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Journal of Translational Medicine Mar 2024Colorectal cancer (CRC) is the third most prevalent cancer globally, and liver metastasis (CRLM) is the primary cause of death. Hence, it is essential to discover novel...
BACKGROUND
Colorectal cancer (CRC) is the third most prevalent cancer globally, and liver metastasis (CRLM) is the primary cause of death. Hence, it is essential to discover novel prognostic biomarkers and therapeutic drugs for CRLM.
METHODS
This study developed two liver metastasis-associated prognostic signatures based on differentially expressed genes (DEGs) in CRLM. Additionally, we employed an interpretable deep learning model utilizing drug sensitivity databases to identify potential therapeutic drugs for high-risk CRLM patients. Subsequently, in vitro and in vivo experiments were performed to verify the efficacy of these compounds.
RESULTS
These two prognostic models exhibited superior performance compared to previously reported ones. Obatoclax, a BCL-2 inhibitor, showed significant differential responses between high and low risk groups classified by prognostic models, and demonstrated remarkable effectiveness in both Transwell assay and CT26 colorectal liver metastasis mouse model.
CONCLUSIONS
This study highlights the significance of developing specialized prognostication approaches and investigating effective therapeutic drugs for patients with CRLM. The application of a deep learning drug response model provides a new drug discovery strategy for translational medicine in precision oncology.
Topics: Animals; Mice; Humans; Precision Medicine; Prognosis; Liver Neoplasms; Drug Discovery; Colorectal Neoplasms
PubMed: 38555418
DOI: 10.1186/s12967-024-05127-5 -
ACS Applied Materials & Interfaces Jun 2016Detouring of conventional DNA damaging anticancer drugs into mitochondria to damage mitochondrial DNA is evolving as a promising strategy in chemotherapy. Inhibiting...
Detouring of conventional DNA damaging anticancer drugs into mitochondria to damage mitochondrial DNA is evolving as a promising strategy in chemotherapy. Inhibiting single target in mitochondria would eventually lead to the emergence of drug resistance. Moreover, targeting mitochondria selectively in cancer cells, keeping them intact in healthy cells, remains a major challenge. Herein, triphenylphosphine (TPP)-coated positively charged 131.6 nm spherical nanoparticles (NPs) comprised of α-tocopheryl succinate (TOS, inhibitor of complex II in electron transport chain) and obatoclax (Obt, inhibitor of Bcl-2) were engineered. The TOS-TPP-Obt-NPs entered into acidic lysosomes via macropinocytosis, followed by lysosomal escape and finally homed into mitochondria over a period of 24 h. Subsequently, these TOS-TPP-Obt-NPs triggered mitochondrial outer membrane permeabilization (MOMP) by inhibiting antiapoptotic Bcl-2, leading to Cytochrome C release. These TOS-TPP-Obt-NPs mediated mitochondrial damage induced cellular apoptosis through caspase-9 and caspase-3 cleavage to show improved efficacy in HeLa cells. Moreover, TOS-TPP-Obt-NPs induced MOMP in drug-resistant triple negative breast cancer cells (MDA-MB-231), leading to remarkable efficacy, compared to the combination of free drugs in higher drug concentrations. Results presented here clearly stimulate the usage of multiple drugs to perturb simultaneously diverse targets, selectively in mitochondria, as next-generation cancer therapeutics.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Drug Carriers; HeLa Cells; Humans; Indoles; Mitochondria; Nanoparticles; Organophosphorus Compounds; Pyrroles; alpha-Tocopherol
