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Special Issue "Tumor Targeting Therapy and Selective Killing"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2017).

Special Issue Editor

Prof. Dr. Hsueh-Wei Chang
E-Mail Website
Guest Editor
Department of Biomedical Science and Environmental Biology, PhD program of Life Science, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
Interests: natural product screening for anticancer; oxidative stress, antioxidant, DNA damage, apoptosis, selective killing, flow cytometry
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Special Issue Information

Dear Colleagues,

Tumor targeting therapies are drugs or other molecules that suppress cancer proliferation or metastasis by interacting with tumor-specific targets. To date, many tumor targeting therapies have been used in clinical cancer treatments, such as apoptosis inducers, hormone therapy, angiogenesis inhibitors, small molecule treatment, and antibody therapy. For example, cancer cells may have a tendency to escape apoptosis due to drug resistance; yet apoptosis inducers may improve the therapeutic effect of drugs by decreasing drug resistance. 

Tumor targeting therapies are expected to specifically target tumor cells and interact less with normal cells than most standard chemotherapy drugs. However, tumor targeting therapies are extremely intricate and not always effective when the target is absent from the tumor. Moreover, serious side effects or treatment resistances to tumor targeting therapies may randomly appear in certain patients. Therefore, current tumor targeting therapies still have some limitations.

Recently, the combinational treatments of different tumor targeting therapies or a tumor targeting therapy combined with one or more standard chemotherapy drug have caught our attention. Accordingly, more chosen targets may be helpful to improve therapeutic effects. Moreover, natural products, or novel small molecules with selective killing inhibition of tumor cells which are less toxic to normal cells, may be effective in tumor therapy when combining tumor targeting therapies. Some natural products potentially reduce the possible side effects of tumor targeting therapies.

This Special Issue on “Tumor Targeting Therapy and Selective Killing” will explore the impact of anticancer effects and its mechanisms of action as well as drug discoveries and novel combinational treatments.

We look forward to receiving reviews and original papers depicting all aspects of tumor targeting therapies and selective killing, such as, but not limited to: tumor targeting treatment, tumor targeting modulators, selective killing agents, selective killing modulators, apoptosis inducers, drug discovery, and natural products, are welcome. We also aim to publish recent progress regarding molecular and pharmacologic aspects of this topic.

Prof. Hsueh-Wei Chang
Guest Editor

Manuscript Submission Information

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Keywords

  • tumor targeting treatment
  • tumor targeting modulators
  • selective killing agents
  • selective killing modulators
  • apoptosis inducers
  • drug discovery
  • natural products
  • combinational treatment

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Published Papers (18 papers)

