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Clinical & Translational Oncology :... Jun 2023Due to their key role in the pathogenesis of cancer through the regulation of apoptosis, the B-cell leukemia/lymphoma-2 (BCL-2) family proteins have been an attractive... (Review)
Review
Due to their key role in the pathogenesis of cancer through the regulation of apoptosis, the B-cell leukemia/lymphoma-2 (BCL-2) family proteins have been an attractive target for cancer therapy for the past decades. Throughout the years, many Bcl-2 family inhibitors have been developed, with Venetoclax being now successfully used in treating hematological malignancies. Although their effectiveness in the treatment of solid tumors is yet to be established, some preclinical evidence indicates their possible clinical application. This review aims to summarize current data from completed clinical trials that used Bcl-2 protein family inhibitors as monotherapy or in combination with other agents for the treatment of solid malignancies. We managed to include clinical trials of various phases which analyze the pharmacokinetics and pharmacodynamics of the drugs, as well as the effectiveness and adverse effects. Active and recruiting clinical trials are also briefly presented and future prospects and challenges are discussed.
Topics: Humans; Proto-Oncogene Proteins c-bcl-2; Antineoplastic Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Apoptosis; Hematologic Neoplasms; Bridged Bicyclo Compounds, Heterocyclic
PubMed: 36639602
DOI: 10.1007/s12094-022-03070-9 -
BioMed Research International 2019B-cell lymphoma 2 (Bcl-2) is a regulator protein involved in apoptosis. In the past few decades, this protein has been demonstrated to have high efficacy in cancer... (Review)
Review
B-cell lymphoma 2 (Bcl-2) is a regulator protein involved in apoptosis. In the past few decades, this protein has been demonstrated to have high efficacy in cancer therapy, and several approaches targeting Bcl-2 have been tested clinically (e.g., oblimersen, ABT-737, ABT-263, obatoclax mesylate, and AT-101). This review reports potential Bcl-2 inhibitors according to current information on their underlying mechanism and the results of clinical trials. In addition, the function and mechanisms of other potentially valuable Bcl-2 inhibitors that did not show efficacy in clinical studies are also discussed. This summary of the development of Bcl-2 inhibitors provides worthwhile viewpoints on the use of biomedical approaches in future cancer therapy.
Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Gossypol; Humans; Lymphoma, B-Cell; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Thionucleotides
PubMed: 31662966
DOI: 10.1155/2019/1212369 -
Blood Advances Jul 2021Overexpression of B-cell leukemia/lymphoma 2 (BCL2) renders acute myeloid leukemia (AML) cells resistant to chemotherapy and has been associated with unfavorable... (Randomized Controlled Trial)
Randomized Controlled Trial
Overexpression of B-cell leukemia/lymphoma 2 (BCL2) renders acute myeloid leukemia (AML) cells resistant to chemotherapy and has been associated with unfavorable outcomes. Oblimersen (G3139) is a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 BCL2 codons. In a phase 1 study of AML patients treated with G3139, cytarabine, and daunorubicin induction with cytarabine consolidation, no antisense-related toxicity was reported, and BCL2 downregulation occurred in patients achieving complete remission. In this phase 3 trial, untreated older AML patients were randomized to cytarabine (100 mg/m2 per day on days 4-10) and daunorubicin (60 mg/m2 per day on days 4-6) followed by cytarabine consolidation (2000 mg/m2 per day on days 4-8) with (arm A) or without (arm B) G3139 (7 mg/m2 per day on days 1-10 [induction] or days 1-8 [consolidation]). A total of 506 patients were enrolled. No differences in toxicity were observed between arms. Estimated overall survival (OS) at 1 year was 43% for arm A and 40% for arm B (1-sided log rank P = .13), with no differences in disease-free (DFS; P = .26) or event-free survival (P = .80). Subgroup analyses showed patients age <70 years in arm A had improved OS by 1 month vs those in arm B (P = .04), and patients with secondary AML in arm A had better DFS vs those in arm B (P = .04). We conclude that addition of G3139 to chemotherapy failed to improve outcomes of older AML patients. However, more effective means of inhibiting BCL2 are showing promising results in combination with chemotherapy in AML. This trial was registered at www.clinicaltrials.gov as #NCT00085124.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Humans; Leukemia, Myeloid, Acute; Thionucleotides
PubMed: 34251414
DOI: 10.1182/bloodadvances.2021004233 -
Langmuir : the ACS Journal of Surfaces... Jun 2023Compared with traditional medical methods, gene therapy and photodynamic therapy are the new fields of cancer treatment, and they more accurately and effectively obtain...