PubMed: 27160664
DOI: 10.1021/acsami.6b00263 -
Leukemia & Lymphoma 2015Obatoclax is a small molecule mimetic of the BH3 domain of BCL-2 family proteins. This phase 1 study combining obatoclax with FR was undertaken in chronic lymphocytic... (Clinical Trial)
Clinical Trial
Obatoclax is a small molecule mimetic of the BH3 domain of BCL-2 family proteins. This phase 1 study combining obatoclax with FR was undertaken in chronic lymphocytic leukemia (CLL) patients relapsed after at least one prior therapy. Obatoclax was given as a 3-h infusion on days 1 and 3 and escalated through three dose levels, with standard dose FR days 1-5. Thirteen patients were enrolled, with a median of two prior therapies. One dose-limiting toxicity (DLT) of a 2-week treatment delay for persistent grade 2-3 neutropenia was observed at the highest obatoclax dose (20 mg/m2), but no maximum tolerated dose (MTD) was reached. The overall response rate (ORR) was 85%, with 15% complete responses (CRs) by NCI-96 criteria and 54% by IWCLL 2008 criteria. Median time to progression was 20 months. It is concluded that obatoclax can be safely administered to relapsed CLL patients in combination with FR and shows promising clinical activity.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Chromosome Aberrations; Combined Modality Therapy; Disease Progression; Female; Humans; Indoles; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Mutation; Neoplasm Staging; Pyrroles; Recurrence; Retreatment; Rituximab; Treatment Outcome; Vidarabine
PubMed: 25971907
DOI: 10.3109/10428194.2015.1048441 -
AIDS (London, England) Jul 2024Some drugs that augment cell-intrinsic defenses or modulate cell death/survival pathways have been reported to selectively kill cells infected with HIV or Simian...
OBJECTIVES
Some drugs that augment cell-intrinsic defenses or modulate cell death/survival pathways have been reported to selectively kill cells infected with HIV or Simian Immunodeficiency Virus (SIV), but comparative studies are lacking. We hypothesized that these drugs may differ in their ability to kill cells infected with intact and defective proviruses.
DESIGN
To investigate this hypothesis, drugs were tested ex vivo on peripheral blood mononuclear cells (PBMC) from nine antiretroviral therapy (ART)-suppressed individuals.
METHODS
We tested drugs currently in clinical use or human trials, including auranofin (p53 modulator), interferon alpha2A, interferon gamma, acitretin (RIG-I inducer), GS-9620/vesatolimod (TLR7 agonist), nivolumab (PD-1 blocker), obatoclax (Bcl-2 inhibitor), birinapant [inhibitor of apoptosis proteins (IAP) inhibitor], bortezomib (proteasome inhibitor), and INK128/sapanisertib [mammalian target of rapamycin mTOR] [c]1/2 inhibitor). After 6 days of treatment, we measured cell counts/viabilities and quantified levels of total, intact, and defective HIV DNA by droplet digital PCR (Intact Proviral DNA Assay).
RESULTS
Obatoclax reduced intact HIV DNA [median = 27-30% of dimethyl sulfoxide control (DMSO)] but not defective or total HIV DNA. Other drugs showed no statistically significant effects.
CONCLUSION
Obatoclax and other Bcl-2 inhibitors deserve further study in combination therapies aimed at reducing the intact HIV reservoir in order to achieve a functional cure and/or reduce HIV-associated immune activation.
Topics: Humans; Indoles; HIV Infections; Pyrroles; Leukocytes, Mononuclear; Proviruses
PubMed: 38626436
DOI: 10.1097/QAD.0000000000003908 -
Cancer Science Feb 2022Several lines of research suggest that Bcl-xL-mediated anti-apoptotic effects may contribute to the pathogenesis of myeloproliferative neoplasms driven by JAK2V617F and...
