- |||||||||| Journal: Curcumin inhibits propofol-induced autophagy of MN9D cells via Akt/mTOR/p70S6K signaling pathway. (Pubmed Central) - Mar 13, 2024
Moreover, curcumin treatment upregulated the Akt/mTOR/p70S6K signaling pathway, suggesting that curcumin potentially curtails autophagy dysregulation in nerve cells by activating Akt/mTOR/p70S6K. In conclusion, our findings suggest that curcumin can ameliorate propofol abuse-induced neurotoxicity, partially through autophagy regulation and Akt/mTOR/p70S6K signaling activation.
- |||||||||| Journal: Bif?1 inhibits activation of inflammasome through autophagy regulatory mechanism. (Pubmed Central) - Mar 12, 2024
Additionally, inhibition of the nuclear factor??B (NF??B) signaling pathway downregulated Bif?1 and inhibited autophagy activity, highlighting the importance of NF??B in the regulation of Bif?1 and autophagy. In summary, the current study revealed that Bif?1 is a critical anti?inflammatory factor against inflammasome activation mediated by a mechanism of autophagy regulation, indicating its potential as a therapeutic target for inflammatory regulation.
- |||||||||| Journal: TMEM16A inhibits autophagy and promotes the invasion of hypopharyngeal squamous cell carcinoma through mTOR pathway. (Pubmed Central) - Mar 12, 2024
Subsequent investigations indicated that knockdown of TMEM16A in HSCC cells could suppress mTOR activation, thereby triggering autophagic cell death by upregulating sequestosome-1 (SQSTM1/P62) and microtubule-associated protein light chain 3 II (LC3II). This study highlights the crucial role of TMEM16A in modulating autophagy in HSCC, suggesting its potential as a therapeutic target for the treatment of this malignancy.
- |||||||||| paclitaxel / Generic mfg., doxorubicin hydrochloride / Generic mfg., docetaxel / Generic mfg.
Journal, IO biomarker: Inhibiting autophagy enhanced mitotic catastrophe-mediated anticancer immune responses by regulating the cGAS-STING pathway. (Pubmed Central) - Mar 12, 2024
Interestingly, the expression of p-TBK1 first increased and then declined; however, autophagy inhibition reversed the decrease in p-TBK1 expression and enhanced mitotic catastrophe-mediated anticancer immune effects. Collectively, the inhibition of autophagy can potentiate mitotic catastrophe-mediated anticancer immune effects by regulating the cGAS-STING pathway, which explains why the anticancer immune effects induced by chemotherapeutics have not fully exerted their therapeutic efficacy in some patients and opens a new area of research in cancer immunotherapy.
- |||||||||| Journal: SRT1720 inhibits bladder cancer cell progression by impairing autophagic flux. (Pubmed Central) - Mar 9, 2024
LAMP2, an important lysosomal associated membrane protein, may mediate SRT1720-inhibited autophagy flux as SRT1720 treatment significantly deacetylated LAMP2 which may influence its activity. Taken together, our results demonstrated that SRT1720 mediated apoptosis and autophagy flux inhibition may be a novel therapeutic strategy for bladder cancer treatment.
- |||||||||| Discovering and Rescuing Toxic Autophagy Derangements in CMT4B3 Using a Novel iPSC-derived Peripheral Nervous System Model of MTMR5 Biology (Colorado Convention Center | Four Seasons 1) - Mar 8, 2024 - Abstract #AAN2024AAN_2388;
Taken together, our results demonstrated that SRT1720 mediated apoptosis and autophagy flux inhibition may be a novel therapeutic strategy for bladder cancer treatment. Our results confirm the biologic fidelity of our novel human PNS cellular system for modeling CMT4B3, and the foundational insights provided by our experimental platform will be invaluable for ongoing mechanistic investigations of MTMR5-related pathophysiology and discovering therapies for CMT4B3 and neurological disorders marked by dysregulated autophagy.
- |||||||||| bleomycin / Generic mfg.
Journal: Astragaloside IV inhibits idiopathic pulmonary fibrosis through activation of autophagy by miR-21-mediated PTEN/PI3K/AKT/mTOR pathway. (Pubmed Central) - Mar 6, 2024
Bleomycin (BLM) or TGF-?1 was treated in mice or alveolar epithelial cells to mimic IPF in vivo as well as in vitro...In addition, levels of inflammatory cytokines and fibrosis markers, autophagy, as well as the PI3K/AKT/mTOR pathway regulated by ASV-IV could be neutralized after treatment with autophagy inhibitors, miR-21 mimics, or si-PTEN. Our study demonstrates that ASV-IV inhibits IPF through activation of autophagy by miR-21-mediated PTEN/PI3K/AKT/mTOR pathway, suggesting that ASV-IV could be acted to be a promising therapeutic method for IPF.
