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Journal of Experimental & Clinical... Apr 2017Osteosarcoma is the most frequent primary malignant bone tumor. Although survival has distinctly increased due to neoadjuvant chemotherapy in the past, patients with...
BACKGROUND
Osteosarcoma is the most frequent primary malignant bone tumor. Although survival has distinctly increased due to neoadjuvant chemotherapy in the past, patients with metastatic disease and poor response to chemotherapy still have an adverse prognosis. Hence, development of new therapeutic strategies is still of utmost importance.
METHODS
Anticancer activity of KP46 against osteosarcoma cell models was evaluated as single agent and in combination approaches with chemotherapeutics and Bcl-2 inhibitors using MTT assay. Underlying mechanisms were tested by cell cycle, apoptosis and autophagy assays.
RESULTS
KP46 exerted exceptional anticancer activity at the nanomolar to low micromolar range, depending on the assay format, against all osteosarcoma cell models with minor but significant differences in IC values. KP46 treatment of osteosarcoma cells caused rapid loss of cell adhesion, weak cell cycle accumulation in S-phase and later signs of apoptotic cell death. Furthermore, already at sub-cytotoxic concentrations KP46 reduced the migratory potential of osteosarcoma cells and exerted synergistic effects with cisplatin, a standard osteosarcoma chemotherapeutic. Moreover, the gallium compound induced signs of autophagy in osteosarcoma cells. Accordingly, blockade of autophagy by chloroquine but also by the Bcl-2 inhibitor obatoclax increased the cytotoxic activity of KP46 treatment significantly, suggesting autophagy induction as a protective mechanism against KP46.
CONCLUSION
Together, our results identify KP46 as a new promising agent to supplement standard chemotherapy and possible future targeted therapy in osteosarcoma.
Topics: Antineoplastic Combined Chemotherapy Protocols; Autophagy; Bone Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Movement; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Indoles; Molecular Targeted Therapy; Organometallic Compounds; Osteosarcoma; Oxyquinoline; Pyrroles
PubMed: 28403890
DOI: 10.1186/s13046-017-0527-z -
Theranostics 2017Although the prognosis of differentiated thyroid cancer (DTC) is relatively good, 30-40% of patients with distant metastases develop resistance to radioactive iodine...
Although the prognosis of differentiated thyroid cancer (DTC) is relatively good, 30-40% of patients with distant metastases develop resistance to radioactive iodine therapy due to tumor dedifferentiation. For DTC patients harboring BRAF mutation, Vemurafenib, a BRAF kinase inhibitor, has dramatically changed the therapeutic landscape, but side effects and drug resistance often lead to termination of the single agent treatment. In the present study, we showed that either LY3009120 or Obatoclax (GX15-070) efficiently inhibited cell cycle progression and induced massive death of DTC cells. We established that BRAF/CRAF dimerization was an underlying mechanism for Vemurafenib resistance. LY3009120, the newly discovered pan-RAF inhibitor, successfully overcame Vemurafenib resistance and suppressed the growth of DTC cells in vitro and in vivo. We also observed that expression of anti-apoptotic Bcl-2 increased substantially following BRAF inhibitor treatment in Vemurafenib-resistant K1 cells, and both Obatoclax and LY3009120 efficiently induced apoptosis of these resistant cells. Specifically, Obatoclax exerted its anti-cancer activity by inducing loss of mitochondrial membrane potential (ΔΨm), dysfunction of mitochondrial respiration, reduction of cellular glycolysis, autophagy, neutralization of lysosomes, and caspase-related apoptosis. Furthermore, the cancer killing effects of LY3009120 and Obatoclax extended to two more Vemurafenib-resistant DTC cell lines, KTC-1 and BCPAP. Taken together, our results highlighted the potential value of LY3009120 for both Vemurafenib-sensitive and -resistant DTC and provided evidence for the combination therapy using Vemurafenib and Obatoclax for radioiodine-refractory DTC.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Models, Animal; Drug Resistance; Enzyme Inhibitors; Heterografts; Humans; Indoles; Mice, Nude; Phenylurea Compounds; Protein Multimerization; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-raf; Pyrimidines; Pyrroles; Sulfonamides; Thyroid Neoplasms; Treatment Outcome; Vemurafenib
PubMed: 28382170
DOI: 10.7150/thno.17322 -
Tumour Biology : the Journal of the... Mar 2017Multiple factors including tumor heterogeneity and intrinsic or acquired resistance have been associated with drug resistance in lung cancer. Increased stemness and the...