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Research

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Open AccessArticle
Tumor Inhibitory Effect of IRCR201, a Novel Cross-Reactive c-Met Antibody Targeting the PSI Domain
Int. J. Mol. Sci. 2017, 18(9), 1968; https://doi.org/10.3390/ijms18091968 - 13 Sep 2017
Cited by 7 | Viewed by 2358
Abstract
Hepatocyte growth factor receptor (HGFR, c-Met) is an essential member of the receptor tyrosine kinase (RTK) family that is often dysregulated during tumor progression, driving a malignant phenotypic state and modulating important cellular functions including tumor growth, invasion, metastasis, and angiogenesis, providing a [...] Read more.
Hepatocyte growth factor receptor (HGFR, c-Met) is an essential member of the receptor tyrosine kinase (RTK) family that is often dysregulated during tumor progression, driving a malignant phenotypic state and modulating important cellular functions including tumor growth, invasion, metastasis, and angiogenesis, providing a strong rationale for targeting HGF/c-Met signaling axis in cancer therapy. Based on its protumorigenic potentials, we developed IRCR201, a potent antagonistic antibody targeting the plexin-semaphorin-integrin (PSI) domain of c-Met, using synthetic human antibody phage libraries. We characterized and evaluated the biochemical properties and tumor inhibitory effect of IRCR201 in vitro and in vivo. IRCR201 is a novel fully-human bivalent therapeutic antibody that exhibits cross-reactivity against both human and mouse c-Met proteins with high affinity and specificity. IRCR201 displayed low agonist activity and rapidly depleted total c-Met protein via the lysosomal degradation pathway, inhibiting c-Met-dependent downstream activation and attenuating cellular proliferation in various c-Met-expressing cancer cells. In vivo tumor xenograft models also demonstrated the superior tumor inhibitory responsiveness of IRCR201. Taken together, IRCR201 provides a promising therapeutic agent for c-Met-positive cancer patients through suppressing the c-Met signaling pathway and tumor growth. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Open AccessArticle
Design and In Vitro Evaluation of a Cytotoxic Conjugate Based on the Anti-HER2 Affibody Fused to the Fc Fragment of IgG1
Int. J. Mol. Sci. 2017, 18(8), 1688; https://doi.org/10.3390/ijms18081688 - 03 Aug 2017
Cited by 10 | Viewed by 2271
Abstract
In our previous work we demonstrated that a small protein called affibody can be used for a cytotoxic conjugate development. The anti-HER2 affibody was armed with one moiety of a highly potent auristatin E and specifically killed HER2-positive cancer cells with a nanomolar [...] Read more.
In our previous work we demonstrated that a small protein called affibody can be used for a cytotoxic conjugate development. The anti-HER2 affibody was armed with one moiety of a highly potent auristatin E and specifically killed HER2-positive cancer cells with a nanomolar IC50. The aim of this study was to improve the anti-HER2 affibody conjugate by increasing its size and the number of conjugated auristatin molecules. The affibody was fused to the Fc fragment of IgG1 resulting in a dimeric construct with the molecular weight of 68 kDa, referred to as ZHER2:2891-Fc, ensuring its prolonged half-life in the blood. Due to the presence of four interchain cysteines, the fusion protein could carry four drug molecules. Notably, the in vitro tests of the improved anti-HER2 conjugate revealed that it exhibits the IC50 of 130 pM for the HER2-positive SK-BR-3 cells and 98 nM for the HER2-negative MDA-MB-231 cells. High efficacy and specificity of the auristatin conjugate based on ZHER2:2891-Fc indicate that this construct is suitable for further in vivo evaluation. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Open AccessArticle
BRD9 Inhibition, Alone or in Combination with Cytostatic Compounds as a Therapeutic Approach in Rhabdoid Tumors
Int. J. Mol. Sci. 2017, 18(7), 1537; https://doi.org/10.3390/ijms18071537 - 16 Jul 2017
Cited by 23 | Viewed by 3273
Abstract
Rhabdoid tumors (RT) are malignant neoplasms of early childhood. Despite intensive therapy, survival is poor and new treatment approaches are required. The only recurrent mutations in these tumors affect SMARCB1 and less commonly SMARCA4, both subunits of the chromatin remodeling complex SWItch/Sucrose [...] Read more.
Rhabdoid tumors (RT) are malignant neoplasms of early childhood. Despite intensive therapy, survival is poor and new treatment approaches are required. The only recurrent mutations in these tumors affect SMARCB1 and less commonly SMARCA4, both subunits of the chromatin remodeling complex SWItch/Sucrose Non-Fermentable (SWI/SNF). Loss of these two core subunits alters the function of the SWI/SNF complex, resulting in tumor development. We hypothesized that inhibition of aberrant SWI/SNF function by selective blockade of the BRD9 subunit of the SWI/SNF complex would reduce tumor cell proliferation. The cytotoxic and anti-proliferative effects of two specific chemical probes (I-BRD9 and BI-9564) which target the bromodomain of SWI/SNF protein BRD9 were evaluated in 5 RT cell lines. Combinatorial effects of I-BRD9 and cytotoxic drugs on cell proliferation were evaluated by cytotoxicity assays. Single compound treatment of RT cells with I-BRD9 and BI-9564 resulted in decreased cell proliferation, G1-arrest and apoptosis. Combined treatment of doxorubicin or carboplatin with I-BRD9 resulted in additive to synergistic inhibitory effects on cell proliferation. In contrast, the combination of I-BRD9 with vincristine demonstrated the antagonistic effects of these two compounds. We conclude that the BRD9 bromodomain is an attractive target for novel therapies in this cancer. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Open AccessArticle
