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Oncotarget Jan 2016The BCL6 oncogene plays a crucial role in sustaining diffuse large B-cell lymphomas (DLBCL) through transcriptional repression of key checkpoint genes. BCL6-targeted...
The BCL6 oncogene plays a crucial role in sustaining diffuse large B-cell lymphomas (DLBCL) through transcriptional repression of key checkpoint genes. BCL6-targeted therapy kills lymphoma cells by releasing these checkpoints. However BCL6 also directly represses several DLBCL oncogenes such as BCL2 and BCL-XL that promote lymphoma survival. Herein we show that DLBCL cells that survive BCL6-targeted therapy induce a phenomenon of "oncogene-addiction switching" by reactivating BCL2-family dependent anti-apoptotic pathways. Thus, most DLBCL cells require concomitant inhibition of BCL6 and BCL2-family members for effective lymphoma killing. Moreover, in DLBCL cells initially resistant to BH3 mimetic drugs, BCL6 inhibition induces a newly developed reliance on anti-apoptotic BCL2-family members for survival that translates in acquired susceptibility to BH3 mimetic drugs ABT-737 and obatoclax. In germinal center B cell-like (GCB)-DLBCL cells, the proteasome inhibitor bortezomib and the NEDD inhibitor MLN4924 post-transcriptionally activated the BH3-only sensitizer NOXA thus counteracting the oncogenic switch to BCL2 induced by BCL6-targeting. Hence our study indicates that BCL6 inhibition induces an on-target feedback mechanism based on the activation of anti-apoptotic BH3 members. This oncogene-addition switching mechanism was harnessed to develop rational combinatorial therapies for GCB-DLBCL.
Topics: Animals; Biphenyl Compounds; Blotting, Western; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Indoles; Lymphoma, Large B-Cell, Diffuse; Male; Mice; Mice, Nude; Nitrophenols; Peptide Fragments; Piperazines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-bcl-6; Pyrroles; RNA, Small Interfering; Rats; Rats, Sprague-Dawley; Sulfonamides; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 26657288
DOI: 10.18632/oncotarget.6513 -
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 -
Molecular Cancer Therapeutics Jun 2019
PubMed: 31160510
DOI: 10.1158/1535-7163.MCT-19-0470 -
Journal of Oncology 2021Hypoxia is a universal feature in the tumor microenvironment (TME). Nonetheless, the heterogeneous hypoxia patterns of TME have still not been elucidated in...
Hypoxia is a universal feature in the tumor microenvironment (TME). Nonetheless, the heterogeneous hypoxia patterns of TME have still not been elucidated in hepatocellular carcinoma (HCC). Using consensus clustering algorithm and public datasets, we identified heterogeneous hypoxia subtypes. We also revealed the specific biological and clinical characteristics via bioinformatic methods. The principal component analysis algorithm was employed to develop a hypoxia-associated risk score (HARS). We identified the two hypoxia subtypes: low hypoxia pattern (C1) and high hypoxia pattern (C2). C1 was less sensitive to immunotherapy compared to C2, consistent with the lack of immune cells and immune checkpoints (ICPs) in C1, whereas C2 was the opposite. C2 displayed worse prognosis and higher sensitivity to obatoclax relative to C1, while C1 was more sensitive to sorafenib. The two subtypes also demonstrated subtype-specific genomic variations including mutation, copy number alteration, and methylation. Moreover, we developed and validated a risk signature: HARS, which had excellent performance for predicting prognosis and immunotherapy. We revealed two hypoxia subtypes with distinct biological and clinical characteristics in HCC, which enhanced the understanding of hypoxia pattern. The risk signature was a promising biomarker for predicting prognosis and immunotherapy.
PubMed: 33552157
DOI: 10.1155/2021/6664386 -
Pharmaceuticals (Basel, Switzerland) Feb 2021Cancer is a multifactorial disease necessitating identification of novel targets for its treatment. Inhibition of Bcl-2 for triggered pro-apoptotic signaling is...
