- |||||||||| chloroquine phosphate / Generic mfg.
Journal: Combined Cytotoxic Effect of Inhibitors of Proteostasis on Human Colon Cancer Cells. (Pubmed Central) - Jul 28, 2022 We tested the autophagy inhibitor, chloroquine, in combination with CL-43. Our results indicate that the use of an inhibitor of HSF1 activity in combination with an autophagy inhibitor results in effective cancer cell death, therefore, this therapeutic approach may be a promising treatment regimen for certain patients.
- |||||||||| Journal: TFAM downregulation promotes autophagy and ESCC survival through mtDNA stress-mediated STING pathway. (Pubmed Central) - Jul 28, 2022
In addition, autophagy inhibitor also ameliorates mitochondrial dysfunction-induced activation of the cGAS-STING signaling pathway and ESCC growth. In conclusion, our results indicate that mtDNA stress induced by mitochondria biogenesis perturbation activates the cGAS-STING pathway and autophagy to promote ESCC growth, revealing an underappreciated therapeutic strategy for ESCC.
- |||||||||| chloroquine phosphate / Generic mfg.
Journal: Plakophilin3 loss leads to an increase in autophagy and radio-resistance. (Pubmed Central) - Jul 28, 2022 The increase in autophagy was required for radioresistance and ROS clearance as inhibiting autophagy using either chloroquine or knocking down ATG3 re-sensitized the PKP3 knockdown clones to radiotherapy. These experiments suggest that autophagy inhibitors could target therapy-resistant PKP3 deficient tumors.
- |||||||||| PX-478 / Seagen
Preclinical, Journal, IO biomarker: HIF-1α enhances autophagy to alleviate apoptosis in marginal cells in the stria vascular in neonatal rats under hypoxia. (Pubmed Central) - Jul 28, 2022 Treatment with PX478, a specific inhibitor of HIF-1α, decreased the HIF-1α level, and the degree of autophagy decreased in hypoxic and apoptotic MCs...Lastly, we silenced Bnip3(Bcl-2/adenovirus E1B 19-kDa interacting protein) in MCs to identify the mechanism of action. Our results show that the HIF-1α-BNIP3 pathway mediates the anti-apoptotic effects through an increase in autophagy.
- |||||||||| Preclinical, Journal: Ras-mutant cancers are sensitive to small molecule inhibition of V-type ATPases in mice. (Pubmed Central) - Jul 28, 2022
A comparison of isogenic SW48 xenografts with different KRAS mutations confirmed that KRASG13D/+ (followed by G12V/+) mutations are especially sensitive to 249C treatment. These data establish proof-of-concept for targeting V-ATPase in cancers driven by specific KRAS mutations such as KRASG13D and G12V.
- |||||||||| sirolimus / Generic mfg.
Journal: Autophagy alleviates indium-induced programmed cell death in wheat roots. (Pubmed Central) - Jul 27, 2022 Furthermore, reinforcing autophagy by activator rapamycin significantly decreased the number of TUNEL-positive nuclei and the activity of caspase-3-like protease, whereas inhibition of autophagy by 3-methyladenine aggravated diagnostic markers for PCD. These results together suggest that autophagy suppresses indium-induced PCD in wheat roots.
- |||||||||| Journal: Neutrophil extracellular traps promote thrombogenicity in cerebral venous sinus thrombosis. (Pubmed Central) - Jul 27, 2022
We demonstrated a previously unidentified mechanism by which SENP6-mediated ANXA1 de-SUMOylation regulates microglial polarization and our results strongly indicated that in microglia, inhibition of SENP6 may be a crucial beneficial therapeutic strategy for ischaemic stroke. NET generation was mediated by PF4 from PLTs through autophagy and contribute to thrombosis in CVST patients.
- |||||||||| Journal: Activated Endolysosomal Cation Channel TRPML1 Facilitates Maturation of α-Synuclein-Containing Autophagosomes. (Pubmed Central) - Jul 27, 2022
These findings suggest, that activating TRPML1 with ML-SA1 facilitates clearance of α-synuclein aggregates primarily by affecting the late steps of the autophagy, i.e., by promoting autophagosome maturation. In agreement with recent work by others, our findings indicate that TRPML1 might constitute a plausible therapeutic target for PD, that warrants further validation in rodent models of α-synuclein pathology.