Analysis of Hypericin-Mediated Effects and Implications for Targeted Photodynamic Therapy
Int. J. Mol. Sci. 2017, 18(7), 1388; https://doi.org/10.3390/ijms18071388 - 29 Jun 2017
Cited by 11 | Viewed by 2560
Abstract
The phototoxic effect of hypericin can be utilized for Photodynamic Therapy (PDT) of cancer. After intravenous application and systemic distribution of the drug in the patient’s body, the tumor site is exposed to light. Subsequently, toxic reactive oxygen species (ROS) are generated, inducing [...] Read more.
The phototoxic effect of hypericin can be utilized for Photodynamic Therapy (PDT) of cancer. After intravenous application and systemic distribution of the drug in the patient’s body, the tumor site is exposed to light. Subsequently, toxic reactive oxygen species (ROS) are generated, inducing tumor cell death. To prevent unwanted activation of the drug in other regions of the body, patients have to avoid light during and after the treatment cycles, consequently impairing quality of life. Here, we characterize toxicity and hypericin-mediated effects on cancer cells in vitro and confirm that its effect clearly depends on concentration and illumination time. To reduce side effects and to increase therapy success, selective accumulation of hypericin in the tumor region is a promising solution. Loading hypericin on superparamagnetic iron oxide nanoparticles (SPIONs) and guiding them to the desired place using an external magnetic field might accomplish this task (referred to as Magnetic Drug Targeting (MDT)). Thus, using a double targeting strategy, namely magnetic accumulation and laser induced photoactivation, might improve treatment effectivity as well as specificity and reduce toxic side effects in future clinical applications. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Open AccessArticle
Montelukast Induces Apoptosis-Inducing Factor-Mediated Cell Death of Lung Cancer Cells
Int. J. Mol. Sci. 2017, 18(7), 1353; https://doi.org/10.3390/ijms18071353 - 24 Jun 2017
Cited by 13 | Viewed by 3407
Abstract
Developing novel chemo-prevention techniques and advancing treatment are key elements to beating lung cancer, the most common cause of cancer mortality worldwide. Our previous cohort study showed that cysteinyl leukotriene receptor antagonists, mainly montelukast, decreased the lung cancer risk in asthma patients. In [...] Read more.
Developing novel chemo-prevention techniques and advancing treatment are key elements to beating lung cancer, the most common cause of cancer mortality worldwide. Our previous cohort study showed that cysteinyl leukotriene receptor antagonists, mainly montelukast, decreased the lung cancer risk in asthma patients. In the current study, we conducted in vivo and in vitro experiments to demonstrate the inhibiting effect of montelukast on lung cancer and to investigate the underlying mechanisms. Using Lewis lung carcinoma-bearing mice, we showed that feeding montelukast significantly delayed the tumor growth in mice (p < 0.0001). Montelukast inhibited cell proliferation and colony formation and induced the cell death of lung cancer cells. Further investigation showed the down-regulation of B-cell lymphoma 2 (Bcl-2), up-regulation of Bcl-2 homologous antagonist/killer (Bak), and nuclear translocation of apoptosis-inducing factor (AIF) in montelukast-treated lung cancer cells. Montelukast also markedly decreased the phosphorylation of several proteins, such as with no lysine 1 (WNK1), protein kinase B (Akt), extracellular signal-regulated kinase 1/2 (Erk1/2), MAPK/Erk kinase (MEK), and proline-rich Akt substrate of 40-kDa (PRAS40), which might contribute to cell death. In conclusion, montelukast induced lung cancer cell death via the nuclear translocation of AIF. This study confirmed the chemo-preventive effect of montelukast shown in our previous cohort study. The utility of montelukast in cancer prevention and treatment thus deserves further studies. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Open AccessArticle
Novel Structurally Related Flavones Augment Cell Death Induced by rhsTRAIL
Int. J. Mol. Sci. 2017, 18(6), 1211; https://doi.org/10.3390/ijms18061211 - 06 Jun 2017
Cited by 3 | Viewed by 1589
Abstract
TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) was identified as a powerful activator of apoptosis in tumor cells and one of the most promising candidates for cancer therapy with no toxicity against normal tissues. However, many tumor cells are resistant to TRAIL-induced apoptosis. The [...] Read more.
TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) was identified as a powerful activator of apoptosis in tumor cells and one of the most promising candidates for cancer therapy with no toxicity against normal tissues. However, many tumor cells are resistant to TRAIL-induced apoptosis. The aim of this work was to analyze the improvement of the anticancer effect of rhsTRAIL (recombinant human soluble TRAIL) by nine flavones: 5-Hydroxyflavone, 6-Hydroxyflavone, 7-Hydroxyflavone and their new synthetic derivatives 5-acetoxyflavone, 5-butyryloxyflavone, 6-acetoxyflavone, 6-butyryloxyflavone, 7-acetoxyflavone and 7-butyryloxyflavone. We examined the cytotoxic and apoptotic effects of rhsTRAIL enhanced by novel structurally-related flavones on SW480 and SW620 colon cancer cells using the3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test, the lactate dehydrogenase assay and annexin V-FITC fluorescence staining. We observed a slight difference in the activities of the flavones that was dependent on their chemical structure. Our study indicates that all nine flavones significantly augment cell death by rhsTRAIL (cytotoxicity range 36.8 ± 1.7%–91.4 ± 1.7%; apoptosis increase of 33.0 ± 0.7%–78.5 ± 0.9%). Our study demonstrates the potential use of tested flavones in TRAIL-based anticancer therapy and prevention. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Open AccessArticle
Nanosecond-Pulsed DBD Plasma-Generated Reactive Oxygen Species Trigger Immunogenic Cell Death in A549 Lung Carcinoma Cells through Intracellular Oxidative Stress
Int. J. Mol. Sci. 2017, 18(5), 966; https://doi.org/10.3390/ijms18050966 - 03 May 2017
Cited by 87 | Viewed by 3559
Abstract
A novel application for non-thermal plasma is the induction of immunogenic cancer cell death for cancer immunotherapy. Cells undergoing immunogenic death emit danger signals which facilitate anti-tumor immune responses. Although pathways leading to immunogenic cell death are not fully understood; oxidative stress is [...] Read more.
A novel application for non-thermal plasma is the induction of immunogenic cancer cell death for cancer immunotherapy. Cells undergoing immunogenic death emit danger signals which facilitate anti-tumor immune responses. Although pathways leading to immunogenic cell death are not fully understood; oxidative stress is considered to be part of the underlying mechanism. Here; we studied the interaction between dielectric barrier discharge plasma and cancer cells for oxidative stress-mediated immunogenic cell death. We assessed changes to the intracellular oxidative environment after plasma treatment and correlated it to emission of two danger signals: surface-exposed calreticulin and secreted adenosine triphosphate. Plasma-generated reactive oxygen and charged species were recognized as the major effectors of immunogenic cell death. Chemical attenuators of intracellular reactive oxygen species successfully abrogated oxidative stress following plasma treatment and modulated the emission of surface-exposed calreticulin. Secreted danger signals from cells undergoing immunogenic death enhanced the anti-tumor activity of macrophages. This study demonstrated that plasma triggers immunogenic cell death through oxidative stress pathways and highlights its potential development for cancer immunotherapy. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Open AccessArticle
Nobiletin Inhibits Angiogenesis by Regulating Src/FAK/STAT3-Mediated Signaling through PXN in ER+ Breast Cancer Cells
Int. J. Mol. Sci. 2017, 18(5), 935; https://doi.org/10.3390/ijms18050935 - 30 Apr 2017
Cited by 36 | Viewed by 2910
Abstract
Tumor angiogenesis is one of the major hallmarks of tumor progression. Nobiletin is a natural flavonoid isolated from citrus peel that has anti-angiogenic activity. Steroid receptor coactivator (Src) is an intracellular tyrosine kinase so that focal adhesion kinase (FAK) binds to Src to [...] Read more.
Tumor angiogenesis is one of the major hallmarks of tumor progression. Nobiletin is a natural flavonoid isolated from citrus peel that has anti-angiogenic activity. Steroid receptor coactivator (Src) is an intracellular tyrosine kinase so that focal adhesion kinase (FAK) binds to Src to play a role in tumor angiogenesis. Signal transducer and activator of transcription 3 (STAT3) is a marker for tumor angiogenesis which interacts with Src. Paxillin (PXN) acts as a downstream target for both FAK and STAT3. The main goal of this study was to assess inhibition of tumor angiogenesis by nobiletin in estrogen receptor positive (ER+) breast cancer cells via Src, FAK, and STAT3-mediated signaling through PXN. Treatment with nobiletin in MCF-7 and T47D breast cancer cells inhibited angiogenesis markers, based on western blotting and RT-PCR. Validation of in vitro angiogenesis in the human umbilical vein endothelial cells (HUVEC) endothelial cell line proved the anti-angiogenic activity of nobiletin. Electrophoretic mobility shift assay and the ChIP assay showed that nobiletin inhibits STAT3/DNA binding activity and STAT3 binding to a novel binding site of the PXN gene promoter. We also investigated the migration and invasive ability of nobiletin in ER+ cells. Nobiletin inhibited tumor angiogenesis by regulating Src, FAK, and STAT3 signaling through PXN in ER+ breast cancer cells. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Open AccessArticle
