Begell House Inc.
Onco Therapeutics
OT
2694-4642
1
4
2010
Nitric Oxide-Mediated Regulation of Cancer Immune Escape
231-249
10.1615/ForumImmunDisTher.v1.i4.10
D. Robert
Siemens
Department of Anatomy and Cell Biology and Department of Urology; Queen's University, Kingston, Ontario
Charles H.
Graham
Department of Anatomy and Cell Biology and Department of Urology; Queen's University, Kingston, Ontario
immune escape
cancer
hypoxia
nitric oxide
NK cell
There is now evidence that nitric oxide (NO) regulates hypoxia-induced malignant phenotypes such as invasiveness, metastatic ability, and drug resistance in tumor cells. Recent studies have also revealed that the ability of tumor cells to avoid destruction by innate immune effector mechanisms (immune escape) is stimulated by hypoxia through a mechanism that appears to involve inhibition of NO signaling. Specifically, it was shown that NO activity blocks the hypoxia-induced resistance of prostate cancer cells to the lytic activity of peripheral blood lymphocytes by preventing the shedding of major histocompatibility complex class I chain-related (MIC) molecules from the tumor cell membrane. MIC plays an important role in tumor immune surveillance through its interaction with the NKG2D receptor on natural killer and cytotoxic T cells. These findings suggest that the hypoxic tumor microenviron-ment contributes to impaired immune surveillance, and that activation of NO signaling is of potential use in cancer immunotherapy.
Nitric Oxide Donor and Mimetic Molecules in Cancer Chemotherapy and Chemoprevention
251-279
10.1615/ForumImmunDisTher.v1.i4.20
S.
Anand
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL
Isaac T.
Schiefer
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL
R. J.
Thatcher
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL
nitric oxide
cancer chemoprevention
hybrid drugs
NO-NSAID
diazeniumdiolates
furoxans
angina
nitrates
quinone methide
Nitric oxide (NO) has been shown in varying circumstances to be involved in mechanisms of both chemical carcinogenesis and chemoprevention. A full understanding of the basis for these contradictory effects of NO is not yet available, but drugs that deliver NO bioactivity by acting as NO donors or NO mimetics show potential in both cancer chemoprevention and chemotherapy. It is useful to understand the differences between the chemical moieties that are incorporated in such drugs to deliver NO bioactivity. The majority of these molecules depend on bioactivation in order to fully obtain their NO mimetic effects; the reliance on bioactivation provides an opportunity to localize and control the delivery of NO bioactivity. The various chemical classes of NO donor warheads and their successful incorporation into hybrid drugs and prodrugs is briefly and critically reviewed here with an emphasis on their potential utility in cancer chemoprevention and chemotherapy.
DETANONOate Is a Potent Chemo\ Radio-Sensitizing Agent in Colon and Colorectal Cancers as Assessed in In Vitro and In Vivo Established Tumor Xenografts
281-295
10.1615/ForumImmunDisTher.v1.i4.30
Sergio
Huerta
Division of Surgery, University of Texas Southwestern Medical Center, Dallas VA Medical Center, 4500 S. Lancaster Road, Dallas, TX 75225
Xiaohuan
Gao
Department of Surgery University of Texas Southwestern Medical Center/Dallas and VA Medical Center, Dallas, TX
Benjamin
Bonavida
Department of Microbiology, Immunology, &
Molecular Genetics, David Geffen School of Medicine at UCLA, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747, USA
rectal cancer
ionizing radiation
pathological complete response
AIF
BAX
Nitric oxide (NO) is a novel cancer therapeutic, and NO donors provide a unique advantage in the study of the properties of NO as an anti-neo-plastic agent because they exhibit novel anti-tumor sensitizing abilities and reverse resistance to cytotoxic therapies. We present evidence on the enhancement by NO, used in combination with chemotherapy, of drug-induced apoptosis in colorectal cancer cells and NO-mediated regression of tumor xenografts resistant to conventional chemo- and radiotherapeutic interventions. Treatment with (Z)-l-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-l-ium-1,2-diolate (DETANONOate) sensitized SW620 metastatic CRC cells to cisplatin (CDDP)-induced apoptosis. Nude mice bearing SW620 xenografts treated with CDDP and DETANONOate demonstrated a 36% reduction in tumor load compared with control, and this was associated with an up-regulation of the expression of the apoptosis-inducing factor (AIF). Similarly, in models of rectal cancer, pretreating radio-resistant HT-29 colorectal cancer cells with DETANONOate for 16 h prior to ionizing radiation resulted in a significant reduction in colony formation (47%) compared with DETANONOate treatment alone. In vivo, SCID mice bearing HT-29 xenografts and treated with irradiation, DETANONOate, or a combination showed tumor growth reduction by 32.5% following the combination treatment. In vitro, the sensitizing activity of DETANONOate was associated with an up-regulation of p21, p27, and BAX, with a concomitant decrease in Bcl-2 expression in DETANONOate-pretreated HT-29 cells compared with controls. Altogether, these results demonstrate that DETANONOate is a potent chemo-radio-sensitizer in colorectal cancer cells that are resistant to conventional chemo- and radiotherapies.
