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1.  The development of MDA-7/IL-24 as a cancer therapeutic 
Pharmacology & therapeutics  2010;128(2):375-384.
The cytokine melanoma differentiation associated gene 7 (mda-7) was identified by subtractive hybridization as a protein whose expression increased during the induction of terminal differentiation, and that was either not expressed or was present at low levels in tumor cells compared to non-transformed cells. Based on conserved structure, chromosomal location and cytokine-like properties, MDA-7, was classified as a member of the interleukin (IL)-10 gene family and designated as MDA-7/IL-24. Multiple studies have demonstrated that expression of MDA-7/IL-24 in a wide variety of tumor cell types, but not in corresponding equivalent non-transformed cells, causes their growth arrest and rapid cell death. In addition, MDA-7/IL-24 has been noted to radiosensitize tumor cells which in part is due to the generation of reactive oxygen species (ROS) and ceramide that cause endoplasmic reticulum stress and suppress protein translation. Phase I clinical trial data has shown that a recombinant adenovirus expressing MDA-7/IL-24 (Ad.mda-7 (INGN-241)) was safe and had measurable tumoricidal effects in over 40% of patients, strongly arguing that MDA-7/IL-24 could have significant therapeutic value. This review describes what is presently known about the impact of MDA-7/IL-24 on tumor cell biology and its potential therapeutic applications.
doi:10.1016/j.pharmthera.2010.08.001
PMCID: PMC2947573  PMID: 20732354
MDA-7; IL-24; Apoptosis; Autophagy; Ceramide; ROS; Ca2+; Clinical trial; Signal transduction; PERK; ER stress; MCL-1
2.  Caspase-, cathepsin-, and PERK-dependent regulation of MDA-7/IL-24-induced cell killing in primary human glioma cells 
Molecular cancer therapeutics  2008;7(2):297-313.
Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a novel cytokine displaying selective apoptosis-inducing activity in transformed cells without harming normal cells. The present studies focused on defining the mechanism(s) by which a GST-MDA-7 fusion protein inhibits cell survival of primary human glioma cells in vitro. GST-MDA-7 killed glioma cells with diverse genetic characteristics that correlated with inactivation of ERK1/2 and activation of JNK1-3. Activation of JNK1-3 was dependent on protein kinase R–like endoplasmic reticulum kinase (PERK), and GST-MDA-7 lethality was suppressed in PERK−/− cells. JNK1-3 signaling activated BAX, whereas inhibition of JNK1-3, deletion of BAX, or expression of dominant-negative caspase-9 suppressed lethality. GST-MDA-7 also promoted a PERK-, JNK-, and cathepsin B–dependent cleavage of BID; loss of BID function promoted survival. GST-MDA-7 suppressed BAD and BIM phosphorylation and heat shock protein 70 (HSP70) expression. GST-MDA-7 caused PERK-dependent vacuolization of LC3-expressing endosomes whose formation was suppressed by incubation with 3-methylade-nine, expression of HSP70 or BiP/GRP78, or knockdown of ATG5 or Beclin-1 expression but not by inhibition of the JNK1-3 pathway. Knockdown of ATG5 or Beclin-1 expression or overexpression of HSP70 reduced GST-MDA-7 lethality. Our data show that GST-MDA-7 induces an endoplasmic reticulum stress response that is causal in the activation of multiple proapoptotic pathways, which converge on the mitochondrion and highlight the complexity of signaling pathways altered by mda-7/IL-24 in glioma cells that ultimately culminate in decreased tumor cell survival.
doi:10.1158/1535-7163.MCT-07-2166
PMCID: PMC3204355  PMID: 18281515
3.  MDA-7/IL-24 as a cancer therapeutic: from bench to bedside 
Anti-cancer drugs  2010;21(8):725-731.
The novel cytokine melanoma differentiation associated gene-7 (mda-7) was identified by subtractive hybridization in the mid-1990s as a protein whose expression increased during the induction of terminal differentiation, and that was either not expressed or was present at low levels in tumor cells compared to non-transformed cells. Based on conserved structure, chromosomal location and cytokine-like properties, MDA-7, has now been classified as a member of the expanding interleukin (IL)-10 gene family and designated as MDA-7/IL-24. Multiple studies have demonstrated that expression of MDA-7/IL-24 in a wide variety of tumor cell types, but not in corresponding equivalent non-transformed cells, causes their growth arrest and ultimately cell death. In addition, MDA-7/IL-24 has been noted to be a radiosensitizing cytokine, which in part is due to the generation of reactive oxygen species (ROS) and ceramide that cause endoplasmic reticulum stress. Phase I clinical trial data has shown that a recombinant adenovirus expressing MDA-7/IL-24 (Ad.mda-7 (INGN-241)) was safe and had measurable tumoricidal effects in over 40% of patients, which strongly argues that MDA-7/IL-24 may have significant therapeutic value. This review describes what is known about the impact of MDA-7/IL-24 on tumor cell biology and its potential therapeutic applications.
doi:10.1097/CAD.0b013e32833cfbe1
PMCID: PMC2915543  PMID: 20613485
MDA-7: melanoma differentiation associated gene 7
4.  Sensitive and Specific Fluorescent Probes for Functional Analysis of the Three Major Types of Mammalian ABC Transporters 
PLoS ONE  2011;6(7):e22429.