Several lines of research suggest that Bcl-xL-mediated anti-apoptotic effects may contribute to the pathogenesis of myeloproliferative neoplasms driven by JAK2V617F and serve as therapeutic target. Here, we used a knock-in JAK2V617F mouse model and confirmed that Bcl-xL was overexpressed in erythroid progenitors. The myeloproliferative neoplasm (MPN)-induced phenotype in the peripheral blood by conditional knock-in of JAK2V617F was abrogated by conditional knockout of Bcl2l1, which presented anemia and thrombocytopenia independently of JAK2 mutation status. Mx1-Cre Jak2V617 /Bcl2l1 mice presented persistent splenomegaly as a result of extramedullary hematopoiesis and pro-apoptotic stimuli in terminally differentiated erythroid progenitors. The pan-BH3 mimetic inhibitor obatoclax showed superior cytotoxicity in JAK2V617F cell models, and reduced clonogenic capacity in ex vivo assay using Vav-Cre Jak2V617F bone marrow cells. Both ruxolitinib and obatoclax significantly reduced spleen weights in a murine Jak2V617F MPN model but did not show additive effect. The tumor burden reduction was observed with either ruxolitinib or obatoclax in terminal differentiation stage neoplastic cells but not in myeloid-erythroid precursors. Therefore, disrupting the BCL2 balance is not sufficient to treat MPN at the stem cell level, but it is certainly an additional option for controlling the critical myeloid expansion of the disease.
Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Models, Animal; Drug Resistance, Neoplasm; Enzyme Inhibitors; Erythroid Precursor Cells; Humans; Indoles; Janus Kinase 2; Mice; Mutation; Myeloproliferative Disorders; Nitriles; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; Pyrroles; Tumor Burden; bcl-X Protein
PubMed: 34808021
DOI: 10.1111/cas.15210 -
PloS One 2014An open-label phase I/II study of single-agent obatoclax determined a maximum tolerated dose (MTD) and schedule, safety, and efficacy in older patients (≥ 70 yr) with... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
An open-label phase I/II study of single-agent obatoclax determined a maximum tolerated dose (MTD) and schedule, safety, and efficacy in older patients (≥ 70 yr) with untreated acute myeloid leukemia (AML).
EXPERIMENTAL DESIGN
Phase I evaluated the safety of obatoclax infused for 3 hours on 3 consecutive days (3 h × 3 d) in 2-week cycles. Initial obatoclax dose was 30 mg/day (3 h × 3 d; n = 3). Obatoclax was increased to 45 mg/day (3 h × 3 d) if ≤ 1 patient had a dose-limiting toxicity (DLT) and decreased to 20 mg/day (3 h × 3 d) if DLT occurred in ≥ 2 patients. In the phase II study, 12 patients were randomized to receive obatoclax at the dose identified during phase I (3 h × 3 d) or 60 mg/day administered by continuous infusion over 24 hours for 3 days (24 h × 3 d) to determine the morphologic complete response rate.
RESULTS
In phase I, two of three patients receiving obatoclax 30 mg/day (3 h × 3 d) experienced grade 3 neurologic DLTs (confusion, ataxia, and somnolence). Obatoclax was decreased to 20 mg/day (3 h × 3 d). In phase II, no clinically relevant safety differences were observed between the 20 mg/day (3 h × 3 d; n = 7) and 60 mg/day (24 h × 3 d; n = 5) arms. Neurologic and psychiatric adverse events were most common and were generally transient and reversible. Complete response was not achieved in any patient.
CONCLUSIONS
Obatoclax 20 mg/day was the MTD (3 h × 3 d) in older patients with AML. In the schedules tested, single-agent obatoclax was not associated with an objective response. Evaluation in additional subgroups or in combination with other chemotherapy modalities may be considered for future study.
TRIAL REGISTRATION
ClinicalTrials.gov NCT00684918.
Topics: Aged; Aged, 80 and over; Blast Crisis; Demography; Drug Administration Schedule; Female; Humans; Indoles; Leukemia, Myeloid, Acute; Male; Neutrophils; Platelet Count; Pyrroles; Treatment Outcome
PubMed: 25285531
DOI: 10.1371/journal.pone.0108694 -
Lung Cancer (Amsterdam, Netherlands) Sep 2014This randomized phase II study assessed the efficacy and safety of obatoclax mesylate, a small-molecule Bcl-2 inhibitor, added to carboplatin/etoposide chemotherapy as... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
This randomized phase II study assessed the efficacy and safety of obatoclax mesylate, a small-molecule Bcl-2 inhibitor, added to carboplatin/etoposide chemotherapy as initial treatment for extensive-stage small-cell lung cancer (ES-SCLC).