Post-Translational Regulation of Fas/CD95 in Cell Death and Survival: Role of Nitric Oxide
297-305
10.1615/ForumImmunDisTher.v1.i4.40
L.
Leon-Bollotte
EPHE, Laboratoire d'immunologie et immunothérapie des cancers, University of Burgundy, Dijon
M.
Lamrani
EPHE, Laboratoire d'immunologie et immunothérapie des cancers, University of Burgundy, Dijon
S.
Plenchette-Colas
EPHE, Laboratoire d'immunologie et immunothérapie des cancers, University of Burgundy, Dijon
Jean-Francois
Jeannin
EPHE Tumor Immunology and Immunotherapy, Laboratory, University of Burgundy, Dijon, France
Ali
Bettaieb
École Pratique des Hautes Études (EPHE), PSL Research University, Paris, France; Laboratoire d'Immunologie et Immunothérapie des Cancers (LIIC), Université de Bourgogne Franche-Comté, Dijon, France
Fas/CD95
phosphorylation
nitration
palmitoylation
glutathionylation
Fas/CD95 or APO-1 is one of the best-characterized members of the tumor necrosis factor receptor (TNFR) superfamily. Triggering of Fas by its ligand (FasL) leads to receptor oligomerization and the formation of the death-induced signaling complex (DISC), and thereby activates the caspase cascade, which culminates in apoptotic cell death. Many post-translational modifications are recognized as critical modifications for the early events of Fas regulation and function. Here, we summarize the current knowledge on Fas post-translational modifications, including phosphorylation, nitration, palmitoylation, and glutathionylation.
Toll-like Receptor 2 and 4 in Cancer Immunotherapy: Is Nitric Oxide a Mediator?
307-315
10.1615/ForumImmunDisTher.v1.i4.50
Amandine
Martin
EPHE, Cancer Immunotherapy Laboratory, University of Burgundy, Dijon
Cedric
Seignez
EPHE, Cancer Immunotherapy Laboratory, University of Burgundy, Dijon
Catherine
Paul
EPHE, Cancer Immunotherapy Laboratory, University of Burgundy, Dijon
Ali
Bettaieb
École Pratique des Hautes Études (EPHE), PSL Research University, Paris, France; Laboratoire d'Immunologie et Immunothérapie des Cancers (LIIC), Université de Bourgogne Franche-Comté, Dijon, France
Jean-Francois
Jeannin
EPHE Tumor Immunology and Immunotherapy, Laboratory, University of Burgundy, Dijon, France
tumor immune response
TLR
NO
chemo-immuno-therapy
The main function of the immune system is to recognize and eliminate pathogens. Recognition of these organisms is done by binding of evolutionary conserved molecules called pathogen-associated molecular patterns (PAMPs) to specific receptors called pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), which are mainly expressed by immune cells. Tumor cells, which do not produce PAMPs, are therefore able to escape from immune surveillance. Consequently, effective cancer immunotherapies using PRR ligands were developed. Thus, the use of Bacillus Calmette-Guerin (BCG), a TLR-2 ligand, and Taxol, a TLR-4 ligand, have become standard cancer immunotherapies. In our laboratory, we have developed an efficient immunotherapy approach in murine models of colon and breast cancers with a lipid A analog, OM-174. After TLR-4 binding, OM-174 induces immune cell recruitment, inflammatory response activation, cytokine secretion, inducible nitric oxide synthase (iNOS) expression, and nitric oxide (NO) production in tumors. Moreover, although NO is not toxic itself for tumor cells, it could sensitize them to the death-induced by tumor necrosis factor (TNF)-family ligands such as the Fas ligand (FasL), TNF-related apoptosis-inducing ligand (TRAIL), and TNF-α. Thus, NO may play a mediator role in efficient immunotherapies based on TLR-2 and TLR-4 activation.