A Human Antibody That Binds to the Sixth Ig-Like Domain of VCAM-1 Blocks Lung Cancer Cell Migration In Vitro
Int. J. Mol. Sci. 2017, 18(3), 566; https://doi.org/10.3390/ijms18030566 - 06 Mar 2017
Cited by 7 | Viewed by 3023
Abstract
Vascular cell adhesion molecule-1 (VCAM-1) is closely associated with tumor progression and metastasis. However, the relevance and role of VCAM-1 in lung cancer have not been clearly elucidated. In this study, we found that VCAM-1 was highly overexpressed in lung cancer tissue compared [...] Read more.
Vascular cell adhesion molecule-1 (VCAM-1) is closely associated with tumor progression and metastasis. However, the relevance and role of VCAM-1 in lung cancer have not been clearly elucidated. In this study, we found that VCAM-1 was highly overexpressed in lung cancer tissue compared with that of normal lung tissue, and high VCAM-1 expression correlated with poor survival in lung cancer patients. VCAM-1 knockdown reduced migration of A549 human lung cancer cells into Matrigel, and competitive blocking experiments targeting the Ig-like domain 6 of VCAM-1 (VCAM-1-D6) demonstrated that the VCAM-1-D6 domain was critical for VCAM-1 mediated A549 cell migration into Matrigel. Next, we developed a human monoclonal antibody specific to human and mouse VCAM-1-D6 (VCAM-1-D6 huMab), which was isolated from a human synthetic antibody library using phage display technology. Finally, we showed that VCAM-1-D6 huMab had a nanomolar affinity for VCAM-1-D6 and that it potently suppressed the migration of A549 and NCI-H1299 lung cancer cell lines into Matrigel. Taken together, these results suggest that VCAM-1-D6 is a key domain for regulating VCAM-1-mediated lung cancer invasion and that our newly developed VCAM-1-D6 huMab will be a useful tool for inhibiting VCAM-1-expressing lung cancer cell invasion. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Open AccessArticle
Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells
Int. J. Mol. Sci. 2017, 18(3), 537; https://doi.org/10.3390/ijms18030537 - 02 Mar 2017
Cited by 5 | Viewed by 3087
Abstract
The gradual emerging of resistance to imatinib urgently calls for the development of new therapy for chronic myeloid leukemia (CML). The fusion protein Bcr-Abl, which promotes the malignant transformation of CML cells, is mainly located in the cytoplasm, while the c-Abl protein which [...] Read more.
The gradual emerging of resistance to imatinib urgently calls for the development of new therapy for chronic myeloid leukemia (CML). The fusion protein Bcr-Abl, which promotes the malignant transformation of CML cells, is mainly located in the cytoplasm, while the c-Abl protein which is expressed in the nucleus can induce apoptosis. Based on the hetero-dimerization of FKBP (the 12-kDa FK506- and rapamycin-binding protein) and FRB (the FKBP-rapamycin binding domain of the protein kinase, mTOR) mediated by AP21967, we constructed a nuclear transport system to induce cytoplasmic Bcr-Abl into nuclear. In this study, we reported the construction of the nuclear transport system, and we demonstrated that FN3R (three nuclear localization signals were fused to FRBT2098L with a FLAG tag), HF2S (two FKBP domains were in tandem and fused to the SH2 domain of Grb2 with an HA tag) and Bcr-Abl form a complexus upon AP21967. Bcr-Abl was imported into the nucleus successfully by the nuclear transport system. The nuclear transport system inhibited CML cell proliferation through mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 5 (STAT5) pathways mainly by HF2S. It was proven that nuclear located Bcr-Abl induced CML cell (including imatinib-resistant K562G01 cells) apoptosis by activation of p73 and its downstream molecules. In summary, our study provides a new targeted therapy for the CML patients even with Tyrosine Kinase Inhibitor (TKI)-resistance. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Open AccessArticle
n-Butylidenephthalide Regulated Tumor Stem Cell Genes EZH2/AXL and Reduced Its Migration and Invasion in Glioblastoma
Int. J. Mol. Sci. 2017, 18(2), 372; https://doi.org/10.3390/ijms18020372 - 10 Feb 2017
Cited by 11 | Viewed by 2494
Abstract
Glioblastoma (GBM) is one of the most common and aggressive types of brain tumor. Due to its highly recurrent rate and poor prognosis, the overall survival time with this type of tumor is only 20–21 months. Recent knowledge suggests that its recurrence is [...] Read more.