- |||||||||| Targeting the lipid kinase PIKfyve upregulates surface expression of MHC class I to augment cancer immunotherapy (Section 40) - Mar 5, 2024 - Abstract #AACR2024AACR_9174;
Further, high PIKfyve expression predicts poor ICB response and is prognostic of poor survival in ICB-treated cohorts. Ultimately, these findings collectively suggest PIKfyve as an effective target to enhance immunotherapies through elevation of MHC-I surface expression in cancer cells, and accordingly, PIKfyve inhibitors have novel potential to increase immunotherapy response in cancer patients.
- |||||||||| voxtalisib (SAR245409) / Sanofi
A genome wide CRISPR-Cas9 screen identifies mediators of resistance to dual PI3K/mTOR inhibition in glioblastoma multiforme (Section 23) - Mar 5, 2024 - Abstract #AACR2024AACR_8085;
The current standard of care, consisting of surgery, radiation, and temozolomide (TMZ), has remained unchanged for over the past 15 years despite its limited efficacy and the serious therapy-related adverse events associated to this regimen...To elucidate mechanisms of resistance to PI3K inhibition in GBM, we used a genome-wide functional CRISPR-Cas9 knockout screen to identify genes that mediate resistance to the dual PI3K/mTOR inhibitor XL765 in PTEN-null SF295 GBM cells...Using orthogonal approaches, we will functionally validate our candidate hits through mechanistic studies, with patient-derived models, and with in vivo orthotopic xenografts. Our findings will elucidate novel mechanisms of resistance to PI3K/mTOR inhibition in GBM and will streamline rational drug combinations aimed to overcome resistance, thus eventually maximizing therapeutic responses to PI3K inhibitors in GBM.
- |||||||||| Lenvima (lenvatinib) / Eisai, Merck (MSD)
TESC mediates resistance to lenvatinib in hepatocellular carcinoma by regulating cell autophagy (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_8051;
Our findings will elucidate novel mechanisms of resistance to PI3K/mTOR inhibition in GBM and will streamline rational drug combinations aimed to overcome resistance, thus eventually maximizing therapeutic responses to PI3K inhibitors in GBM. TESC expression levels are associated with the sensitivity of liver cancer cells to lenvatinib, possibly by inhibiting autophagy and affecting the sensitivity of liver cancer cells to lenvatinib.
- |||||||||| ESK981 / Esanik Therap
Deletion of the lipid kinase PIKfyve in Kras-driven pancreatic genetically engineered mouse model (Section 14) - Mar 5, 2024 - Abstract #AACR2024AACR_7054;
We demonstrated that the deletion of PIKfyve in pancreatic tissue significantly reduces the pancreatic mass weight compared to the PIKfyve wildtype counterpart and is coupled with less pancreatic intraepithelial neoplasia (PanIN) and PDAC development in KPC and KC mice. Compared to the vehicle treatment, pharmacological inhibition of PIKfyve by ESK981 on KPC mice resulted in a significant increase in the percentage of normal pancreatic tissue and reduced pancreatic lesion development.
- |||||||||| Lumakras (sotorasib) / Amgen, DCC-3116 / Deciphera
Inhibition of ULK and KRASG12C control tumor growth in preclinical models of lung cancer (Section 14) - Mar 5, 2024 - Abstract #AACR2024AACR_7053;
Consequently, we have generated genetically engineered mouse models (GEMMs) of KRASG12C-driven lung cancer in which LKB1 is silenced to further investigate the role of LKB1 in the autophagy response of KRASG12C-driven lung cancers to pathway-targeted blockade of oncogenic KRAS signaling. We have treated KRASG12C-driven GEMMs with sotorasib and/or DCC-3116 to test the sensitivity of lung tumors to these treatment options.
- |||||||||| Interrogation of autophagy inhibition in anaplastic large cell lymphoma (ALCL) (Section 14) - Mar 5, 2024 - Abstract #AACR2024AACR_7051;
With the addition of crizotinib or brentuximab vedotin to the ALCL99 chemotherapy backbone, the recently reported Children's Oncology Group ANHL12P1 study demonstrated a 2-year event-free survival for ALCL patients of 79%...Target engagement of autophagy inhibition (ULK-101 directed against ULK1/2 and hydroxychloroquine (HCQ) targeting the lysosome) was assessed by western blot using phospho-ATG14S29 and LC3B-II intensity in 6-point dose response curves...Decreased viability in Karpas 299 cells was observed after crizotinib, ceritinib and lorlatinib treatments with nanomolar potency...ALK inhibition activates autophagy in ALCL cells and autophagy activation is effectively mitigated through concurrent autophagy inhibition. ALK inhibitor resistance in Karpas 299 cells will be further evaluated to determine whether autophagy contributes to the resistant phenotype.
