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Journal of Nanobiotechnology May 2022By hindering energy supply pathway for cancer cells, an alternative therapeutic strategy modality is put forward: tumor starvation therapy. And yet only in this blockade...
Boosting nutrient starvation-dominated cancer therapy through curcumin-augmented mitochondrial Ca overload and obatoclax-mediated autophagy inhibition as supported by a novel nano-modulator GO-Alg@CaP/CO.
BACKGROUND
By hindering energy supply pathway for cancer cells, an alternative therapeutic strategy modality is put forward: tumor starvation therapy. And yet only in this blockade of glucose supply which is far from enough to result in sheer apoptosis of cancer cells.
RESULTS
In an effort to boost nutrient starvation-dominated cancer therapy, here a novel mitochondrial Ca modulator Alg@CaP were tailor-made for the immobilization of Glucose oxidase for depriving the intra-tumoral glucose, followed by the loading of Curcumin to augment mitochondrial Ca overload to maximize the therapeutic efficiency of cancer starvation therapy via mitochondrial dysfunctions. Also, autophagy inhibitors Obatoclax were synchronously incorporated in this nano-modulator to highlight autophagy inhibition.
CONCLUSION
Here, a promising complementary modality for the trebling additive efficacy of starvation therapy was described for cutting off the existing energy sources in starvation therapy through Curcumin-augmented mitochondrial Ca overload and Obatoclax-mediated autophagy inhibition.
Topics: Apoptosis; Autophagy; Cell Line, Tumor; Curcumin; Glucose; Humans; Indoles; Neoplasms; Nutrients; Pyrroles; Starvation
PubMed: 35551609
DOI: 10.1186/s12951-022-01439-0 -
Molecular Pharmacology Dec 2012Previous studies showed that lapatinib and obatoclax interact in a greater-than-additive fashion to cause cell death and do so through a toxic form of autophagy. The...
Previous studies showed that lapatinib and obatoclax interact in a greater-than-additive fashion to cause cell death and do so through a toxic form of autophagy. The present studies sought to extend our analyses. Lapatinib and obatoclax killed multiple tumor cell types, and cells lacking phosphatase and tensin homolog (PTEN) function were relatively resistant to drug combination lethality; expression of PTEN in PTEN-null breast cancer cells restored drug sensitivity. Coadministration of lapatinib with obatoclax elicited autophagic cell death that was attributable to the actions of mitochondrial reactive oxygen species. Wild-type cells but not mitochondria-deficient rho-zero cells were radiosensitized by lapatinib and obatoclax treatment. Activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH(2)-terminal kinase 1/2 (JNK1/2) by the drug combination was enhanced by radiation, and signaling by p38 MAPK and JNK1/2 promoted cell killing. In immunohistochemical analyses, the autophagosome protein p62 was determined to be associated with protein kinase-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1, as well as with binding immunoglobulin protein/78-kDa glucose-regulated protein, in drug combination-treated cells. Knockdown of PERK suppressed drug-induced autophagy and protected tumor cells from the drug combination. Knockdown of PERK suppressed the reduction in Mcl-1 expression after drug combination exposure, and overexpression of Mcl-1 protected cells. Our data indicate that mitochondrial function plays an essential role in cell killing by lapatinib and obatoclax, as well as radiosensitization by this drug combination.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Autophagy; Breast Neoplasms; Cell Line, Tumor; Endoplasmic Reticulum Stress; Female; HSP70 Heat-Shock Proteins; Humans; Indoles; Lapatinib; Membrane Proteins; Mice; Mice, Nude; Mitochondria; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinase 9; Pyrroles; Quinazolines; Reactive Oxygen Species; eIF-2 Kinase; p38 Mitogen-Activated Protein Kinases
PubMed: 22989520
DOI: 10.1124/mol.112.081539 -
Journal of Clinical Oncology : Official... Sep 2012The B-cell lymphoma/leukemia 2 (BCL-2) family of proteins has attracted the attention of cancer biologists since the cloning of BCL-2 more than 25 years ago. In the... (Review)
Review
The B-cell lymphoma/leukemia 2 (BCL-2) family of proteins has attracted the attention of cancer biologists since the cloning of BCL-2 more than 25 years ago. In the intervening decades, the way the BCL-2 family controls commitment to programmed cell death has been greatly elucidated. Several drugs directed at inhibiting BCL-2 and related antiapoptotic proteins have been tested clinically, with some showing considerable promise, particularly in lymphoid malignancies. A better understanding of the BCL-2 family has also provided insight into how conventional chemotherapy selectively kills cancer cells and why some cancers are more chemosensitive than others. Further exploitation of our understanding of the BCL-2 family promises to offer improved predictive biomarkers for oncologists and improved therapies for patients with cancer.
Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Drug Resistance, Neoplasm; Humans; Indoles; Molecular Targeted Therapy; Neoplasms; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides; Thionucleotides; Treatment Outcome
PubMed: 22649144
DOI: 10.1200/JCO.2011.37.0981 -
Current Opinion in Hematology Jul 2009To review new agents under investigation for the treatment of patients with peripheral T-cell lymphoma. (Review)
Review
PURPOSE OF REVIEW
To review new agents under investigation for the treatment of patients with peripheral T-cell lymphoma.
RECENT FINDINGS
New agents being evaluated in these patients include histone deacetylase inhibitors (e.g. romidepsin, vorinostat, and balinostat), purine analogs and agents that interfere with the purine metabolic pathway (e.g. forodesine), immunomodulatory agents, proapoptotic small molecules (e.g. oblimersen, obatoclax, and gossypol), antifols (e.g. pralatrexate), proteasome inhibitors (e.g. bortezomib), monoclonal antibodies against T-cell antigens (e.g. CD30 and CD52), and immunotoxins (e.g. denileukin diftitox).
SUMMARY
The development of rational combinations of such agents in clinical trials will be required to improve the outcome of these patients.
Topics: Antineoplastic Agents; Bendamustine Hydrochloride; Boronic Acids; Bortezomib; Cladribine; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Humans; Lymphoma, T-Cell, Peripheral; Nitrogen Mustard Compounds; Pyrazines; Vidarabine
PubMed: 19367159
DOI: 10.1097/MOH.0b013e32832ad69a -
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... Sep 2017Autophagy is an essential catabolic program that forms part of the stress response and enables cells to break down their own intracellular components within lysosomes... (Review)
Review
Autophagy is an essential catabolic program that forms part of the stress response and enables cells to break down their own intracellular components within lysosomes for recycling. Accumulating evidence suggests that autophagy plays vital roles in determining pathological outcomes of immune responses and tumorigenesis. Autophagy regulates innate and adaptive immunity affecting the pathologies of infectious, inflammatory, and autoimmune diseases. In cancer, autophagy appears to play distinct roles depending on the context of the malignancy by either promoting or suppressing key determinants of cancer cell survival. This review covers recent developments in the understanding of autophagy and discusses potential therapeutic interventions that may alter the outcomes of certain diseases.
Topics: Adaptive Immunity; Animals; Autoimmune Diseases; Autophagy; Benzylisoquinolines; Cholecalciferol; Humans; Immune System Diseases; Immunity, Innate; Indoles; Infections; Isoquinolines; Lysosomes; Maprotiline; Metformin; Neoplasms; Phenols; Pyrroles; Resveratrol; Sirolimus; Spermidine; Stilbenes; Tetrahydroisoquinolines; Trehalose
PubMed: 28895911
DOI: 10.3390/ijms18091959 -
Neoplasia (New York, N.Y.) Apr 2011Small cell lung cancer (SCLC) is an aggressive disease in which, after initial sensitivity to platinum/etoposide chemotherapy, patients frequently relapse with...
