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1.
J Cell Physiol ; 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38775127

RESUMEN

Primary, glioblastoma, and secondary brain tumors, from metastases outside the brain, are among the most aggressive and therapeutically resistant cancers. A physiological barrier protecting the brain, the blood-brain barrier (BBB), functions as a deterrent to effective therapies. To enhance cancer therapy, we developed a cancer terminator virus (CTV), a unique tropism-modified adenovirus consisting of serotype 3 fiber knob on an otherwise Ad5 capsid that replicates in a cancer-selective manner and simultaneously produces a potent therapeutic cytokine, melanoma differentiation-associated gene-7/interleukin-24 (MDA-7/IL-24). A limitation of the CTV and most other viruses, including adenoviruses, is an inability to deliver systemically to treat brain tumors because of the BBB, nonspecific virus trapping, and immune clearance. These obstacles to effective viral therapy of brain cancer have now been overcome using focused ultrasound with a dual microbubble treatment, the focused ultrasound-double microbubble (FUS-DMB) approach. Proof-of-principle is now provided indicating that the BBB can be safely and transiently opened, and the CTV can then be administered in a second set of complement-treated microbubbles and released in the brain using focused ultrasound. Moreover, the FUS-DMB can be used to deliver the CTV multiple times in animals with glioblastoma  growing in their brain thereby resulting in a further enhancement in survival. This strategy permits efficient therapy of primary and secondary brain tumors enhancing animal survival without promoting harmful toxic or behavioral side effects. Additionally, when combined with a standard of care therapy, Temozolomide, a further increase in survival is achieved. The FUS-DMB approach with the CTV highlights a noninvasive strategy to treat brain cancers without surgery. This innovative delivery scheme combined with the therapeutic efficacy of the CTV provides a novel potential translational therapeutic approach for brain cancers.

2.
J Immunother Cancer ; 11(11)2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37935566

RESUMEN

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective therapies and with poor prognosis, causing 7% of all cancer-related fatalities in the USA. Considering the lack of effective therapies for this aggressive cancer, there is an urgent need to define newer and more effective therapeutic strategies. Polyinosine-polycytidylic acid (pIC) is a synthetic double-stranded RNA (dsRNA) which directly activates dendritic cells and natural killer cells inhibiting tumor growth. When pIC is delivered into the cytoplasm using polyethyleneimine (PEI), pIC-PEI, programmed-cell death is induced in PDAC. Transfection of [pIC]PEI into PDAC cells inhibits growth, promotes toxic autophagy and also induces apoptosis in vitro and in vivo in animal models. METHODS: The KPC transgenic mouse model that recapitulates PDAC development in patients was used to interrogate the role of an intact immune system in vivo in PDAC in response to [pIC]PEI. Antitumor efficacy and survival were monitored endpoints. Comprehensive analysis of the tumor microenvironment (TME) and immune cells, cytokines and chemokines in the spleen, and macrophage polarization were analyzed. RESULTS: Cytosolic delivery of [pIC]PEI induces apoptosis and provokes strong antitumor immunity in vivo in immune competent mice with PDAC. The mechanism underlying the immune stimulatory properties of [pIC]PEI involves Stat1 activation resulting in CCL2 and MMP13 stimulation thereby provoking macrophage polarization. [pIC]PEI induces apoptosis via the AKT-XIAP pathway, as well as macrophage differentiation and T-cell activation via the IFNγ-Stat1-CCL2 signaling pathways in PDAC. In transgenic tumor mouse models, [pIC]PEI promotes robust and profound antitumor activity implying that stimulating the immune system contributes to biological activity. The [pIC]PEI anti-PDAC effects are enhanced when used in combination with a standard of care (SOC) treatment, that is, gemcitabine. CONCLUSIONS: In summary, [pIC]PEI treatment is non-toxic toward normal pancreatic cells while displaying strong cytotoxic and potent immune activating activities in PDAC, making it an attractive therapeutic when used alone or in conjunction with SOC therapeutic agents, potentially providing a safe and effective treatment protocol with translational potential for the effective therapy of PDAC.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animales , Humanos , Ratones , Carcinoma Ductal Pancreático/genética , Quimiocina CCL2/metabolismo , Quimiocina CCL2/uso terapéutico , Citoplasma/metabolismo , Citoplasma/patología , Ratones Transgénicos , Neoplasias Pancreáticas/metabolismo , Poli C/uso terapéutico , Factor de Transcripción STAT1/metabolismo , Microambiente Tumoral
3.
Proc Natl Acad Sci U S A ; 120(45): e2307094120, 2023 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-37922327