Glioblastoma (GBM) is one of the most common and aggressive types of brain tumor. Due to its highly recurrent rate and poor prognosis, the overall survival time with this type of tumor is only 20–21 months. Recent knowledge suggests that its recurrence is in part due to the presence of cancer stem cells (CSCs), which display radioresistant, chemoresistant, self-renewal and tumorigenic potential. Enhancers of Zeste 2 (EZH2) and AXL receptor tyrosine kinase (AXL) are both highly expressed in GBM. Additionally, they are an essential regulator involved in CSCs maintenance, migration, invasion, epithelial-to-mesenchymal transition (EMT), stemness, metastasis and patient survival. In this study, we used a small molecule, n-butylidenephthalide (BP), to assess the anti-GBM stem-like cells potential, and then tried to find out the associated genes involved with regulation in migration and invasion. We demonstrated that BP reduced the expression of AXL and stemness related genes in a dose-dependent manner. The migratory and invasive capabilities of GBM stem-like cells could be reduced by AXL/EZH2. Finally, in the overexpression of AXL, EZH2 and Sox2 by transfection in GBM stem-like cells, we found that AXL/EZH2/TGF-ꞵ1, but not Sox2, might be a key regulator in tumor invasion, migration and EMT. These results might help in the development of a new anticancer compound and can be a target for treating GBM. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Open AccessArticle
Obatoclax, a Pan-BCL-2 Inhibitor, Targets Cyclin D1 for Degradation to Induce Antiproliferation in Human Colorectal Carcinoma Cells
Int. J. Mol. Sci. 2017, 18(1), 44; https://doi.org/10.3390/ijms18010044 - 27 Dec 2016
Cited by 10 | Viewed by 2737
Abstract
Colorectal cancer is the third most common cancer worldwide. Aberrant overexpression of antiapoptotic BCL-2 (B-cell lymphoma 2) family proteins is closely linked to tumorigenesis and poor prognosis in colorectal cancer. Obatoclax is an inhibitor targeting all antiapoptotic BCL-2 proteins. A previous study has [...] Read more.
Colorectal cancer is the third most common cancer worldwide. Aberrant overexpression of antiapoptotic BCL-2 (B-cell lymphoma 2) family proteins is closely linked to tumorigenesis and poor prognosis in colorectal cancer. Obatoclax is an inhibitor targeting all antiapoptotic BCL-2 proteins. A previous study has described the antiproliferative action of obatoclax in one human colorectal cancer cell line without elucidating the underlying mechanisms. We herein reported that, in a panel of human colorectal cancer cell lines, obatoclax inhibits cell proliferation, suppresses clonogenicity, and induces G1-phase cell cycle arrest, along with cyclin D1 downregulation. Notably, ectopic cyclin D1 overexpression abrogated clonogenicity suppression but also G1-phase arrest elicited by obatoclax. Mechanistically, pre-treatment with the proteasome inhibitor MG-132 restored cyclin D1 levels in all obatoclax-treated cell lines. Cycloheximide chase analyses further revealed an evident reduction in the half-life of cyclin D1 protein by obatoclax, confirming that obatoclax downregulates cyclin D1 through induction of cyclin D1 proteasomal degradation. Lastly, threonine 286 phosphorylation of cyclin D1, which is essential for initiating cyclin D1 proteasomal degradation, was induced by obatoclax in one cell line but not others. Collectively, we reveal a novel anticancer mechanism of obatoclax by validating that obatoclax targets cyclin D1 for proteasomal degradation to downregulate cyclin D1 for inducing antiproliferation. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Open AccessArticle
Implication of the Receptor Tyrosine Kinase AXL in Head and Neck Cancer Progression
Int. J. Mol. Sci. 2017, 18(1), 7; https://doi.org/10.3390/ijms18010007 - 22 Dec 2016
Cited by 9 | Viewed by 3005
Abstract
Head and neck squamous cell carcinoma (HNSCC) remains a clinical challenge and identification of novel therapeutic targets is necessary. The receptor tyrosine kinase AXL has been implicated in several tumor entities and a selective AXL small molecule inhibitor (BGB324) is currently being tested [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) remains a clinical challenge and identification of novel therapeutic targets is necessary. The receptor tyrosine kinase AXL has been implicated in several tumor entities and a selective AXL small molecule inhibitor (BGB324) is currently being tested in clinical trials for patients suffering from non-small cell lung cancer or acute myeloid leukemia. Our study investigates AXL expression during HNSCC progression and its use as a potential therapeutic target in HNSCC. AXL protein expression was determined in a HNSCC cohort (n = 364) using immunohistochemical staining. For functional validation, AXL was either overexpressed or inhibited with BGB324 in HNSCC cell lines to assess proliferation, migration and invasion. We found AXL protein expression increasing during tumor progression with highest expression levels in recurrent tumors. In HNSCC cell lines in vitro, AXL overexpression increased migration as well as invasion. Both properties could be reduced through treatment with BGB324. In contrast, proliferation was neither affected by AXL overexpression nor by inhibition with BGB324. Our patient-derived data and in vitro results show that, in HNSCC, AXL is important for the progression to more advanced tumor stages. Moreover, they suggest that AXL could be a target for precision medicine approaches in this dismal tumor entity. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Review