An underlying mechanism for multi drug resistance (MDR) is up-regulation of the transmembrane ATP-binding cassette (ABC) transporter proteins. ABC transporters also determine the general fate and effect of pharmaceutical agents in the body. The three major types of ABC transporters are MDR1 (P-gp, P-glycoprotein, ABCB1), MRP1/2 (ABCC1/2) and BCRP/MXR (ABCG2) proteins. Flow cytometry (FCM) allows determination of the functional expression levels of ABC transporters in live cells, but most dyes used as indicators (rhodamine 123, DiOC2(3), calcein-AM) have limited applicability as they do not detect all three major types of ABC transporters. Dyes with broad coverage (such as doxorubicin, daunorubicin and mitoxantrone) lack sensitivity due to overall dimness and thus may yield a significant percentage of false negative results. We describe two novel fluorescent probes that are substrates for all three common types of ABC transporters and can serve as indicators of MDR in flow cytometry assays using live cells. The probes exhibit fast internalization, favorable uptake/efflux kinetics and high sensitivity of MDR detection, as established by multidrug resistance activity factor (MAF) values and Kolmogorov-Smirnov statistical analysis. Used in combination with general or specific inhibitors of ABC transporters, both dyes readily identify functional efflux and are capable of detecting small levels of efflux as well as defining the type of multidrug resistance. The assay can be applied to the screening of putative modulators of ABC transporters, facilitating rapid, reproducible, specific and relatively simple functional detection of ABC transporter activity, and ready implementation on widely available instruments.
doi:10.1371/journal.pone.0022429
PMCID: PMC3142157  PMID: 21799851
5.  Effect of Peierls transition in armchair carbon nanotube on dynamical behaviour of encapsulated fullerene 
Nanoscale Research Letters  2011;6(1):216.
The changes of dynamical behaviour of a single fullerene molecule inside an armchair carbon nanotube caused by the structural Peierls transition in the nanotube are considered. The structures of the smallest C20 and Fe@C20 fullerenes are computed using the spin-polarized density functional theory. Significant changes of the barriers for motion along the nanotube axis and rotation of these fullerenes inside the (8,8) nanotube are found at the Peierls transition. It is shown that the coefficients of translational and rotational diffusions of these fullerenes inside the nanotube change by several orders of magnitude. The possibility of inverse orientational melting, i.e. with a decrease of temperature, for the systems under consideration is predicted.
doi:10.1186/1556-276X-6-216
PMCID: PMC3211273  PMID: 21711764
6.  Mechanism of In Vitro Pancreatic Cancer Cell Growth Inhibition by mda-7/IL-24 and Perillyl Alcohol 
Cancer research  2008;68(18):7439-7447.
The death rate for pancreatic cancer approximates the number of new cases each year and when diagnosed current therapeutic regimens provide little benefit in extending patient survival. These dire statistics necessitate the development of enhanced single or combinatorial therapies to decrease the pathogenesis of this invariably fatal disease. Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) is a potent cancer gene therapeutic because of its broad-spectrum cancer-specific apoptosis-inducing properties as well as its multi-pronged indirect anti-tumor activities. However, pancreatic cancer cells demonstrate inherent resistance to mda-7/IL-24 that is caused by a block of translation of mda-7/IL-24 mRNA in these tumor cells. We now reveal that a dietary agent perillyl alcohol (POH) in combination with Ad.mda-7 efficiently reverses the mda-7/IL-24 ‘protein translational block' by inducing reactive oxygen species thereby resulting in MDA-7/IL-24 protein production, growth suppression and apoptosis. Pharmacological inhibitor and siRNA studies identify xanthine oxidase as a major source of superoxide radical production causing these toxic effects. Since both POH and Ad.mda-7 are being evaluated in clinical trials, combining a dietary agent and a virally delivered therapeutic cytokine provide an innovative approach for potentially treating human pancreatic cancer.
doi:10.1158/0008-5472.CAN-08-0072
PMCID: PMC2596728  PMID: 18768668
mda-7/IL-24; POH; reactive oxygen species; cancer-selective apoptosis; xanthine oxidase
7.  Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24): novel gene therapeutic for metastatic melanoma 
Toxicology and applied pharmacology  2006;224(3):300-307.
