fundamental event for tumor growth and metastasis. A number of angiogenesis inhibitors have been found and prove to be effective in pre clinical studies but very few of them have therapeutic effects in clinical trials [19].
IL24 secreted from transfected 293 cells inhibits endothelial cells differentiation and tumor growth. The inhibition of tumor growth was observed to be associated with reduced tumor vascularization.
IL24 secreted from transfected 293 cells was detected to be more potent in inhibiting endothelial cell differentiation than endostatin. IL24 inhibits the endothelial cell migration [20].

Combination Therapy with IL24
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. Induction of apoptosis by IL24 can be enhanced by treating ovarian cells with ionizing radiation in combination with Ad.IL24 [11].

IL24 in cancer therapy
IL24 has clinical potential as an anti-cancer drug. It has many advantages compared to existing cancer therapeutics. These include activity against broad range of tumor types, lack of cytotoxicity against normal human cells, ability to induce antitumor bystander activity [18], ability to inhibit tumor angiogenesis and synergy with radiation, chemotherapy and monoclonal antibody therapies [8]. IL24 as fusion protein or with combination of viral vector confirm anticancer effects and immune modulatory activity [10].

CONCLUSION
IL24 has progressed from a laboratory discovery to a potential therapeutic agent for Mycobacterium tuberculosis and cancer. Further investigations are clearly required to have a precise understanding of the mechanism of action of IL24 in cancer. Future research will be focused on the application of nanotechnology and stem cell to deliver IL24 therapeutically.