Compared with traditional medical methods, gene therapy and photodynamic therapy are the new fields of cancer treatment, and they more accurately and effectively obtain preferable therapeutic effects. In this study, a chemotherapy drug-free nanotherapeutic system based on ZIF-90 encapsulated with Ce6-G3139 and Ce6-DNAzyme for gene and photodynamic therapies was constructed. Once entering the cancer cell, the therapy system will decompose and release Zn, Ce6-G3139, and Ce6-DNAzyme in the acidic environment. On the one hand, G3139 binds to the antiapoptotic gene in tumor cells and downregulates related proteins to inhibit tumor proliferation. On the other hand, Zn produced by the decomposition of ZIF-90 can be used as a cofactor to activate the cleavage activity of DNAzyme to initiate gene therapy. Proliferation and metastasis of tumors were further inhibited by DNAzyme, targeting and cutting the gene of human early growth factor-1 (EGR-1). In addition, the photosensitizer Ce6 carried by the nucleic acid will produce cytotoxic ROS to kill cancer cells after irradiation. The results of this study demonstrated that the designed nanoplatform, which synergistically combines gene and photodynamic therapies, has shown great potential for cancer treatment.
Topics: Humans; Female; Breast Neoplasms; Metal-Organic Frameworks; DNA, Catalytic; Photosensitizing Agents; Photochemotherapy; Cell Line, Tumor; Porphyrins; Nanoparticles
PubMed: 37236267
DOI: 10.1021/acs.langmuir.3c00667 -
International Journal of Pharmaceutics Sep 2022G3139 is an antisense oligodeoxyribonucleotide (ODN) developed as a Bcl-2 down-regulating agent for the treatment of acute myelogenous leukemia (AML). However, the...
G3139 is an antisense oligodeoxyribonucleotide (ODN) developed as a Bcl-2 down-regulating agent for the treatment of acute myelogenous leukemia (AML). However, the clinical efficacy of G3139 has been shown to be limited due to its rapid plasma clearance and low permeability. To enhance the effective delivery of G3139, this work prepared a novel nano gene delivery vector (aCD33-NKSN) consisting of a CD33 antigbody (aCD33), a nuclear localization signal (NLS), gene fusion peptides (KALA), and stearic acid (SA) for CD33 antigen targeting and nuclear localization. The aCD33-NKSN/G3139 nanoparticles were spherical and uniformly sized with a positive charge and sustained release. They had an excellent G3139 loading capacity and colloidal stability. The aCD33-NKSN/G3139 delivered G3139 into the nucleus of Kasumi-1 cells and aCD33-NKSN/G3139 could more effectively inhibited Bcl-2 expression and induced apoptosis in Kasumi-1 cells versus free G3139. The aCD33-NKSN/G3139 administration was more effective at inhibiting tumor growth, and significantly prolonged the survival time of mice in contrast to free G3139. The results illustrate that aCD33-NKSN/G3139 nanoparticles could improve the antitumor activity of encapsulated G3139 due to aCD33 targeting and the ability to perform nuclear localization, The results offer a promising clinical application potential for the treatment of acute myeloid leukemia.
Topics: Animals; Cell Line, Tumor; Leukemia, Myeloid, Acute; Mice; Nanoparticles; Oligonucleotides; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Sialic Acid Binding Ig-like Lectin 3; Thionucleotides
PubMed: 35932928
DOI: 10.1016/j.ijpharm.2022.122074 -
ACS Applied Materials & Interfaces Mar 2021Exosomes are natural delivery vehicles because of their original feature such as low immunogenicity, excellent biocompatibility, and migration capability. Engineering...
Exosomes are natural delivery vehicles because of their original feature such as low immunogenicity, excellent biocompatibility, and migration capability. Engineering exosomes with appropriate ligands are effective approaches to improve the low cellular uptake efficiency of exosomes. However, current strategies face considerable challenges due to the tedious and labor-intensive operational process. Here, we designed a novel peptides-equipped exosomes platform which can be assembled under convenient and mild reaction condition. Cell-penetrating peptides (CPPs) was conjugated on HepG2 cells-derived exosomes surface which can not only enhance the penetrating capacity of exosomes but also assist exosomes in loading antisense oligonucleotides (ASOs). The cellular uptake mechanism was investigated and we compared the difference between natural exosomes and modified exosomes. The resulting nanosystem demonstrated a preferential tropism for cells that are parented to their source tumor cells and could remarkably increase the cellular delivery of G3139 with efficient downregulation of antiapoptotic Bcl-2. This work developed a rapid strategy for intracellular delivery of nucleic acids, thus providing more possibilities toward personalized cancer medicine.