Design, Synthesis, Anticancer Activity, and Solid Lipid Nanoparticle Formulation of Indole- and Benzimidazole-Based Compounds as Pro-Apoptotic Agents Targeting Bcl-2 Protein.
Cancer is a multifactorial disease necessitating identification of novel targets for its treatment. Inhibition of Bcl-2 for triggered pro-apoptotic signaling is considered a promising strategy for cancer treatment. Within the current work, we aimed to design and synthesize a new series of benzimidazole- and indole-based derivatives as inhibitors of Bcl-2 protein. The market pan-Bcl-2 inhibitor, obatoclax, was the lead framework compound for adopted structural modifications. The obatoclax's pyrrolylmethine linker was replaced with straight alkylamine or carboxyhydrazine methylene linkers providing the new compounds. This strategy permitted improved structural flexibility of synthesized compounds adopting favored maneuvers for better fitting at the Bcl-2 major hydrophobic pocket. Anti-cancer activity of the synthesized compounds was further investigated through MTT-cytotoxic assay, cell cycle analysis, RT-PCR, ELISA and DNA fragmentation. Cytotoxic results showed compounds , and with promising cytotoxicity against MDA-MB-231/breast cancer cells (IC = 12.69 ± 0.84 to 12.83 ± 3.50 µM), while and depicted noticeable activities against A549/lung adenocarcinoma cells (IC = 23.05 ± 1.45 and 11.63 ± 2.57 µM, respectively). The signaling Bcl-2 inhibition pathway was confirmed by molecular docking where significant docking energies and interactions with key Bcl-2 pocket residues were depicted. Moreover, the top active compound, , showed significant upregulated expression levels of pro-apoptotic/anti-apoptotic of genes; , , , , and through RT-PCR assay. Improving the compound's pharmaceutical profile was undertaken by introducing within drug-solid/lipid nanoparticle formulation prepared by hot melting homogenization technique and evaluated for encapsulation efficiency, particle size, and zeta potential. Significant improvement was seen at the compound's cytotoxic activity. In conclusion, is introduced as a promising anti-cancer lead candidate that worth future fine-tuned lead optimization and development studies while exploring its potentiality through in-vivo preclinical investigation.
PubMed: 33535550
DOI: 10.3390/ph14020113 -
Endocrine-related Cancer Oct 2014Poorly differentiated tumors of the thyroid gland (PDTC) are generally characterized by a poor prognosis due to their resistance to available therapeutic approaches. The...
Poorly differentiated tumors of the thyroid gland (PDTC) are generally characterized by a poor prognosis due to their resistance to available therapeutic approaches. The relative rarity of these tumors is a major obstacle to our understanding of the molecular mechanisms leading to tumor aggressiveness and drug resistance, and consequently to the development of novel therapies. By simultaneously activating Kras and deleting p53 (Trp53) in thyroid follicular cells, we have generated a novel mouse model that develops papillary thyroid cancer invariably progressing to PDTC. In several cases, tumors further progress to anaplastic carcinomas. The poorly differentiated tumors are morphologically and functionally similar to their human counterparts and depend on MEK/ERK signaling for proliferation. Using primary carcinomas as well as carcinoma-derived cell lines, we also demonstrate that these tumors are intrinsically resistant to apoptosis due to high levels of expression of the Bcl2 family members, Bcl2a1 (Bcl2a1a) and Mcl1, and can be effectively targeted by Obatoclax, a small-molecule pan-inhibitor of the Bcl2 family. Furthermore, we show that Bcl2 family inhibition synergizes with MEK inhibition as well as with doxorubicin in inducing cell death. Thus, our studies in a novel, relevant mouse model have uncovered a promising druggable feature of aggressive thyroid cancers.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Humans; Indoles; MAP Kinase Kinase Kinase 1; MAP Kinase Kinase Kinase 2; Mice, Transgenic; Minor Histocompatibility Antigens; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Pyrroles; RNA, Messenger; Thyroid Neoplasms; Tumor Burden
PubMed: 25012986
DOI: 10.1530/ERC-14-0268 -
Leukemia & Lymphoma Dec 2014Obatoclax, a BH3 mimetic inhibitor of anti-apoptotic Bcl-2 proteins, demonstrates synergy with bortezomib in preclinical models of mantle cell lymphoma (MCL). This phase...