RESUMEN

Bone metastasis is a frequent and incurable consequence of advanced prostate cancer (PC). An interplay between disseminated tumor cells and heterogeneous bone resident cells in the metastatic niche initiates this process. Melanoma differentiation associated gene-9 (mda-9/Syntenin/syndecan binding protein) is a prometastatic gene expressed in multiple organs, including bone marrow-derived mesenchymal stromal cells (BM-MSCs), under both physiological and pathological conditions. We demonstrate that PDGF-AA secreted by tumor cells induces CXCL5 expression in BM-MSCs by suppressing MDA-9-dependent YAP/MST signaling. CXCL5-derived tumor cell proliferation and immune suppression are consequences of the MDA-9/CXCL5 signaling axis, promoting PC disease progression. mda-9 knockout tumor cells express less PDGF-AA and do not develop bone metastases. Our data document a previously undefined role of MDA-9/Syntenin in the tumor and microenvironment in regulating PC bone metastasis. This study provides a framework for translational strategies to ameliorate health complications and morbidity associated with advanced PC.


Asunto(s)
Neoplasias Óseas , Melanoma , Neoplasias de la Próstata , Masculino , Humanos , Sinteninas/genética , Sinteninas/metabolismo , Melanoma/metabolismo , Neoplasias de la Próstata/genética , Transducción de Señal/genética , Neoplasias Óseas/genética , Línea Celular Tumoral , Microambiente Tumoral , Metástasis de la Neoplasia
4.
Mol Syst Biol ; 19(11): e11670, 2023 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-37815040

RESUMEN

Cells have evolved their communication methods to sense their microenvironments and send biological signals. In addition to communication using ligands and receptors, cells use diverse channels including gap junctions to communicate with their immediate neighbors. Current approaches, however, cannot effectively capture the influence of various microenvironments. Here, we propose a novel approach to investigate cell neighbor-dependent gene expression (CellNeighborEX) in spatial transcriptomics (ST) data. To categorize cells based on their microenvironment, CellNeighborEX uses direct cell location or the mixture of transcriptome from multiple cells depending on ST technologies. For each cell type, CellNeighborEX identifies diverse gene sets associated with partnering cell types, providing further insight. We found that cells express different genes depending on their neighboring cell types in various tissues including mouse embryos, brain, and liver cancer. Those genes are associated with critical biological processes such as development or metastases. We further validated that gene expression is induced by neighboring partners via spatial visualization. The neighbor-dependent gene expression suggests new potential genes involved in cell-cell interactions beyond what ligand-receptor co-expression can discover.


Asunto(s)
Neoplasias Hepáticas , Transcriptoma , Animales , Ratones , Transcriptoma/genética , Perfilación de la Expresión Génica , Encéfalo , Comunicación Celular , Microambiente Tumoral
5.
Mol Cancer Ther ; 22(10): 1115-1127, 2023 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-37721536