Multiple factors including tumor heterogeneity and intrinsic or acquired resistance have been associated with drug resistance in lung cancer. Increased stemness and the plasticity of cancer cells have been identified as important mechanisms of resistance; therefore, treatments targeting cancer cells independent of stemness phenotype would be much more effective in treating lung cancer. In this article, we have characterized the anticancer effects of the antibiotic Nigericin in cells displaying varying degrees of stemness and resistance to anticancer drugs, arising from (1) routine culture conditions, (2) prolonged periods of serum starvation. These cells are highly resistant to conventional anticancer drugs such as Paclitaxel, Hydroxyurea, Colchicine, Obatoclax, Wortmannin, and LY294002, and the multidrug-resistant phenotype of cells growing under prolonged periods of serum starvation is likely the result of extensive rewiring of signaling pathways, and (3) lung tumorspheres that are enriched for cancer stem-like cells. We found that Nigericin potently inhibited the viability of cells growing under routine culture conditions, prolonged periods of serum starvation, and lung tumorspheres. In addition, we found that Nigericin downregulated the expression of key proteins in the Wnt canonical signaling pathway such as LRP6, Wnt5a/b, and β-catenin, but promotes β-catenin translocation into the nucleus. The antitumor effects of Nigericin were potentiated by the Wnt activator HLY78 and by therapeutic levels of the US Food and Drug Administration-approved drug Digitoxin and its novel synthetic analog MonoD. We believe that Nigericin may be used in a co-therapy model in combination with other novel chemotherapeutic agents in order to achieve potent inhibition of cancers that display varying degrees of stemness, potentially leading to sustained anticancer effects.
Topics: Antineoplastic Agents; Benzodioxoles; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Neoplastic Stem Cells; Nigericin; Phenanthridines; Wnt Signaling Pathway
PubMed: 28351327
DOI: 10.1177/1010428317694310 -
Biochemical Pharmacology Jul 2017BH3 mimetics are a novel class of anticancer agents designed to specifically target pro-survival proteins of the Bcl-2 family. Like endogenous BH3-only proteins, BH3... (Review)
Review
BH3 mimetics are a novel class of anticancer agents designed to specifically target pro-survival proteins of the Bcl-2 family. Like endogenous BH3-only proteins, BH3 mimetics competitively bind to surface hydrophobic grooves of pro-survival Bcl-2 family members, counteracting their protective effects and thus facilitating apoptosis in cancer cells. Among the small-molecule BH3 mimetics identified, ABT-737 and its analogs, obatoclax as well as gossypol derivatives are the best characterized. The anticancer potential of these compounds applied as a single agent or in combination with chemotherapeutic drugs is currently being evaluated in preclinical studies and in clinical trials. In spite of promising results, the actual mechanisms of their anticancer action remain to be identified. Findings from preclinical studies point to additional activities of BH3 mimetics in cancer cells that are not connected with apoptosis induction. These off-target effects involve induction of autophagy and necrotic cell death as well as modulation of the cell cycle and multiple cell signaling pathways. For the optimization and clinical implementation of BH3 mimetics, a detailed understanding of their role as inhibitors of the pro-survival Bcl-2 proteins, but also of their possible additional effects is required. This review summarizes the most representative BH3 mimetic compounds with emphasis on their off-target effects. Based on the present knowledge on the multifaceted effects of BH3 mimetics on cancer cells, the commentary outlines the potential pitfalls and highlights the considerable promise for cancer treatment with BH3 mimetics.
Topics: Animals; Antineoplastic Agents; BH3 Interacting Domain Death Agonist Protein; Biomimetic Materials; Forecasting; Humans; Neoplasms
PubMed: 28288819
DOI: 10.1016/j.bcp.2017.03.006 -
Nature Communications Jan 2017Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response to chemotherapy and dismal survival. Identification of effective strategies to target PTCL...
Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response to chemotherapy and dismal survival. Identification of effective strategies to target PTCL biology represents an urgent need. Here we report that PTCL are sensitive to transcription-targeting drugs, and, in particular, to THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7). The STAT-signalling pathway is highly vulnerable to THZ1 even in PTCL cells that carry the activating STAT3 mutation Y640F. In mutant cells, CDK7 inhibition decreases STAT3 chromatin binding and expression of highly transcribed target genes like MYC, PIM1, MCL1, CD30, IL2RA, CDC25A and IL4R. In surviving cells, THZ1 decreases the expression of STAT-regulated anti-apoptotic BH3 family members MCL1 and BCL-XL sensitizing PTCL cells to BH3 mimetic drugs. Accordingly, the combination of THZ1 and the BH3 mimetic obatoclax improves lymphoma growth control in a primary PTCL ex vivo culture and in two STAT3-mutant PTCL xenografts, delineating a potential targeted agent-based therapeutic option for these patients.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Survival; Chromatin; Cyclin-Dependent Kinases; Female; Gain of Function Mutation; Gene Expression Regulation, Neoplastic; Humans; Indoles; Lymphoma, T-Cell; Male; Mice; Mice, Inbred NOD; Mice, SCID; Phenylenediamines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Pyrroles; STAT3 Transcription Factor; Signal Transduction; Transcription, Genetic; Treatment Outcome; Xenograft Model Antitumor Assays; Cyclin-Dependent Kinase-Activating Kinase
PubMed: 28134252
DOI: 10.1038/ncomms14290 -
Current Hematologic Malignancy Reports Feb 2017The BCL-2 family of proteins integrates pro- and anti-apoptotic signals within the cell and is responsible for initiation of caspase-dependent apoptosis. Chronic... (Review)
Review
The BCL-2 family of proteins integrates pro- and anti-apoptotic signals within the cell and is responsible for initiation of caspase-dependent apoptosis. Chronic lymphocytic leukemia (CLL) cells are particularly dependent on the anti-apoptotic protein BCL-2 for their survival, making this an attractive therapeutic target in CLL. Several early efforts to create inhibitors of the anti-apoptotic family members faced significant challenges, but eventually, the BCL-2 specific inhibitor venetoclax moved forward in CLL. Overall and complete response rates to venetoclax monotherapy in relapsed, refractory CLL are approximately 80 and 20%, respectively, even in patients with high-risk 17p deletion. Toxicities have been manageable and include neutropenia, diarrhea, and nausea. The risk of tumor lysis syndrome (TLS), seen in early experience with the drug, has been mitigated by the use of appropriate TLS risk assessment, prophylaxis, and management. Future studies of venetoclax will focus on combination approaches, predictive biomarker discovery, and mechanisms of resistance.
Topics: Aniline Compounds; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Gossypol; Humans; Indoles; Leukemia, Lymphocytic, Chronic, B-Cell; Neutropenia; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides; Thionucleotides
PubMed: 28116634
DOI: 10.1007/s11899-017-0359-0 -
The Annals of Pharmacotherapy May 2017To review the pharmacology, efficacy, and safety of venetoclax for treatment of lymphoid malignancies. (Review)
Review
OBJECTIVE
To review the pharmacology, efficacy, and safety of venetoclax for treatment of lymphoid malignancies.
DATA SOURCES
A literature search was performed of PubMed and MEDLINE databases (2005 to September 2016), abstracts from the American Society of Hematology and the American Society of Clinical Oncology, and ongoing studies from clinicaltrials.gov. Searches were performed utilizing the following key terms: venetoclax, ABT-199, GDC-199, obatoclax, GX15-070, BCL-2 inhibitor, navitoclax, ABT-263, and Venclexta.
STUDY SELECTION/DATA EXTRACTION
Studies of pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of venetoclax in lymphoid malignancies were identified.
DATA SYNTHESIS
Recently, treatment of B-cell lymphoproliferative disorders has shifted from conventional cytotoxic chemotherapy to novel small-molecule inhibitors. The advent of recently Food and Drug Administration-approved oral agents ibrutinib and idelalisib has shifted the paradigm of chronic lymphocytic leukemia (CLL) treatment; however, complete remission is uncommon, and the outcome for patients progressing on these treatments remains poor. Attention has been focused on a novel target, the B-cell lymphoma-2 protein (BCL-2), which serves an essential role in regulation of apoptosis. Venetoclax has demonstrated efficacy in multiple subtypes of lymphoid malignancies, including patients with relapsed/refractory CLL harboring deletion 17p, with an overall response rate of nearly 80%. Venetoclax is generally well tolerated, with the significant adverse effect being tumor lysis syndrome, for which there are formal management recommendations.
CONCLUSION
Venetoclax has demonstrated promising results in relapsed/refractory lymphoid malignancies, with an acceptable adverse effect profile. As the role of BCL-2 inhibition in various malignancies becomes further elucidated, venetoclax may offer benefit to a myriad other patient populations.
Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Remission Induction; Sulfonamides; Treatment Outcome; Tumor Burden; Tumor Lysis Syndrome
PubMed: 28056525
DOI: 10.1177/1060028016685803 -
Oncotarget Jan 2017Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, Schwann cell-derived neoplasms of the peripheral nervous system that have recently been shown to...