MATERIALS AND METHODS
Chemotherapy-naïve subjects with ES-SCLC and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 received carboplatin/etoposide with (CbEOb) or without (CbE) obatoclax for up to six cycles. Responders to CbEOb could receive maintenance obatoclax until disease progression. The primary endpoint was objective response rate (ORR).
RESULTS
155 subjects (median age 62, 58% male, 10% ECOG PS 2) were treated with CbEOb (n=77) or CbE (n=78); 65% and 59% of subjects, respectively, completed six cycles. ORR was 62% with CbEOb versus 53% with CbE (1-sided p=0.143). Clinical benefit (ORR+ stable disease) trended better with CbEOb (81% versus 68%; p=0.054). Median progression-free survival (PFS) and overall survival (OS) were 5.8 months (95% confidence interval [CI]: 5.3-6.5) and 10.5 months (8.9-13.8) with CbEOb and 5.2 months (95% CI: 4.1-5.7) and 9.8 months (7.2-11.2) with CbE. Median OS was 10.5 months (95% CI: 8.9-13.8) and 9.8 months (7.2-11.2) with a nonsignificant hazard ratio for OS, 0.823; 1-sided p=0.121. Grade 3/4 adverse events (AEs) were primarily hematologic and similar in frequency between treatment arms. Obatoclax-related somnolence and euphoria were grade 1/2, transient, and did not require treatment discontinuation.
CONCLUSION
Obatoclax was well tolerated when added to carboplatin/etoposide in first-line treatment of ES-SCLC, but failed to significantly improve ORR, PFS, or OS.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Comorbidity; Etoposide; Female; Humans; Indoles; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Pyrroles; Small Cell Lung Carcinoma; Treatment Outcome
PubMed: 24997137
DOI: 10.1016/j.lungcan.2014.05.003 -
Toxicological Research Oct 2023Autophagy play contradictory roles in cellular transformation. We previously found that the knockout (KO) of autophagy-related 5 (Atg5), which is essential for...
UNLABELLED
Autophagy play contradictory roles in cellular transformation. We previously found that the knockout (KO) of autophagy-related 5 (Atg5), which is essential for autophagy, leads to the malignant transformation of NIH 3T3 cells. In this study, we explored the mechanism by which autophagy contributes to this malignant transformation using two transformed cell lines, Atg5 KO and Ras-NIH 3T3. Monomeric red fluorescent protein-green fluorescent protein-light chain 3 reporter and Cyto-ID staining revealed that Ras-NIH 3T3 cells exhibited higher basal autophagy activity than NIH 3T3 cells. Additionally, transformed cells, regardless of their Atg5 KO status, were more sensitive to autophagy inhibitors (SBI-0206965, chloroquine, and obatoclax) than the untransformed NIH 3T3 cells, suggesting that the transformed cells are more autophagy-dependent than the normal cells. Loss of Atg5 improved the cell viability and mobility, especially in Ras-NIH 3T3 cells. Furthermore, we discovered that autophagy was alternatively induced in a Rab9-dependent manner in Ras-NIH 3T3 and NIH 3T3/Atg5 KO cells. In particular, Atg5 KO cells showed reduced mTOR-mediated phosphorylation of Akt (pAkt S473), indicating the mTOR-independent occurrence of alternative autophagy in Atg5 KO cells. Therefore, our study provides evidence that alternative autophagy may contribute to tumorigenesis in cells with an impaired Atg5-dependent autophagy pathway.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s43188-023-00191-3.
PubMed: 37779593
DOI: 10.1007/s43188-023-00191-3 -
International Journal of Molecular... Nov 2022Bladder cancer is the 10th most common cancer worldwide. Due to the lack of understanding of the oncogenic mechanisms between muscle-invasive bladder cancer (MIBC) and...