RESUMEN

Genome-wide gene expression analysis and animal modeling indicate that melanoma differentiation associated gene-9 (mda-9, Syntenin, Syndecan binding protein, referred to as MDA-9/Syntenin) positively regulates melanoma metastasis. The MDA-9/Syntenin protein contains two tandem PDZ domains serving as a nexus for interactions with multiple proteins that initiate transcription of metastasis-associated genes. Although targeting either PDZ domain abrogates signaling and prometastatic phenotypes, the integrity of both domains is critical for full biological function. Fragment-based drug discovery and NMR identified PDZ1i, an inhibitor of the PDZ1 domain that effectively blocks cancer invasion in vitro and in vivo in multiple experimental animal models. To maximize disruption of MDA-9/Syntenin signaling, an inhibitor has now been developed that simultaneously binds and blocks activity of both PDZ domains. PDZ1i was joined to the second PDZ binding peptide (TNYYFV) with a PEG linker, resulting in PDZ1i/2i (IVMT-Rx-3) that engages both PDZ domains of MDA-9/Syntenin. IVMT-Rx-3 blocks MDA-9/Syntenin interaction with Src, reduces NF-κB activation, and inhibits MMP-2/MMP-9 expression, culminating in repression of melanoma metastasis. The in vivo antimetastatic properties of IVMT-Rx-3 are enhanced when combined with an immune-checkpoint inhibitor. Collectively, our results support the feasibility of engineering MDA-9 dual-PDZ inhibitors with enhanced antimetastatic activities and applications of IVMT-Rx-3 for developing novel therapeutic strategies effectively targeting melanoma and in principle, a broad spectrum of human cancers that also overexpress MDA-9/Syntenin.


Asunto(s)
Melanoma , Animales , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/metabolismo , Sinteninas/química , Transducción de Señal , Péptidos/metabolismo
6.
Adv Cancer Res ; 159: 285-341, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37268399

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC), a prominent cause of cancer deaths worldwide, is a highly aggressive cancer most frequently detected at an advanced stage that limits treatment options to systemic chemotherapy, which has provided only marginal positive clinical outcomes. More than 90% of patients with PDAC die within a year of being diagnosed. PDAC is increasing at a rate of 0.5-1.0% per year, and it is expected to be the second leading cause of cancer-related mortality by 2030. The resistance of tumor cells to chemotherapeutic drugs, which can be innate or acquired, is the primary factor contributing to the ineffectiveness of cancer treatments. Although many PDAC patients initially responds to standard of care (SOC) drugs they soon develop resistance caused partly by the substantial cellular heterogeneity seen in PDAC tissue and the tumor microenvironment (TME), which are considered key factors contributing to resistance to therapy. A deeper understanding of molecular mechanisms involved in PDAC progression and metastasis development, and the interplay of the TME in all these processes is essential to better comprehend the etiology and pathobiology of chemoresistance observed in PDAC. Recent research has recognized new therapeutic targets ushering in the development of innovative combinatorial therapies as well as enhancing our comprehension of several different cell death pathways. These approaches facilitate the lowering of the therapeutic threshold; however, the possibility of subsequent resistance development still remains a key issue and concern. Discoveries, that can target PDAC resistance, either alone or in combination, have the potential to serve as the foundation for future treatments that are effective without posing undue health risks. In this chapter, we discuss potential causes of PDAC chemoresistance and approaches for combating chemoresistance by targeting different pathways and different cellular functions associated with and mediating resistance.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Gemcitabina , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Resistencia a Antineoplásicos , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Línea Celular Tumoral , Microambiente Tumoral , Neoplasias Pancreáticas
7.
Front Oncol ; 12: 812560, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35402258

RESUMEN

melanoma differentiation associated gene-7 or Interleukin-24 (mda-7, IL-24) displays expansive anti-tumor activity without harming corresponding normal cells/tissues. This anticancer activity has been documented in vitro and in vivo in multiple preclinical animal models, as well as in patients with advanced cancers in a phase I clinical trial. To enhance the therapeutic efficacy of MDA-7 (IL-24), we engineered a designer cytokine (a "Superkine"; IL-24S; referred to as M7S) with enhanced secretion and increased stability to engender improved "bystander" antitumor effects. M7S was engineered in a two-step process by first replacing the endogenous secretory motif with an alternate secretory motif to boost secretion. Among four different signaling peptides, the insulin secretory motif significantly enhanced the secretion of MDA-7 (IL-24) protein and was chosen for M7S. The second modification engineered in M7S was designed to enhance the stability of MDA-7 (IL-24), which was accomplished by replacing lysine at position K122 with arginine. This engineered "M7S Superkine" with increased secretion and stability retained cancer specificity. Compared to parental MDA-7 (IL-24), M7S (IL-24S) was superior in promoting anti-tumor and bystander effects leading to improved outcomes in multiple cancer xenograft models. Additionally, combinatorial therapy using MDA-7 (IL-24) or M7S (IL-24S) with an immune checkpoint inhibitor, anti-PD-L1, dramatically reduced tumor progression in murine B16 melanoma cells. These results portend that M7S (IL-24S) promotes the re-emergence of an immunosuppressive tumor microenvironment, providing a solid rationale for prospective translational applications of this therapeutic designer cytokine.