A potentially less toxic approach for cancer therapy comprises induction of tumor cells to lose growth potential irreversibly and terminally differentiate. Combining this scheme termed ‘differentiation therapy of cancer’ with subtraction hybridization to human melanoma cells resulted in the cloning of melanoma differentiation associated (mda) genes displaying elevated expression as a consequence of induction of terminal differentiation. One originally novel gene, mda-7, was found to display elevated expression in normal melanocytes and nevi with progressive loss of expression as a consequence of melanoma development and progression to metastasis. Based on structure, biochemical properties and chromosomal location, mda-7 has now been reclassified as interleukin (IL)-24 a member of the expanding IL-10 family of cytokines. In vitro cell culture and in vivo animal studies indicate that mda-7/IL-24 selectively induces programmed cell death (apoptosis) in multiple human cancers (including melanomas), without harming normal cells, and promotes profound anti-tumor activity in nude mice containing human tumor xenografts. Based on these remarkable properties, a Phase I Clinical trial was conducted to test the safety of administration of mda-7/IL-24 by a replication incompetent adenovirus (Ad.mda-7; INGN 241) in patients with advanced solid cancers including melanoma. mda-7/IL-24 was found to be safe and to promote significant clinical activity, particularly in the context of patients with metastatic melanoma. These results provide an impetus for further clinical studies, and document a central paradigm of cancer therapy, namely translation of basic science from the “bench to the bedside.”
doi:10.1016/j.taap.2006.11.021
PMCID: PMC2739016  PMID: 17208263
mda-7/IL-24; apoptosis; metastatic melanoma; Phase I Clinical Trial
8.  mda-7/IL-24: Multifunctional cancer-specific apoptosis-inducing cytokine 
Pharmacology & therapeutics  2006;111(3):596-628.
“Differentiation therapy” provides a unique and potentially effective, less toxic treatment paradigm for cancer. Moreover, combining “differentiation therapy” with molecular approaches presents an unparalleled opportunity to identify and clone genes mediating cancer growth control, differentiation, senescence, and programmed cell death (apoptosis). Subtraction hybridization applied to human melanoma cells induced to terminally differentiate by treatment with fibroblast interferon (IFN-β) plus mezerein (MEZ) permitted cloning of melanoma differentiation associated (mda) genes. Founded on its novel properties, one particular mda gene, mda-7, now classified as a member of the interleukin (IL)-10 gene family (IL-24) because of conserved structure, chromosomal location, and cytokine-like properties has become the focus of attention of multiple laboratories. When administered by transfection or adenovirus-transduction into a spectrum of tumor cell types, melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) induces apoptosis, whereas no toxicity is apparent in normal cells. mda-7/IL-24 displays potent “bystander antitumor” activity and also has the capacity to enhance radiation lethality, to induce immune-regulatory activities, and to inhibit tumor angiogenesis. Based on these remarkable attributes and effective antitumor therapy in animal models, this cytokine has taken the important step of entering the clinic. In a Phase I clinical trial, intratumoral injections of adenovirus-administered mda-7/IL-24 (Ad.mda-7) was safe, elicited tumor-regulatory and immune-activating processes, and provided clinically significant activity. This review highlights our current understanding of the diverse activities and properties of this novel cytokine, with potential to become a prominent gene therapy for cancer.
doi:10.1016/j.pharmthera.2005.11.005
PMCID: PMC1781515  PMID: 16464504
mda-7/IL-24; Differentiation therapy of cancer; Programmed cell death; Antitumor bystander activity; Radiosensitization; Angiogenesis; Cell signaling; Phase I clinical trial
9.  Ionizing Radiation Enhances Adenoviral Vector Expressing mda-7/IL-24-mediated Apoptosis in Human Ovarian Cancer 
Journal of cellular physiology  2006;208(2):298-306.
Ovarian cancer is the fifth most common cause of cancer-related death in women. Current interventional approaches, including debulking surgery, chemotherapy, and/or radiation have proven minimally effective in preventing the recurrence and/or mortality associated with this malignancy. Subtraction hybridization applied to terminally differentiating human melanoma cells identified melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), whose unique properties include the ability to selectively induce growth suppression, apoptosis, and radiosensitization in diverse cancer cells, without causing any harmful effects in normal cells. Previously, it has been shown that adenovirus-mediated mda-7/IL-24 therapy (Ad.mda-7) induces apoptosis in ovarian cancer cells, however, the apoptosis induction was relatively low. We now document that apoptosis can be enhanced by treating ovarian cancer cells with ionizing radiation (IR) in combination with Ad.mda-7. Additionally, we demonstrate that mda-7/IL-24 gene delivery, under the control of a minimal promoter region of progression elevated gene-3 (PEG-3), which functions selectively in diverse cancer cells with minimal activity in normal cells, displays a selective radiosensitization effect in ovarian cancer cells. The present studies support the use of IR in combination with mda-7/IL-24 as a means of augmenting the therapeutic benefit of this gene in ovarian cancer, particularly in the context of tumors displaying resistance to radiation therapy.
doi:10.1002/jcp.20663
PMCID: PMC2203216  PMID: 16646087

Results 1-9 (9)