Small cell lung cancer (SCLC) is an aggressive disease in which, after initial sensitivity to platinum/etoposide chemotherapy, patients frequently relapse with drug-resistant disease. Deregulation of the Bcl-2 pathway is implicated in the pathogenesis of SCLC, and early phase studies of Bcl-2 inhibitors have been initiated in SCLC. Obatoclax is a small-molecule drug designed to target the antiapoptotic Bcl-2 family members to a proapoptotic effect. Preclinical studies were conducted to clarify the kinetics of obatoclax-induced apoptosis in a panel of SCLC cell lines to assist with the interpretation of biomarker data generated during early phase clinical trials. In vitro, obatoclax was synergistic with cisplatin and etoposide, and "priming" cells with obatoclax before the cytotoxics maximized tumor cell death. Peak levels of apoptosis, reflected by cleaved cytokeratin 18 (CK18) levels (M30 ELISA) and caspase activity (SR-DEVD-FMK), occurred 24 hours after obatoclax treatment. A phase 1b-2 trial of obatoclax administered using two infusion regimens in combination with carboplatin and etoposide has been completed in previously untreated patients with extensive-stage SCLC. Circulating pharmacodynamic biomarkers of cell death, full-length and/or cleaved CK18, and oligonucleosomal DNA were studied in the phase 1b trial. All SCLC patients classified as "responders" after two cycles of treatment showed significantly increased levels of full-length and cleaved CK18 (M65 ELISA) on day 3 of study. However, the preclinical data and the absence of a peak in circulating caspase-cleaved CK18 in trial patients suggest suboptimal timing of blood sampling, which will need refinement in future trials incorporating obatoclax.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Blood Chemical Analysis; Calibration; Cell Death; Cell Line, Tumor; Cell Proliferation; Cisplatin; Clinical Trials, Phase I as Topic; Drug Synergism; Etoposide; Humans; Indoles; Lung Neoplasms; Prognosis; Pyrroles; Small Cell Lung Carcinoma
PubMed: 21472138
DOI: 10.1593/neo.101524 -
Chemistry (Weinheim An Der Bergstrasse,... Dec 2011Synthetic prodiginine obatoclax shows promise as a potential anticancer drug. This compound promotes apoptosis of cancer cells, although the mechanism of action is...
Synthetic prodiginine obatoclax shows promise as a potential anticancer drug. This compound promotes apoptosis of cancer cells, although the mechanism of action is unclear. To date, only the inhibition of BCL-2 proteins has been proposed as a mechanism of action. To gain insight into other possible modes of action, we have studied the anion-binding properties of obatoclax and related analogues in solution, in the solid state, and by means of density functional theory calculations. These compounds are well suited to interact with anions such as chloride and bicarbonate. The anion-transport properties of the compounds synthesized were assayed in model phospholipid liposomes by using a chloride-selective-electrode technique and (13)C NMR spectroscopy. The results demonstrated that these compounds are efficient anion exchangers that promote chloride, bicarbonate, and nitrate transport through lipid bilayers at very low concentrations. In vitro studies on small-cell lung carcinoma cell line GLC4 showed that active ionophores are able to discharge pH gradients in living cells and the cytotoxicity of these compounds correlates well with ionophoric activity.
Topics: Animals; Anions; Antineoplastic Agents; Apoptosis; Biological Transport; Cattle; Cell Line, Tumor; Crystallography, X-Ray; Humans; Indoles; Ion Transport; Ionophores; Liposomes; Lung Neoplasms; Magnetic Resonance Spectroscopy; Prodigiosin; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Tumor Cells, Cultured
PubMed: 22069220
DOI: 10.1002/chem.201101547 -
Physical Chemistry Chemical Physics :... Oct 2015Prodiginine molecules (prodigiosin and obatoclax) are well-known pH-chromic dyes with promising anti-tumor properties. They present multiple tautomeric and rotameric...