8.
Cancers (Basel) ; 14(6)2022 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-35326649

RESUMEN

Progression-elevated gene-3 (PEG-3) and rat growth arrest and DNA damage-inducible gene-34 (GADD34) display significant sequence homology with regulation predominantly transcriptional. The rat full-length (FL) and minimal (min) PEG-3 promoter display cancer-selective expression in rodent and human tumors, allowing for cancer-directed regulation of transgenes, viral replication and in vivo imaging of tumors and metastases in animals, whereas the FL- and min-GADD34-Prom lack cancer specificity. Min-PEG-Prom and min-GADD34-Prom have identical sequences except for two single-point mutation differences (at -260 bp and +159 bp). Engineering double mutations in the min-GADD34-Prom produce the GAPE-Prom. Changing one base pair (+159) or both point mutations in the min-GADD34-Prom, but not the FL-GADD34-Prom, results in cancer-selective transgene expression in diverse cancer cells (including prostate, breast, pancreatic and neuroblastoma) vs. normal counterparts. Additionally, we identified a GATA2 transcription factor binding site, promoting cancer specificity when both min-PEG-Prom mutations are present in the GAPE-Prom. Taken together, introducing specific point mutations in a rat min-GADD34-Prom converts this non-cancer-specific promoter into a cancer-selective promoter, and the addition of GATA2 with existing AP1 and PEA3 transcription factors enhances further cancer-selective activity of the GAPE-Prom. The GAPE-Prom provides a genetic tool to specifically regulate transgene expression in cancer cells.

9.
Proc Natl Acad Sci U S A ; 118(21)2021 05 25.
Artículo en Inglés | MEDLINE | ID: mdl-34016751

RESUMEN

Melanoma differentiation associated gene-9 (MDA-9), Syntenin-1, or syndecan binding protein is a differentially regulated prometastatic gene with elevated expression in advanced stages of melanoma. MDA-9/Syntenin expression positively associates with advanced disease stage in multiple histologically distinct cancers and negatively correlates with patient survival and response to chemotherapy. MDA-9/Syntenin is a highly conserved PDZ-domain scaffold protein, robustly expressed in a spectrum of diverse cancer cell lines and clinical samples. PDZ domains interact with a number of proteins, many of which are critical regulators of signaling cascades in cancer. Knockdown of MDA-9/Syntenin decreases cancer cell metastasis, sensitizing these cells to radiation. Genetic silencing of MDA-9/Syntenin or treatment with a pharmacological inhibitor of the PDZ1 domain, PDZ1i, also activates the immune system to kill cancer cells. Additionally, suppression of MDA-9/Syntenin deregulates myeloid-derived suppressor cell differentiation via the STAT3/interleukin (IL)-1ß pathway, which concomitantly promotes activation of cytotoxic T lymphocytes. Biologically, PDZ1i treatment decreases metastatic nodule formation in the lungs, resulting in significantly fewer invasive cancer cells. In summary, our observations indicate that MDA-9/Syntenin provides a direct therapeutic target for mitigating aggressive breast cancer and a small-molecule inhibitor, PDZ1i, provides a promising reagent for inhibiting advanced breast cancer pathogenesis.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Interleucina-1beta/genética , Neoplasias Pulmonares/tratamiento farmacológico , Oxadiazoles/farmacología , Pirimidinas/farmacología , Sinteninas/genética , Animales , Antineoplásicos/síntesis química , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Línea Celular Tumoral , Quimiocina CCL11/genética , Quimiocina CCL11/inmunología , Quimiocina CCL17/genética , Quimiocina CCL17/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Interleucina-10/genética , Interleucina-10/inmunología , Interleucina-1alfa/genética , Interleucina-1alfa/inmunología , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/inmunología , Subunidad p19 de la Interleucina-23/genética , Subunidad p19 de la Interleucina-23/inmunología , Interleucina-5/genética , Interleucina-5/inmunología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/secundario , Ratones , Ratones Endogámicos BALB C , Oxadiazoles/síntesis química , Pirimidinas/síntesis química , Transducción de Señal , Sinteninas/antagonistas & inhibidores , Sinteninas/inmunología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/patología , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
10.
J Cell Physiol ; 236(11): 7775-7791, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-33834508