Obatoclax, a BH3 mimetic inhibitor of anti-apoptotic Bcl-2 proteins, demonstrates synergy with bortezomib in preclinical models of mantle cell lymphoma (MCL). This phase I/II study assessed obatoclax plus bortezomib in patients with relapsed/refractory MCL. Twenty-three patients received obatoclax 30 or 45 mg plus bortezomib 1.0 or 1.3 mg/m(2), administered intravenously on days 1, 4, 8 and 11 of a 21-day cycle. In phase I, the combination was feasible at all doses. Obatoclax 45 mg plus bortezomib 1.3 mg/m(2) was selected for phase II study. Common adverse events were somnolence (87%), fatigue (61%) and euphoric mood (57%), all primarily grade 1/2. Grade 3/4 events included thrombocytopenia (21%), anemia (13%) and fatigue (13%). Objective responses occurred in 4/13 (31%) evaluable patients (three complete and one partial response). Six patients (46%) had stable disease lasting ≥ 8 weeks. Obatoclax plus bortezomib was feasible, but the synergy demonstrated in preclinical models was not confirmed.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Combined Modality Therapy; Disease Progression; Female; Humans; Indoles; Lymphoma, Mantle-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Proto-Oncogene Proteins c-bcl-2; Pyrazines; Pyrroles; Treatment Outcome
PubMed: 24679008
DOI: 10.3109/10428194.2014.907891 -
Oncotarget Aug 2016Bcl2 and IAP families are anti-apoptotic proteins deregulated in multiple myeloma (MM) cells. Pharmacological inhibition of each of these families has shown significant...
Bcl2 and IAP families are anti-apoptotic proteins deregulated in multiple myeloma (MM) cells. Pharmacological inhibition of each of these families has shown significant activity only in subgroups of MM patients. Here, we have examined a broad-spectrum Bcl2 family inhibitor Obatoclax (OBX) in combination with a Smac mimetic LCL161 in MM cell lines and patient cells. LCL161/OBX combination induced synergistic cytotoxicity and anti-proliferative effects on a broad range of human MM cell lines. The cytotoxicity was mediated through inhibition of the IAPs, activation of caspases and up regulation of the pro-apoptotic proteins Bid, Bim, Puma and Noxa by the drug combination. In addition, we observed that OBX caused ER stress and activated the Unfolded Protein Response (UPR) leading to drug resistance. LCL161, however inhibited spliced Xbp-1, a pro-survival factor. In addition, we observed that OBX increased GRP78 localization to the cell surface, which then induced PI3K dependent Akt activation and resistance to cell death. LCL161 was able to block OBX induced Akt activation contributing to synergistic cell death. Our results support clinical evaluation of this combination strategy in relapsed refractory MM patients.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Caspases; Cell Line, Tumor; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Heat-Shock Proteins; Humans; Indoles; Intracellular Signaling Peptides and Proteins; Mitochondrial Proteins; Multiple Myeloma; Neoplasm Recurrence, Local; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Thiazoles; Unfolded Protein Response; Up-Regulation; X-Box Binding Protein 1
PubMed: 27494845
DOI: 10.18632/oncotarget.11028 -
Oncotarget Jan 2023Overexpression of the dihydrolipoamide S-succinyltransferase () is associated with poor outcome in neuroblastoma patients and triple-negative breast cancer (TNBC) and...