- |||||||||| Review, Journal: The Roles of ATP13A2 Gene Mutations Leading to Abnormal Aggregation of α-Synuclein in Parkinson's Disease. (Pubmed Central) - Jul 27, 2022
In this article, we first summarize the types of mutations in the ATP13A2 gene and their effects on ATP13A2 mRNA and protein structure; then, we discuss lysosomal autophagy inhibition and the molecular mechanism of abnormal α-synuclein accumulation caused by decreased levels and dysfunction of the ATP13A2 protein in lysosomes. Finally, this article provides a new direction for future research on the pathogenesis and therapeutic targets for ATP13A2 gene-related PD from the perspective of ATP13A2 gene mutations and abnormal aggregation of α-synuclein.
- |||||||||| Review, Journal: Review: Protective Immunity and Immunopathology of Ehrlichiosis. (Pubmed Central) - Jul 26, 2022
The high level of HMGB1 in lethal ehrlichiosis suggests a role in toxic shock. Studies of primary bone marrow-derived macrophages infected by highly avirulent or mildly avirulent ehrlichiae reveal divergent M1 and M2 macrophage polarization that links with generation of pathogenic CD8 T cells, neutrophils, and excessive inflammation or with strong expansion of protective Th1 and NKT cells, resolution of inflammation and clearance of infection, respectively.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Scemblix (asciminib) / Novartis, Iclusig (ponatinib) / Takeda, Otsuka, Incyte
Beyond TKI Therapy in CML (Level 4, Grand Ballroom G-L) - Jul 26, 2022 - Abstract #SOHO2022SOHO_109; P2 Another trial has recruited accelerated- and BP-CML patients alongside BCR-ABL1-positive AML cases and is evaluating a combined regimen of ponatinib, venetoclax, and decitabine (NCT04188405)...Clinical utility may be derived by disturbing this bioenergetic niche: by interrupting antiapoptotic mechanisms; by inhibiting autophagy and mitophagy, to deleteriously enhance ROS production; or by reducing ROS directly to diminish mutagenesis. The aim is either to circumvent TKI insensitivity, or to abolish potential TKI resistance before it can arise.
- |||||||||| Iclusig (ponatinib) / Takeda, Otsuka, Incyte, Olysio (simeprevir) / J&J, Medivir, Tasigna (nilotinib) / Novartis, Inhibikase
FDA event, Journal: Repurposing of FDA-approved drugs as autophagy inhibitors in tumor cells. (Pubmed Central) - Jul 23, 2022 We anticipate from our computational results that these drugs may become potent candidates to inhibit autophagy and exhibit the apoptosis in the tumor microenvironment and combat the current limitation of potent autophagy inhibitors; however, to substantiate our in-silico results, further experimental validations of these drug molecules are currently in progress. Communicated by Ramaswamy H. Sarma.
- |||||||||| Journal: Bunyavirus SFTSV exploits autophagic flux for viral assembly and egress. (Pubmed Central) - Jul 23, 2022
Importantly, SFTSV utilized autophagy for the viral life cycle, which not only assembled in autophagosomes derived from the ERGIC and Golgi complex, but also utilized autophagic vesicles for exocytosis. Taken together, our results suggest a novel virus-autophagy interaction model in which bunyavirus SFTSV induces classical autophagy flux for viral assembly and egress processes, suggesting that autophagy inhibition may be a novel therapy for treating or releasing SFTS.
- |||||||||| Ninlaro (ixazomib) / Takeda
Journal: LAMP3 inhibits autophagy and contributes to cell death by lysosomal membrane permeabilization. (Pubmed Central) - Jul 23, 2022 LAMP3 expression resulted in degradation of LAMP1 increasing lysosomal membrane permeabilization and relocalization of cathepsins to the cytoplasm, resulting in destabilizing autophagic flux and caspase activation. These findings highlight the central role of LAMP3 expression in the pathogenesis of SS.
- |||||||||| hydroxychloroquine / Generic mfg., sirolimus / Generic mfg.