Topics: Cell-Penetrating Peptides; Down-Regulation; Drug Carriers; Exosomes; Gene Silencing; Hep G2 Cells; Humans; Oligodeoxyribonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Thionucleotides
PubMed: 33621039
DOI: 10.1021/acsami.1c00016 -
Nucleic Acid Therapeutics Aug 2021A sensitive and specific capillary electrophoresis with laser-induced fluorescence (CE-LIF) and a simple extraction process was developed to simultaneously detect G3139...
A sensitive and specific capillary electrophoresis with laser-induced fluorescence (CE-LIF) and a simple extraction process was developed to simultaneously detect G3139 and its metabolites as a model of antisense oligonucleotides (ASOs). This method has shown excellent linearity within the tested concentration range for G3139 and its metabolites, with a detection limit of 3.0 pM and a recovery of >84.2%. Based on our developed plasma extraction method, we have evaluated the pharmacokinetics and metabolites from rat plasma after intravenous administration of G3139 at 0.76 mg/kg. The results showed that G3139 and its metabolites were successfully simultaneously detected and analyzed through a single run using CE-LIF with baseline separation until the 30-h test sampling time point. The half-life of G3139 and its metabolites was observed at 31 and 68 h, respectively. This study may provide an effective analytical method for the pharmacokinetic and metabolite evaluation required to develop ASOs to treat a variety of diseases.
Topics: Animals; Electrophoresis, Capillary; Lasers; Oligonucleotides, Antisense; Rats; Thionucleotides
PubMed: 33784473
DOI: 10.1089/nat.2020.0922 -
Biomeditsinskaia Khimiia Feb 2023The effect of modulators of VDAC channels - G3139 and erastin on the mitochondrial permeability transition pore (mPTP) functioning and changes in the content of proteins...
The effect of modulators of VDAC channels - G3139 and erastin on the mitochondrial permeability transition pore (mPTP) functioning and changes in the content of proteins involved in regulation of mPTP (VDAC, CNPase, and TSPO) has been investigated in liver mitochondria of rats with chronic alcohol intoxication. It was shown that the mitochondria of rats treated with ethanol were more sensitive to mPTP induction. Moreover, ethanol induced changes in the expression of mPTP regulator proteins. G3139 and erastin were also able to influence the studied mitochondrial parameters, and they increased their effect in the liver mitochondria of rats treated with ethanol, as compared to the mitochondria of control rats. We hypothesize that the results of this study may help to elucidate the mechanisms of chronic action of ethanol on mitochondria and contribute to the development of new therapeutic strategies for treating the consequences of ethanol-related diseases.
Topics: Animals; Rats; Mitochondria, Liver; Alcoholism; Mitochondria; Ethanol
PubMed: 36857428
DOI: 10.18097/PBMC20236901062 -
Journal of the American Chemical Society Feb 2022The voltage-dependent anion channel (VDAC), the most abundant protein in the outer mitochondrial membrane, is responsible for the transport of all ions and metabolites...
The voltage-dependent anion channel (VDAC), the most abundant protein in the outer mitochondrial membrane, is responsible for the transport of all ions and metabolites into and out of mitochondria. Larger than any of the β-barrel structures determined to date by magic-angle spinning (MAS) NMR, but smaller than the size limit of cryo-electron microscopy (cryo-EM), VDAC1's 31 kDa size has long been a bottleneck in determining its structure in a near-native lipid bilayer environment. Using a single two-dimensional (2D) crystalline sample of human VDAC1 in lipids, we applied proton-detected fast magic-angle spinning NMR spectroscopy to determine the arrangement of β strands. Combining these data with long-range restraints from a spin-labeled sample, chemical shift-based secondary structure prediction, and previous MAS NMR and atomic force microscopy (AFM) data, we determined the channel's structure at a 2.2 Å root-mean-square deviation (RMSD). The structure, a 19-stranded β-barrel, with an N-terminal α-helix in the pore is in agreement with previous data in detergent, which was questioned due to the potential for the detergent to perturb the protein's functional structure. Using a quintuple mutant implementing the channel's closed state, we found that dynamics are a key element in the protein's gating behavior, as channel closure leads to the destabilization of not only the C-terminal barrel residues but also the α2 helix. We showed that cholesterol, previously shown to reduce the frequency of channel closure, stabilizes the barrel relative to the N-terminal helix. Furthermore, we observed channel closure through steric blockage by a drug shown to selectively bind to the channel, the Bcl2-antisense oligonucleotide G3139.
Topics: Binding Sites; Cholesterol; Humans; Ion Channel Gating; Ligands; Lipid Bilayers; Mutation; Nuclear Magnetic Resonance, Biomolecular; Protein Binding; Thionucleotides; Voltage-Dependent Anion Channel 1
PubMed: 35164499
DOI: 10.1021/jacs.1c09848