Overexpression of the dihydrolipoamide S-succinyltransferase () is associated with poor outcome in neuroblastoma patients and triple-negative breast cancer (TNBC) and specifically with the oxidative phosphorylation (OXPHOS) pathway. Inhibitors of OXPHOS were previously suggested as a potential therapeutic strategy for a subset of patients with high-risk neuroblastoma. Here, we tested if cell lines with amplifications or high mRNA levels were associated with sensitivity to 250 drugs from the Genomics of Drug Sensitivity in Cancer (GDSC) dataset by comparing them to cell lines without these changes. -altered cell lines were more sensitive to 7 approved drugs, among these obatoclax mesylate, a BCL2 inhibitor that reduces OXPHOS in human leukemia stem cells. Moreover, several protein kinase inhibitors were identified to be efficient in cell lines with amplifications or high mRNA levels, suggesting a vulnerability of -altered cell lines for drugs targeting the ERK/MAPK pathway. Furthermore, increased expression in cell lines with driver mutations in supported this relationship. We therefore conclude that, in addition to OXPHOS, protein kinases could be potential targets of therapy in the presence of amplifications or high mRNA levels. The new drug candidates proposed here could serve in experimental testing on drug efficacy in knock-in cell lines and -activated tumors.
Topics: Humans; RNA, Messenger; Cell Line; Neuroblastoma; Cell Line, Tumor
PubMed: 36634214
DOI: 10.18632/oncotarget.28342 -
Journal of Virology Nov 2021Targeting host factors is a promising strategy to develop broad-spectrum antiviral drugs. Drugs targeting anti-apoptotic Bcl-2 family proteins that were originally...
Targeting host factors is a promising strategy to develop broad-spectrum antiviral drugs. Drugs targeting anti-apoptotic Bcl-2 family proteins that were originally developed as tumor suppressors have been reported to inhibit multiplication of different types of viruses. However, the mechanisms whereby Bcl-2 inhibitors exert their antiviral activity remain poorly understood. In this study, we have investigated the mechanisms by which obatoclax (OLX) and ABT-737 Bcl-2 inhibitors exhibited a potent antiviral activity against the mammarenavirus lymphocytic choriomeningitis virus (LCMV). OLX and ABT-737 potent anti-LCMV activity was not associated with their proapoptotic properties but rather with their ability to induce cell arrest at the G0/G1 phase. OLX- and ABT-737-mediated inhibition of Bcl-2 correlated with reduced expression levels of thymidine kinase 1 (TK1), cyclin A2 (CCNA2), and cyclin B1 (CCNB1) cell cycle regulators. In addition, small interfering RNA (siRNA)-mediated knockdown of TK1, CCNA2, and CCNB1 resulted in reduced levels of LCMV multiplication. The antiviral activity exerted by Bcl-2 inhibitors correlated with reduced levels of viral RNA synthesis at early times of infection. Importantly, ABT-737 exhibited moderate efficacy in a mouse model of LCMV infection, and Bcl-2 inhibitors displayed broad-spectrum antiviral activities against different mammarenaviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results suggest that Bcl-2 inhibitors, actively being explored as anticancer therapeutics, might be repositioned as broad-spectrum antivirals. Antiapoptotic Bcl-2 inhibitors have been shown to exert potent antiviral activities against various types of viruses via mechanisms that are currently poorly understood. This study has revealed that Bcl-2 inhibitors' mediation of cell cycle arrest at the G0/G1 phase, rather than their proapoptotic activity, plays a critical role in blocking mammarenavirus multiplication in cultured cells. In addition, we show that Bcl-2 inhibitor ABT-737 exhibited moderate antimammarenavirus activity and that Bcl-2 inhibitors displayed broad-spectrum antiviral activities against different mammarenaviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results suggest that Bcl-2 inhibitors, actively being explored as anticancer therapeutics, might be repositioned as broad-spectrum antivirals.
Topics: A549 Cells; Animals; Antiviral Agents; Apoptosis; Apoptosis Regulatory Proteins; Arenaviridae; Biphenyl Compounds; COVID-19; Cell Cycle; Cell Cycle Checkpoints; Cells, Cultured; Chlorocebus aethiops; Cyclin A2; Cyclin B1; G1 Phase; Humans; Indoles; Mice; Mice, Inbred C57BL; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Resting Phase, Cell Cycle; SARS-CoV-2; Sulfonamides; Thymidine Kinase; Vero Cells; COVID-19 Drug Treatment
PubMed: 34586865
DOI: 10.1128/JVI.01399-21