Prodiginine molecules (prodigiosin and obatoclax) are well-known pH-chromic dyes with promising anti-tumor properties. They present multiple tautomeric and rotameric forms. The protonation state and the structure of such flexible ligands in interaction with a protein are crucial to understand and to model the protein's biological activities. The determination of the protonation state via UV/vis absorption is possible if the ligand spectra of the neutral and protonated states are sufficiently different, and also if we can eliminate other factors potentially impacting the spectrum. Upon measuring the absorption spectra of the ligand in solution, varying solvents and pH values, we have determined that the optical properties of prodigiosin and obatoclax depend on the protonation state and not on the solvent permittivity constant. In parallel, action spectroscopy (using tunable lasers coupled to ion traps) in the gas phase of protonated and sodiated prodigiosin and obatoclax molecules has been performed to evaluate the sensitivity of the charge and the conformational state to their optical properties free of solvent. The spectra are interpreted using computational simulations of molecular structures and electronic excitations. The excitation energies are only slightly sensitive to various isomerizations, and may be used to distinguish between protonated and deprotonated states, even in the presence of a sodium counter-ion.
Topics: Antineoplastic Agents; Indoles; Isomerism; Mass Spectrometry; Models, Molecular; Molecular Conformation; Prodigiosin; Protons; Pyrroles; Sodium; Spectrophotometry, Ultraviolet
PubMed: 26120608
DOI: 10.1039/c5cp01498k -
Cell Death and Differentiation Sep 2013Obatoclax (GX15-070), a small-molecule inhibitor of antiapoptotic Bcl-2 proteins, has been reported to trigger cell death via autophagy. However, the underlying...
Obatoclax (GX15-070), a small-molecule inhibitor of antiapoptotic Bcl-2 proteins, has been reported to trigger cell death via autophagy. However, the underlying molecular mechanisms have remained elusive. Here, we identify GX15-070-stimulated assembly of the necrosome on autophagosomal membranes as a key event that connects GX15-070-stimulated autophagy to necroptosis. GX15-070 predominately induces a non-apoptotic form of cell death in rhabdomyosarcoma cells, as evident by lack of typical apoptotic features such as DNA fragmentation or caspase activation and by insensitivity to the broad-range caspase inhibitor zVAD.fmk. Instead, GX15-070 triggers massive accumulation of autophagosomes, which are required for GX15-070-induced cell death, as blockade of autophagosome formation by silencing of Atg5 or Atg7 abolishes GX15-070-mediated cell death. Co-immunoprecipitation studies reveal that GX15-070 stimulates the interaction of Atg5, a constituent of autophagosomal membranes, with components of the necrosome such as FADD, RIP1 and RIP3. This GX15-070-induced assembly of the necrosome on autophagosomes occurs in a Atg5-dependent manner, as knockdown of Atg5 abrogates formation of this complex. RIP1 is necessary for GX15-070-induced cell death, as both genetic and pharmacological inhibition of RIP1 by shRNA-mediated knockdown or by the RIP1 inhibitor necrostatin-1 blocks GX15-070-induced cell death. Similarly, RIP3 knockdown rescues GX15-070-mediated cell death and suppression of clonogenic survival. Interestingly, RIP1 or RIP3 silencing has no effect on GX15-070-stimulated autophagosome formation, underlining that RIP1 and RIP3 mediate cell death downstream of autophagy induction. Of note, GX15-070 significantly suppresses tumor growth in a RIP1-dependent manner in the chorioallantoic membrane model in vivo. In conclusion, GX15-070 triggers necroptosis by promoting the assembly of the necrosome on autophagosomes. These findings provide novel insights into the molecular mechanisms of GX15-070-induced non-apoptotic cell death.
Topics: Autophagy; Autophagy-Related Protein 5; Autophagy-Related Protein 7; Cell Death; Cell Line; Fas-Associated Death Domain Protein; GTPase-Activating Proteins; HEK293 Cells; Humans; Imidazoles; Indoles; Microtubule-Associated Proteins; Necrosis; Phagosomes; Pyrroles; RNA Interference; RNA, Small Interfering; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 23744296
DOI: 10.1038/cdd.2013.45