Journal, IO biomarker: The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males. (Pubmed Central) - Jul 23, 2022 An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways.Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor.
- |||||||||| chloroquine phosphate / Generic mfg.
Journal: Susceptibility to autophagy inhibition is enhanced by dual IGF1R and MAPK/ERK inhibition in pancreatic cancer. (Pubmed Central) - Jul 23, 2022 To identify targets that sensitize PDAC cells to autophagy inhibition, we performed a CRISPR-Cas9 genetic loss-of-function screen in cells treated with the lysosomal inhibitor chloroquine (CQ) and identified IGF1R as a sensitizer...IGF1R and MAPK/ERK inhibition converge on suppression of glycolysis. In summary, IGF1R and MAPK/ERK signaling promotes resistance to CQ/HCQ in PDAC, and their dual inhibition increases sensitivity to autophagy inhibitors.
- |||||||||| Review, Journal: Autophagy in lupus nephritis: A delicate balance between regulation and disease. (Pubmed Central) - Jul 23, 2022
In addition, the extent and timing of autophagy inhibition still require additional studies before clinical translation may be attempted. In this review, we will also discuss the effect of several clinically available drugs that can regulate the autophagic flux and their effect in lupus nephritis patients.
- |||||||||| Journal: Direct cleavage of caspase-8 by herpes simplex virus 1 tegument protein US11. (Pubmed Central) - Jul 23, 2022
Additional, in an in vitro model, we demonstrated that Us11-recombinant protein induces caspase-8-p18 cleavage by physically interacting with the caspase-8 recombinant protein. Finally, we found that, during HSV-1 replication, activated-caspase-8 cleaves Atg3 protein to potentially block autophagy and support its replication.
- |||||||||| SB-705498 / GSK
DOPAMINE REGULATES AUTOPHAGY DURING TGF-Β1-INDUCED ACTIVATION OF HEPATIC STELLATE CELLS (Science Lounge) - Jul 20, 2022 - Abstract #UEGW2022UEGW_1982; Dopamine may act as a protective factor in the process of liver fibrosis. Dopamine may activate TRPV1 calcium channel on cell membrane to mediate extracellular calcium influx, leading to intracellular calcium remodeling, and then inhibit the autophagy and activation of HSCs mediated by TGF-β1/Smad3 signaling pathway, and finally play an anti-fibrosis role.
- |||||||||| doxorubicin hydrochloride / Generic mfg.
Journal, Gene Signature: An Autophagy-Related Gene Signature can Better Predict Prognosis and Resistance in Diffuse Large B-Cell Lymphoma. (Pubmed Central) - Jul 20, 2022 The results of ESTIMATE, ssGSEA, and mRNAsi showed that the high-risk group exhibited lower immune cell infiltration and immune activation responses and had higher similarity to cancer stem cells. We proposed a novel and reliable autophagy-related gene signature that was capable of predicting the survival and resistance of patients with DLBCL and could guide individualized treatment in future.
- |||||||||| Review, Journal, Cancer stem cells: Targeting Autophagy in Thyroid Cancer: EMT, Apoptosis, and Cancer Stem Cells. (Pubmed Central) - Jul 20, 2022
Autophagy modulation has become an attractive target for improving outcomes in thyroid cancer. This review aims to provide a comprehensive picture of the current knowledge regarding the role of autophagy in thyroid cancer, focusing on the potential mechanism(s) through which inhibition of autophagy may enhance cancer therapy and outcomes.
- |||||||||| thioguanine / Generic mfg.
Journal: Evaluation of Pharmaceuticals for DNA Damage in the Chicken Egg Genotoxicity Assay (CEGA). (Pubmed Central) - Jul 20, 2022 No DNA damage was detected for 7 compounds, including the purine antagonist 6-thioguanine, antipyretic analgesics acetaminophen and phenacetin, antibiotic ciprofloxacin, antilipidemic clofibrate, anti-inflammatory ibuprofen, and sedative phenobarbital...Overall, results in CEGA were largely in concordance with the outcomes in other systems in vitro and in vivo, indicating that CEGA provides reliable detection of DNA damaging activity of genotoxic compounds. Further evaluations with a broader set of compounds would support this conclusion.
|