- |||||||||| NXP800 / Nuvectis Pharma
HSF1 inhibition induces pancreatic ductal adenocarcinoma autophagy through JNK (Section 14) - Mar 5, 2024 - Abstract #AACR2024AACR_7050;
Objective: The objective of this study is to investigate the molecular mechanism of HSF1 inhibition in PDAC autophagy.Methods and In human PDAC cells, Western blotting analysis revealed that HSF1 inhibition via small molecular including CCT361814/NXP800, an HSF1 inhibitor in phase I clinical trials, increased autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3) lipidation and decreased expression of phosphorylation of HSF1 at Ser326 and total HSF1 protein, conversely using HSF1 overexpression model reversed this effect... In conclusion, JNK1/2 is involved in HSF1 inhibition-induced PDAC autophagy, targeting autophagy could unveil a novel treatment strategy for pancreatic cancer through targeted HSF1 inhibition.
- |||||||||| The role of autophagy in triple negative breast cancer (Section 14) - Mar 5, 2024 - Abstract #AACR2024AACR_7048;
Finally, Imaging studies and expression analysis on protein level have documented the apoptotic effects rendered by autophagy inhibition.Research endeavours continue to unravel the intricate landscape of TNBC, seeking novel avenues for targeted treatments, immunotherapies, and personalized medicine, aiming to transform the paradigm of care for those affected by this enigmatic form of breast cancer. As evident from the results, our combination has also managed to reduce the cells migration effectively which reflects that it can be initiated with aggressive metastatic tumours like TNBC.
- |||||||||| Investigation the role of DDI2 in autophagy (Section 14) - Mar 5, 2024 - Abstract #AACR2024AACR_7047;
We demonstrated that upon depletion of ubiquitin shuttle factor DDI2, secretory protein CCN1 accumulates leading to the subsequent induction of autophagy. These findings improve our understanding of the molecular basis governing DDI2's role in crosstalk between protein degradation pathways.
- |||||||||| Rapid photoinhibition of the autophagy pathway (Section 53) - Mar 5, 2024 - Abstract #AACR2024AACR_4763;
These findings suggest that combining MADD deletion with inhibitors of PI3K/Akt/mTOR pathway could provide an attractive new therapeutic option for ATC. Abstract is embargoed at this time.
- |||||||||| Off-target autophagy inhibition by SHP2 allosteric inhibitors and therapeutic implications for aberrant RAS-driven cancers (Section 25) - Mar 5, 2024 - Abstract #AACR2024AACR_4128;
We also demonstrated that SHP2 allosteric inhibitors harboring this off-target activity not only suppress oncogenic RAS signaling but also overcome drug resistance such as MAPK rebound and protective autophagy in response to RAS-MAPK pathway blockage. Finally, we exemplified a new therapeutic framework that harnesses both the on- and off-target activities of SHP2 allosteric inhibitors for improved treatment of mutant RAS driven and drug resistant malignancies such as pancreatic and colorectal cancers.
- |||||||||| SBI-756 - TGen, National Cancer Institute - Bethesda, Sanford / Burnham Medical Research Institute
Targeting the translation initiation complex component eIF4G1 in melanoma (Section 29) - Mar 5, 2024 - Abstract #AACR2024AACR_4089;
Leveraging our findings with the small molecule SBI-756, which interacts with eIF4G1 and impairs eIF4F complex assembly, we set to map domains that are required for SBI-756 activity...Among those, autophagy inhibitors synergized with our lead compound, M19-6, resulting in efficient melanoma cell death, using notably lower concentrations of these inhibitors. Our findings identify the eIF4G1 MA3 domain as an important player in eIF4F assembly and a potential target for cancer therapy.
- |||||||||| Journal: Assessment of Autophagy in Leishmania Parasites. (Pubmed Central) - Mar 5, 2024
Flow cytometry enabled us to identify the amount of acridine orange dye accumulating in the acidic vacuolar compartments in Leishmania major by detecting fluorescence in the red laser when autophagic inhibitors or enhancers were included. These methods will advance studies that aim to understand autophagic regulation in Leishmania parasites that could provide insights into developing improved therapeutic targets against leishmaniasis.
- |||||||||| metformin / Generic mfg.
Journal, Combination therapy: (-)-Epicatechin and colonic metabolite 2,3-dihydroxybenzoic acid, alone or in combination with metformin, protect cardiomyocytes from high glucose/high palmitic acid-induced damage by regulating redox status, apoptosis and autophagy. (Pubmed Central) - Mar 5, 2024
JNK inhibition improved protective changes to redox status, apoptosis and autophagy that were observed in EC-, DHBA- and MIX-mediated protection. Despite no additive or synergistic effects being detected when phenolic compounds and MET were combined, these results provide the first evidence for the benefits of EC and DHBA, comparable to those of MET alone, to ameliorate cardiomyocyte damage, that involve an improvement in antioxidant competence, autophagy and apoptosis, these effects being mediated at least by targeting JNK.