RESUMEN

Neuroblastoma (NB) is a common solid extracranial tumor developing in pediatric populations. NB can spontaneously regress or grow and metastasize displaying resistance to therapy. This tumor is derived from primitive cells, mainly those of the neural crest, in the sympathetic nervous system and usually develops in the adrenal medulla and paraspinal ganglia. Our understanding of the molecular characteristics of human NBs continues to advance documenting abnormalities at the genome, epigenome, and transcriptome levels. The high-risk tumors have MYCN oncogene amplification, and the MYCN transcriptional regulator encoded by the MYCN oncogene is highly expressed in the neural crest. Studies on the biology of NB has enabled a more precise risk stratification strategy and a concomitant reduction in the required treatment in an expanding number of cases worldwide. However, newer treatment strategies are mandated to improve outcomes in pediatric patients who are at high-risk and display relapse. To improve outcomes and survival rates in such high-risk patients, it is necessary to use a multicomponent therapeutic approach. Accuracy in clinical staging of the disease and assessment of the associated risks based on biological, clinical, surgical, and pathological criteria are of paramount importance for prognosis and to effectively plan therapeutic approaches. This review discusses the staging of NB and the biological and genetic features of the disease and several current therapies including targeted delivery of chemotherapy, novel radiation therapy, and immunotherapy for NB.


Asunto(s)
Antineoplásicos/uso terapéutico , Inmunoterapia , Neuroblastoma/terapia , Animales , Antineoplásicos/efectos adversos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoterapia/efectos adversos , Terapia Molecular Dirigida , Estadificación de Neoplasias , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patología , Dosis de Radiación , Transducción de Señal
11.
Cancers (Basel) ; 13(4)2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33670594

RESUMEN

Combining cancer-selective viral replication and simultaneous production of a therapeutic cytokine, with potent "bystander" anti-tumor activity, are hallmarks of the cancer terminator virus (CTV). To expand on these attributes, we designed a next generation CTV that additionally enables simultaneous non-invasive imaging of tumors targeted for eradication. A unique tripartite CTV "theranostic" adenovirus (TCTV) has now been created that employs three distinct promoters to target virus replication, cytokine production and imaging capabilities uniquely in cancer cells. Conditional replication of the TCTV is regulated by a cancer-selective (truncated PEG-3) promoter, the therapeutic component, MDA-7/IL-24, is under a ubiquitous (CMV) promoter, and finally the imaging capabilities are synchronized through another cancer selective (truncated tCCN1) promoter. Using in vitro studies and clinically relevant in vivo models of breast and prostate cancer, we demonstrate that incorporating a reporter gene for imaging does not compromise the exceptional therapeutic efficacy of our previously reported bipartite CTV. This TCTV permits targeted treatment of tumors while monitoring tumor regression, with potential to simultaneously detect metastasis due to the cancer-selective activity of reporter gene expression. This "theranostic" virus provides a new genetic tool for distinguishing and treating localized and metastatic cancers.

12.
Int J Mol Sci ; 23(1)2021 Dec 22.
Artículo en Inglés | MEDLINE | ID: mdl-35008495

RESUMEN

Melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24), a secreted protein of the IL-10 family, was first identified more than two decades ago as a novel gene differentially expressed in terminally differentiating human metastatic melanoma cells. MDA-7/IL-24 functions as a potent tumor suppressor exerting a diverse array of functions including the inhibition of tumor growth, invasion, angiogenesis, and metastasis, and induction of potent "bystander" antitumor activity and synergy with conventional cancer therapeutics. MDA-7/IL-24 induces cancer-specific cell death through apoptosis or toxic autophagy, which was initially established in vitro and in preclinical animal models in vivo and later in a Phase I clinical trial in patients with advanced cancers. This review summarizes the history and our current understanding of the molecular/biological mechanisms of MDA-7/IL-24 action rendering it a potent cancer suppressor.