Systems Drug Design for Muscle Invasive Bladder Cancer and Advanced Bladder Cancer by Genome-Wide Microarray Data and Deep Learning Method with Drug Design Specifications.
Bladder cancer is the 10th most common cancer worldwide. Due to the lack of understanding of the oncogenic mechanisms between muscle-invasive bladder cancer (MIBC) and advanced bladder cancer (ABC) and the limitations of current treatments, novel therapeutic approaches are urgently needed. In this study, we utilized the systems biology method via genome-wide microarray data to explore the oncogenic mechanisms of MIBC and ABC to identify their respective drug targets for systems drug discovery. First, we constructed the candidate genome-wide genetic and epigenetic networks (GWGEN) through big data mining. Second, we applied the system identification and system order detection method to delete false positives in candidate GWGENs to obtain the real GWGENs of MIBC and ABC from their genome-wide microarray data. Third, we extracted the core GWGENs from the real GWGENs by selecting the significant proteins, genes and epigenetics via the principal network projection (PNP) method. Finally, we obtained the core signaling pathways from the corresponding core GWGEN through the annotations of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway to investigate the carcinogenic mechanisms of MIBC and ABC. Based on the carcinogenic mechanisms, we selected the significant drug targets NFKB1, LEF1 and MYC for MIBC, and LEF1, MYC, NOTCH1 and FOXO1 for ABC. To design molecular drug combinations for MIBC and ABC, we employed a deep neural network (DNN)-based drug-target interaction (DTI) model with drug specifications. The DNN-based DTI model was trained by drug-target interaction databases to predict the candidate drugs for MIBC and ABC, respectively. Subsequently, the drug design specifications based on regulation ability, sensitivity and toxicity were employed as filter criteria for screening the potential drug combinations of Embelin and Obatoclax for MIBC, and Obatoclax, Entinostat and Imiquimod for ABC from their candidate drugs. In conclusion, we not only investigated the oncogenic mechanisms of MIBC and ABC, but also provided promising therapeutic options for MIBC and ABC, respectively.
Topics: Humans; Urinary Bladder Neoplasms; Deep Learning; Microarray Analysis; Drug Design; Muscles
PubMed: 36430344
DOI: 10.3390/ijms232213869 -
Genes & Cancer Nov 2014Glioblastoma has shown resistance to histone deacetylase inhibitors (HDACi) as radiosensitizers in cultures with Bcl-XL over-expression. We study the efficacy of...
Glioblastoma has shown resistance to histone deacetylase inhibitors (HDACi) as radiosensitizers in cultures with Bcl-XL over-expression. We study the efficacy of SAHA/RTx and LBH589/RTx when manipulating Bcl-2 family proteins using the Bcl-2 inhibitor Obatoclax in patient-derived glioblastoma stem-like cell (GSC) cultures. GSC cultures in general have a deletion in phosphatase and tensin homolog (PTEN). Synergy was determined by the Chou Talalay method. The effects on apoptosis and autophagy were studied by measuring caspase-3/7, Bcl-XL, Mcl-1 and LC3BI/II proteins. The relation between treatment response and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, recurrence and gene expression levels of the tumors were studied. Obatoclax synergized with SAHA and LBH589 and sensitized cells to HDACi/RTx. Over 50% of GSC cultures were responsive to Obatoclax with either single agent. Combined with HDACi/RTx treatment, Obatoclax increased caspase-3/7 and inhibited Bcl-2 family proteins Bcl-XL and Mcl-1 more effectively than other treatments. Genes predictive for treatment response were identified, including the F-box/WD repeat-containing protein-7, which was previously related to Bcl-2 inhibition and HDACi sensitivity. We emphasize the functional relation between Bcl-2 proteins and radiosensitization by HDACi and provide a target for increasing responsiveness in glioblastoma by using the Bcl-2 inhibitor Obatoclax.
PubMed: 25568669
DOI: 10.18632/genesandcancer.42