- |||||||||| Journal: Celastrus orbiculatus extract reverses precancerous lesions of gastric cancer by inhibiting autophagy via regulating the PDCD4-ATG5 signaling pathway. (Pubmed Central) - Mar 5, 2024
Despite no additive or synergistic effects being detected when phenolic compounds and MET were combined, these results provide the first evidence for the benefits of EC and DHBA, comparable to those of MET alone, to ameliorate cardiomyocyte damage, that involve an improvement in antioxidant competence, autophagy and apoptosis, these effects being mediated at least by targeting JNK. The study revealed that COE could regulate the PDCD4-ATG5 signaling pathway to inhibit autophagy in gastric epithelial cells, which contributes to reversing the progression of PLGC.
- |||||||||| Preclinical, Journal: Adipose mesenchymal stem cell-derived exosomes promote skin wound healing in diabetic mice by regulating epidermal autophagy. (Pubmed Central) - Mar 4, 2024
Finally, sequencing results showed that increased expression of autophagy-related genes nicotinamide phosphoribosyltransferase (NAMPT), CD46, vesicle-associated membrane protein 7 (VAMP7), VAMP3 and eukaryotic translation initiation factor 2 subunit alpha (EIF2S1) may contribute to the underlying mechanism of ADSC-Exo action. This study elucidated the molecular mechanism through which ADCS-Exos regulate autophagy in skin epithelial cells, thereby providing a new theoretical basis for the treatment and repair of skin epithelial damage by ADSC-Exos.
- |||||||||| Journal: Protective autophagy enhances antistress ability through AMPK/ULK1 signaling pathway in human immortalized keratinocytes. (Pubmed Central) - Mar 4, 2024
Finally, we simulated external environmental damage using ultraviolet B (UVB) at a dose of 60?mJ/cm2 and observed that low-dose ALA-PDT mitigated UVB-induced cell apoptosis; however, this protective effect was reversed when using the autophagy inhibitor 3-methyladenine. Overall, these findings highlight how low-dose ALA-PDT enhances antistress ability in HaCaT cells through controlling ROS generation and activating the AMPK/ULK1 pathway to arouse cellular autophagy.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Autophagy sustains mitochondrial respiration and determines resistance to BRAFV600E inhibition in thyroid carcinoma cells. (Pubmed Central) - Mar 4, 2024
In agreement, downregulation of the glycolytic pathway results in enhanced mitochondrial respiration and vemurafenib resistance. Our work provides new insights into the role of autophagy in thyroid cancer metabolism and supports mitochondrial targeting in combination with vemurafenib to eliminate BRAFV600E-positive thyroid carcinoma cells.Abbreviations: AMP: adenosine monophosphate; ATC: anaplastic thyroid carcinoma; ATG: autophagy related; ATP: adenosine triphosphate; BRAF: B-Raf proto-oncogene, serine/threonine kinase; Cas9: CRISPR-associated protein; CREB: cAMP responsive element binding protein; CRISPR: clustered regularly interspaced short palindromic repeats; 2DG: 2-deoxyglucose; FA: fatty acid; FAO: fatty acid oxidation; FASN: fatty acid synthase; FCCP: trifluoromethoxy carbonyl cyanide phenylhydrazone; LAMP1: lysosomal associated membrane protein 1; LIPE/HSL: lipase E, hormone sensitive type; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation; PRKA/PKA: protein kinase cAMP-activated; PTC: papillary thyroid carcinoma; SREBF1/SREBP1: sterol regulatory element binding transcription factor 1.
- |||||||||| Journal: Lopinavir enhances anoikis by remodeling autophagy in a circRNA-dependent manner. (Pubmed Central) - Mar 4, 2024
Furthermore, we determined that the FDA-approved compound lopinavir efficiently enhanced anoikis and prevented metastasis by eliminating repression of ELAVL1 on circSPECC1. In summary, this study provides novel insights into ATG4B-mediated autophagy and introduces a viable clinical inhibitor of autophagy, which may be beneficial for the treatment of GC with metastasis.
- |||||||||| chloroquine phosphate / Generic mfg.
Journal, PD(L)-1 Biomarker, IO biomarker: CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in colorectal cancer. (Pubmed Central) - Mar 4, 2024
Inhibition of autophagy by ATG7 knockdown and chloroquine (CQ) further decreased cell viability induced by CDK12 inhibition...Thus, our study founded that CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in CRC. We revealed the roles of CDK12/FOXO3/ATG7 in regulating CRC progression, suggesting potential biomarkers and therapeutic target for CRC.
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