Asunto(s)
Interleucinas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Apoptosis/fisiología , Autofagia/fisiología , Muerte Celular/fisiología , Humanos , Melanoma/metabolismo
14.
Pharmacol Res ; 155: 104695, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32061839

RESUMEN

The primary cause of cancer-related death from solid tumors is metastasis. While unraveling the mechanisms of this complicated process continues, our ability to effectively target and treat it to decrease patient morbidity and mortality remains disappointing. Early detection of metastatic lesions and approaches to treat metastases (both pharmacological and genetic) are of prime importance to obstruct this process clinically. Metastasis is complex involving both genetic and epigenetic changes in the constantly evolving tumor cell. Moreover, many discrete steps have been identified in metastatic spread, including invasion, intravasation, angiogenesis, attachment at a distant site (secondary seeding), extravasation and micrometastasis and tumor dormancy development. Here, we provide an overview of the metastatic process and highlight a unique pro-metastatic gene, melanoma differentiation associated gene-9/Syntenin (MDA-9/Syntenin) also called syndecan binding protein (SDCBP), which is a major contributor to the majority of independent metastatic events. MDA-9 expression is elevated in a wide range of carcinomas and other cancers, including melanoma, glioblastoma multiforme and neuroblastoma, suggesting that it may provide an appropriate target to intervene in metastasis. Pre-clinical studies confirm that inhibiting MDA-9 either genetically or pharmacologically profoundly suppresses metastasis. An additional benefit to blocking MDA-9 in metastatic cells is sensitization of these cells to a second therapeutic agent, which converts anti-invasion effects to tumor cytocidal effects. Continued mechanistic and therapeutic insights hold promise to advance development of truly effective therapies for metastasis in the future.


Asunto(s)
Metástasis de la Neoplasia/genética , Neoplasias/terapia , Sinteninas/genética , Animales , Humanos , Neoplasias/genética , Neoplasias/patología
15.
Semin Cancer Biol ; 66: 140-154, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-31356866

RESUMEN

Apoptosis and autophagy play seminal roles in maintaining organ homeostasis. Apoptosis represents canonical type I programmed cell death. Autophagy is viewed as pro-survival, however, excessive autophagy can promote type II cell death. Defective regulation of these two obligatory cellular pathways is linked to various diseases, including cancer. Biologic or chemotherapeutic agents, which can reprogram cancer cells to undergo apoptosis- or toxic autophagy-mediated cell death, are considered effective tools for treating cancer. Melanoma differentiation associated gene-7 (mda-7) selectively promotes these effects in cancer cells. mda-7 was identified more than two decades ago by subtraction hybridization showing elevated expression during induction of terminal differentiation of metastatic melanoma cells following treatment with recombinant fibroblast interferon and mezerein (a PKC activating agent). MDA-7 was classified as a member of the IL-10 gene family based on its chromosomal location, and the presence of an IL-10 signature motif and a secretory sequence, and re-named interleukin-24 (MDA-7/IL-24). Multiple studies have established MDA-7/IL-24 as a potent anti-cancer agent, which when administered at supra-physiological levels induces growth arrest and cell death through apoptosis and toxic autophagy in a wide variety of tumor cell types, but not in corresponding normal/non-transformed cells. Furthermore, in a phase I/II clinical trial, MDA-7/IL-24 administered by means of a non-replicating adenovirus was well tolerated and displayed significant clinical activity in patients with multiple advanced cancers. This review examines our current comprehension of the role of MDA-7/IL-24 in mediating cancer-specific cell death via apoptosis and toxic autophagy.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/fisiología , Autofagia/fisiología , Interleucinas/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Muerte Celular/fisiología , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Humanos , Neoplasias/patología
16.
Oncotarget ; 10(49): 5103-5117, 2019 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-31489119