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, Schwann cell-derived neoplasms of the peripheral nervous system that have recently been shown to possess an autocrine CXCL12/CXCR4 signaling loop that promotes tumor cell proliferation and survival. Importantly, the CXCL12/CXCR4 signaling axis is driven by availability of the CXCL12 ligand rather than CXCR4 receptor levels alone. Therefore, pharmacological reduction of CXCL12 expression could be a potential chemotherapeutic target for patients with MPNSTs or other pathologies wherein the CXCL12/CXCR4 signaling axis is active. AT101 is a well-established BCL-2 homology domain 3 (BH3) mimetic that we recently demonstrated functions as an iron chelator and thus acts as a hypoxia mimetic. In this study, we found that AT101 significantly reduces CXCL12 mRNA and secreted protein in established human MPNST cell lines in vitro. This effect was recapitulated by other BH3 mimetics [ABT-737 (ABT), obatoclax (OBX) and sabutoclax (SBX)] but not by desferrioxamine (DFO), an iron chelator and known hypoxia mimetic. These data suggest that CXCL12 reduction is a function of AT101's BH3 mimetic property rather than its iron chelation ability. Additionally, this study investigates a potential mechanism of BH3 mimetic-mediated CXCL12 suppression: liberation of a negative CXCL12 transcriptional regulator, poly (ADP-Ribose) polymerase I (PARP1) from its physical interaction with BCL-2. These data suggest that clinically available BH3 mimetics might prove therapeutically useful at least in part by virtue of their ability to suppress CXCL12 expression.
Topics: Antineoplastic Agents; Biphenyl Compounds; Cell Line, Tumor; Chemokine CXCL12; Down-Regulation; Gene Expression Regulation, Neoplastic; Gossypol; Humans; Indoles; Molecular Mimicry; Neurilemmoma; Nitrophenols; Piperazines; Poly (ADP-Ribose) Polymerase-1; Protein Binding; Protein Interaction Domains and Motifs; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides
PubMed: 28055968
DOI: 10.18632/oncotarget.14398 -
Antiviral Research Mar 2017An epidemic of Zika virus (ZIKV) infection associated with congenital abnormalities such as microcephaly, is ongoing in the Americas and the Pacific. Currently there are...
An epidemic of Zika virus (ZIKV) infection associated with congenital abnormalities such as microcephaly, is ongoing in the Americas and the Pacific. Currently there are no approved therapies to treat this emerging viral disease. Here, we tested three cell-directed broad-spectrum antiviral compounds against ZIKV replication using human retinal pigment epithelial (RPE) cells and a low-passage ZIKV strain isolated from fetal brain. We found that obatoclax, SaliPhe, and gemcitabine inhibited ZIKV infections at noncytotoxic concentrations. Moreover, all three compounds prevented production of viral RNA and proteins as well as activation of cellular caspase 8, 3 and 7. However, these compounds differentially affected ZIKV-mediated transcription, translation and posttranslational modifications of cellular factors as well as metabolic pathways indicating that these agents possess different mechanisms of action. Interestingly, combination of obatoclax and SaliPhe at nanomolar concentrations had a synergistic effect against ZIKV infection. Thus, our results provided the foundation for development of broad-spectrum cell-directed antivirals or their combinations for treatment of ZIKV and other emerging viral diseases.
Topics: Amides; Antiviral Agents; Brain; Caspases; Deoxycytidine; Drug Combinations; Enzyme Inhibitors; Fetus; Humans; Indoles; Metabolic Networks and Pathways; Pyrroles; RNA, Viral; Retinal Pigment Epithelium; Salicylates; Signal Transduction; Virus Replication; Zika Virus; Gemcitabine
PubMed: 28049006
DOI: 10.1016/j.antiviral.2016.12.022 -
International Journal of Molecular... Dec 2016Colorectal cancer is the third most common cancer worldwide. Aberrant overexpression of antiapoptotic BCL-2 (B-cell lymphoma 2) family proteins is closely linked to...
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.
Topics: Carcinoma; Cell Proliferation; Colorectal Neoplasms; Cyclin D1; Down-Regulation; G1 Phase Cell Cycle Checkpoints; HCT116 Cells; HT29 Cells; Humans; Indoles; Proteolysis; Proto-Oncogene Proteins c-bcl-2; Pyrroles
PubMed: 28035994
DOI: 10.3390/ijms18010044