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Open AccessReview
Overcoming Oncogenic Mediated Tumor Immunity in Prostate Cancer
Int. J. Mol. Sci. 2017, 18(7), 1542; https://doi.org/10.3390/ijms18071542 - 17 Jul 2017
Cited by 21 | Viewed by 4137
Abstract
Immunotherapy is being tested intensively in clinical trials for prostate cancer; it includes immune checkpoint inhibition, prostate specific antigen (PSA) vaccines and dendritic cell-based strategies. Despite increasing evidence for clinical responses, the consensus of multiple trials is that prostate cancers are poorly responsive [...] Read more.
Immunotherapy is being tested intensively in clinical trials for prostate cancer; it includes immune checkpoint inhibition, prostate specific antigen (PSA) vaccines and dendritic cell-based strategies. Despite increasing evidence for clinical responses, the consensus of multiple trials is that prostate cancers are poorly responsive to immunotherapy. Prostate cancer has a high degree of pathological and genetic heterogeneity compared to other cancer types, which may account for immunotherapeutic resistance. This hypothesis also implies that select types of prostate tumors may be differentially responsive to immune-based strategies and that the clinical stage, pathological grade and underlying genetic landscape may be important criteria in identifying tumors that respond to immune therapies. One strategy is to target oncogenic driver pathways in combination with immunotherapies with the goal of overcoming tumor immunity and broadening the number of patients achieving a clinical response. In this analysis, we address the hypothesis that driver oncogenic signaling pathways regulate cancer progression, tumor immunity and resistance to current immune therapeutics in prostate cancer. We propose that increased responsiveness may be achieved through the combined use of immunotherapies and inhibitors targeting tumor cell autonomous pathways that contribute towards anti-tumor immunity in patients with prostate cancer. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Open AccessReview
TRAIL, Wnt, Sonic Hedgehog, TGFβ, and miRNA Signalings Are Potential Targets for Oral Cancer Therapy
Int. J. Mol. Sci. 2017, 18(7), 1523; https://doi.org/10.3390/ijms18071523 - 14 Jul 2017
Cited by 16 | Viewed by 2265
Abstract
Clinical studies and cancer cell models emphasize the importance of targeting therapies for oral cancer. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is highly expressed in cancer, and is a selective killing ligand for oral cancer. Signaling proteins in the wingless-type mouse mammary [...] Read more.
Clinical studies and cancer cell models emphasize the importance of targeting therapies for oral cancer. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is highly expressed in cancer, and is a selective killing ligand for oral cancer. Signaling proteins in the wingless-type mouse mammary tumor virus (MMTV) integration site family (Wnt), Sonic hedgehog (SHH), and transforming growth factor β (TGFβ) pathways may regulate cell proliferation, migration, and apoptosis. Accordingly, the genes encoding these signaling proteins are potential targets for oral cancer therapy. In this review, we focus on recent advances in targeting therapies for oral cancer and discuss the gene targets within TRAIL, Wnt, SHH, and TGFβ signaling for oral cancer therapies. Oncogenic microRNAs (miRNAs) and tumor suppressor miRNAs targeting the genes encoding these signaling proteins are summarized, and the interactions between Wnt, SHH, TGFβ, and miRNAs are interpreted. With suitable combination treatments, synergistic effects are expected to improve targeting therapies for oral cancer. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Open AccessReview
Pharmacogenomics of Targeted Agents for Personalization of Colorectal Cancer Treatment
Int. J. Mol. Sci. 2017, 18(7), 1522; https://doi.org/10.3390/ijms18071522 - 14 Jul 2017
Cited by 14 | Viewed by 3253
Abstract
The use of targeted agents in the treatment of metastatic colorectal cancer (CRC) has improved patient outcomes. Anti-epidermal growth factor receptor (anti-EGFR) agents (cetuximab and panitumumab) and antiangiogenic molecules (bevacizumab, regorafeninb, ramucirumab, and aflibercept) have been successfully integrated into clinical practice. Other drugs [...] Read more.