RESUMEN

Melanoma differentiation associated gene-7 (mda-7/IL-24) is a member of the IL-10 family of cytokines, with ubiquitous direct and "bystander" tumor-selective killing properties. MDA-7/IL-24 protein binds distinct type II cytokine heterodimeric receptor complexes, IL-20R1/IL-20R2, IL-22R1/IL-20R1 and IL-22R1/IL-20R2. Recombinant MDA-7/IL-24 protein induces endogenous mda-7/IL-24 expression in a receptor-dependent manner; since A549 cells that lack a complete set of cognate receptors are not responsive to exogenous protein. The mechanism of MDA-7/IL-24 ligand-receptor biology is not well understood. We explored the interaction of MDA-7/IL-24 with its' receptors and the consequences of ligand-receptor docking. Using both pharmacological and genetic approaches we demonstrate that MDA-7/IL-24 internalization employs the clathrin-mediated endocytic pathway leading to degradation of receptors via the lysosomal/ubiquitin proteosomal pathway. This clathrin-mediated endocytosis is dynamin-dependent. This study resolves a novel mechanism of MDA-7/IL-24 protein "bystander" function, which involves receptor/protein-mediated internalization and receptor degradation.

17.
Oncogene ; 38(41): 6781-6793, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31406249

RESUMEN

Despite multi-modality treatments, prognosis for advanced stage neuroblastoma (NB) remains challenging with residual long-term disabilities in survivors. Advanced stage NB is metastatic, which is a principal cause of cancer-related deaths. We presently document a primary role of MDA-9 in NB progression and define the molecular mechanisms by which MDA-9 promotes transformed phenotypes. NB cell lines and clinical samples display elevated MDA-9 expression and bioinformatic analysis supports an association between elevated MDA-9 and bone metastasis and poor prognosis. Genetic (shmda-9, mda-9 siRNA) or pharmacological (small molecule inhibitor of protein-protein interactions; PDZ1i) blockade of MDA-9 decreases NB migration, invasion, and metastasis. Blocking mda-9 expression or disrupting MDA-9 partner protein interactions downregulates integrin α6 and ß4, diminishing Src activity and suppressing Rho-Rac-Cdc42 activity. These signaling changes inhibit cofilin and matrix metalloproteinases reducing in vitro and in vivo NB cell migration. Overexpression of integrin α6 and ß4 rescues the invasion phenotype and increases Src activity, supporting integrins as essential regulators of MDA-9-mediated NB migration and invasion. We identify MDA-9 as a key contributor to NB pathogenesis and show that genetic or pharmacological inhibition suppresses NB pathogenesis by an integrin-mediated Src-disruption pathway.


Asunto(s)
Invasividad Neoplásica , Metástasis de la Neoplasia , Neuroblastoma/patología , Sinteninas/metabolismo , Línea Celular Tumoral , Humanos , Integrinas/metabolismo , Neuroblastoma/genética , Neuroblastoma/metabolismo
18.
Mol Cancer Ther ; 18(11): 1997-2007, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31345950

RESUMEN

Metastasis is the primary determinant of death in patients with diverse solid tumors and MDA-9/Syntenin (SDCBP), a pro-metastatic and pro-angiogenic gene, contributes to this process. Recently, we documented that by physically interacting with IGF-1R, MDA-9/Syntenin activates STAT3 and regulates prostate cancer pathogenesis. These observations firmly established MDA-9/Syntenin as a potential molecular target in prostate cancer. MDA-9/Syntenin contains two highly homologous PDZ domains predicted to interact with a plethora of proteins, many of which are central to the cancerous process. An MDA-9/Syntenin PDZ1 domain-targeted small molecule (PDZ1i) was previously developed using fragment-based drug discovery (FBDD) guided by NMR spectroscopy and was found to be well-tolerated in vivo, had significant half-life (t 1/2 = 9 hours) and displayed substantial anti-prostate cancer preclinical in vivo activity. PDZ1i blocked tumor cell invasion and migration in vitro, and metastasis in vivo Hence, we demonstrate that PDZ1i an MDA-9/Syntenin PDZ1 target-specific small-molecule inhibitor displays therapeutic potential for prostate and potentially other cancers expressing elevated levels of MDA-9/Syntenin.