The use of targeted agents in the treatment of metastatic colorectal cancer (CRC) has improved patient outcomes. Anti-epidermal growth factor receptor (anti-EGFR) agents (cetuximab and panitumumab) and antiangiogenic molecules (bevacizumab, regorafeninb, ramucirumab, and aflibercept) have been successfully integrated into clinical practice. Other drugs have been designed to target additional deregulated pathways in CRC, such as MAPK (mitogen-activated protein kinase)/PI3K-AKT (phosphatidylinositol-3-kinase-AKT serine/threonine kinase)/mTOR (mammalian target of rapamycin), HER-2 and 3 ( human epidermal growth factor receptor-2 and -3), and BRAF. A major issue with targeted treatment is early identification of patients with primary or secondary drug resistance. Pharmacogenomic research has demonstrated its value in this field, highlighting some tumor mutations that could discriminate responders from non-responders. The tumor genetic profile of the RAS/RAF pathway is needed before treatment with anti-EGFR agents; mutations in EGFR pathway genes have also been explored in relation to antiangiogenic molecules although further data are required prior to their integration into clinical practice. The introduction of immunotherapy has paved the way for a new generation of predictive markers, including genome-wide assessment of the tumor landscape. Furthermore, the development of next generation sequencing technology and non-invasive approaches to analyze circulating tumor DNA will make real-time monitoring of the tumor pharmacogenomic markers possible in the clinical routine, rendering precision medicine available to every patient. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Open AccessReview
Fine-Tuning Tumor Endothelial Cells to Selectively Kill Cancer
Int. J. Mol. Sci. 2017, 18(7), 1401; https://doi.org/10.3390/ijms18071401 - 30 Jun 2017
Cited by 13 | Viewed by 2960
Abstract
Tumor endothelial cells regulate several aspects of tumor biology, from delivering oxygen and nutrients to shaping the immune response against a tumor and providing a barrier against tumor cell dissemination. Accordingly, targeting tumor endothelial cells represents an important modality in cancer therapy. Whereas [...] Read more.
Tumor endothelial cells regulate several aspects of tumor biology, from delivering oxygen and nutrients to shaping the immune response against a tumor and providing a barrier against tumor cell dissemination. Accordingly, targeting tumor endothelial cells represents an important modality in cancer therapy. Whereas initial anti-angiogenic treatments focused mainly on blocking the formation of new blood vessels in cancer, emerging strategies are specifically influencing certain aspects of tumor endothelial cells. For instance, efforts are generated to normalize tumor blood vessels in order to improve tumor perfusion and ameliorate the outcome of chemo-, radio-, and immunotherapy. In addition, treatment options that enhance the properties of tumor blood vessels that support a host’s anti-tumor immune response are being explored. Hence, upcoming anti-angiogenic strategies will shape some specific aspects of the tumor blood vessels that are no longer limited to abrogating angiogenesis. In this review, we enumerate approaches that target tumor endothelial cells to provide anti-cancer benefits and discuss their therapeutic potential. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Open AccessCommentary
The between Now and Then of Lung Cancer Chemotherapy and Immunotherapy
Int. J. Mol. Sci. 2017, 18(7), 1374; https://doi.org/10.3390/ijms18071374 - 27 Jun 2017
Cited by 24 | Viewed by 2558
Abstract
Lung cancer is the most common cancer worldwide. Disappointingly, despite great effort in encouraging screening or, at least, a close surveillance of high-risk individuals, most of lung cancers are diagnosed when already surgically unresectable because of local advancement or metastasis. In these cases, [...] Read more.
Lung cancer is the most common cancer worldwide. Disappointingly, despite great effort in encouraging screening or, at least, a close surveillance of high-risk individuals, most of lung cancers are diagnosed when already surgically unresectable because of local advancement or metastasis. In these cases, the treatment of choice is chemotherapy, alone or in combination with radiotherapy. Here, we will briefly review the most successful and recent advances in the identification of novel lung cancer genetic lesions and in the development of new drugs specifically targeting them. However, lung cancer is still the leading cause of cancer-related mortality also because, despite impressive initial responses, the patients often develop resistance to novel target therapies after a few months of treatment. Thus, it is literally vital to continue the search for new therapeutic options. So, here, on the basis of our recent findings on the role of the tumor suppressor CCDC6 protein in lung tumorigenesis, we will also discuss novel therapeutic approaches we envision for lung cancer. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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