Asunto(s)
Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Neoplasias de la Próstata/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Sinteninas/química , Animales , Sitios de Unión/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Humanos , Masculino , Ratones , Dominios Proteicos , Receptor IGF Tipo 1/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Sinteninas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
19.
J Pharm Bioallied Sci ; 11(Suppl 2): S321-S324, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-31198362

RESUMEN

BACKGROUND: Dental anxiety is one of the prime reasons for discouraging children to receive dental treatment. Measurement of the dental anxiety is very useful to know the prevalence level among 6- to 12-year-old children. Thus, the aim of the study was to determine the dental anxiety among 6- to 12-year-old children using Modified Dental Anxiety Scale (MDAS) score. MATERIALS AND METHODS: A total of 400 south Indian children in the age group of 6-12 years who had visited Dental College and Hospital were recruited in the study. Dental anxiety was measured before dental treatment using MDAS. Statistical analysis was performed using Wilcoxon signed rank test. RESULTS: Of the 400 children, 240 (61.5%) had severe dental anxiety, 92 (23%) had mild anxiety, and 78 (17%) had no anxiety. Females had higher anxiety level compared to males. Many study subjects answered that local anesthesia (LA) injection was considered most fearful. Dental anxiety was highest in smaller age groups. CONCLUSION: In our research, high percentage of children had dental anxiety, so counseling before dental visits is very important to reduce the dental anxiety among these 6- to 12-year-old children.

20.
Proc Natl Acad Sci U S A ; 116(12): 5687-5692, 2019 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-30842276

RESUMEN

Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a multifunctional cytokine displaying broad-spectrum anticancer activity in vitro or in vivo in preclinical animal cancer models and in a phase 1/2 clinical trial in patients with advanced cancers. mda-7/IL-24 targets specific miRNAs, including miR-221 and miR-320, for down-regulation in a cancer-selective manner. We demonstrate that mda-7/IL-24, administered through a replication incompetent type 5 adenovirus (Ad.mda-7) or with His-MDA-7/IL-24 protein, down-regulates DICER, a critical regulator in miRNA processing. This effect is specific for mature miR-221, as it does not affect Pri-miR-221 expression, and the DICER protein, as no changes occur in other miRNA processing cofactors, including DROSHA, PASHA, or Argonaute. DICER is unchanged by Ad.mda-7/IL-24 in normal immortal prostate cells, whereas Ad.mda-7 down-regulates DICER in multiple cancer cells including glioblastoma multiforme and prostate, breast, lung, and liver carcinoma cells. MDA-7/IL-24 protein down-regulates DICER expression through canonical IL-20/IL-22 receptors. Gain- and loss-of-function studies confirm that overexpression of DICER rescues deregulation of miRNAs by mda-7/IL-24, partially rescuing cancer cells from mda-7/IL-24-mediated cell death. Stable overexpression of DICER in cancer cells impedes Ad.mda-7 or His-MDA-7/IL-24 inhibition of cell growth, colony formation, PARP cleavage, and apoptosis. In addition, stable overexpression of DICER renders cancer cells more resistant to Ad.mda-7 inhibition of primary and secondary tumor growth. MDA-7/IL-24-mediated regulation of DICER is reactive oxygen species-dependent and mediated by melanogenesis-associated transcription factor. Our research uncovers a distinct role of mda-7/IL-24 in the regulation of miRNA biogenesis through alteration of the MITF-DICER pathway.


Asunto(s)
ARN Helicasas DEAD-box/metabolismo , Interleucinas/metabolismo , MicroARNs/metabolismo , Factor de Transcripción Asociado a Microftalmía/metabolismo , Ribonucleasa III/metabolismo , Animales , Apoptosis/fisiología , Diferenciación Celular/fisiología , Línea Celular Tumoral , Proliferación Celular/fisiología , ARN Helicasas DEAD-box/biosíntesis , ARN Helicasas DEAD-box/genética , Regulación hacia Abajo , Genes Supresores de Tumor , Humanos , Interleucinas/genética , Masculino , Ratones , Ratones Desnudos , MicroARNs/biosíntesis , Factor de Transcripción Asociado a Microftalmía/genética , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/parasitología , Especies Reactivas de Oxígeno/metabolismo , Ribonucleasa III/biosíntesis , Ribonucleasa III/genética , Transducción de Señal , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
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