- |||||||||| Preclinical, Journal, IO biomarker: CdTe quantum dots trigger oxidative stress and endoplasmic reticulum stress-induced apoptosis and autophagy in rat schwann cell line RSC96. (Pubmed Central) - Nov 15, 2022
Moreover, autophagy-related proteins LC3II, Beclin1 and P62 all increased after CdTe QDs exposure, suggesting that CdTe QDs exposure both promoted autophagosome formation and inhibited autophagosome degradation, and that CdTe QDs affected the autophagic flow in RSC96 cells. In conclusion, CdTe QDs are able to cause apoptosis and autophagy in RSC96 cells through mitochondrial and endoplasmic reticulum stress pathways, and the possible neurotoxicity of CdTe QDs should be further investigated.
- |||||||||| omipalisib (GSK2126458) / GSK
Journal: LncRNA RHPN1-AS1 inhibition induces autophagy and apoptosis in prostate cancer cells via the miR-7-5p/EGFR/PI3K/AKT/mTOR signaling pathway. (Pubmed Central) - Nov 15, 2022
Furthermore, overexpression of RHPN1-AS1 promoted phosphorylation of phosphatidylinositol 3-kinase (PI3K), AKT and mTOR, inhibited LC3-I to LC3-II conversion and reduced apoptosis in PCa cells, while GSK2126458 (an inhibitor of PI3K) reversed the effect of RHPN1-AS1 on PCa cells. In summary, RHPN1-AS1 acted as a ceRNA of miR-7-5p to upregulate EGFR expression, silencing RHPN1-AS1 suppressed PCa tumor progression by inducing autophagy and apoptosis in PCa cells through the miR-7-5p/EGFR/PI3K/AKT/mTOR pathway.
- |||||||||| hydroxychloroquine / Generic mfg.
Journal: Inducing Autophagy and Blocking Autophagic Flux via a Virus-Mimicking Nanodrug for Cancer Therapy. (Pubmed Central) - Nov 15, 2022
In this work, to exploit the lysosome escape and autophagy-inducing properties of JEV for cancer therapy, we constructed a virus-mimicking nanodrug consisting of anti-PDL1 antibody-decorated JEV-mimicking virosome encapsulated with a clinically available autophagy inhibitor, hydroxychloroquine (HCQ). Our study indicated that the nanodrug can upregulate the autophagy level and inhibit the autophagic flux, thereby inducing the apoptosis of tumor cells, and further activating the immune response, which can greatly improve the antitumor and tumor metastasis suppression effects and provide a potential therapeutic strategy for tumor treatment.
- |||||||||| FGFR3 gene mutation causes hypochondroplasia via autophagy inhibition (Rome, Italy) - Nov 13, 2022 - Abstract #ESPE2022ESPE_1368;
Our study indicated that the nanodrug can upregulate the autophagy level and inhibit the autophagic flux, thereby inducing the apoptosis of tumor cells, and further activating the immune response, which can greatly improve the antitumor and tumor metastasis suppression effects and provide a potential therapeutic strategy for tumor treatment. Our findings reveal that mutant activated FGFR3 inhibits the autophagic activity through activating ERK/p-ERK signaling pathway by increasing the HSPB6 expression level, which may play an essential role in the pathogenesis and treatment of HCH.
- |||||||||| Journal: Oxidative Stress Impairs Autophagy via Inhibition of Lysosomal Transport of VAMP8. (Pubmed Central) - Nov 12, 2022
Since we also observed decreased lysosomal localization of VAMP8 and inhibition of autophagosome-lysosome fusion in endocytosis inhibitor-treated cells, oxidative stress may inhibit VAMP8 trafficking by suppressing endocytosis and impair autophagy. Our findings suggest that oxidative stress-induced inhibition of VAMP8 trafficking to lysosomes is associated with the development of neurodegenerative diseases due to the blocked autophagosome-lysosome fusion, and may provide a new therapeutic target for restoring the autophagic activity.
- |||||||||| chloroquine phosphate / Generic mfg.
Preclinical, Journal: Increased autophagy leads to decreased apoptosis during β-thalassaemic mouse and patient erythropoiesis. (Pubmed Central) - Nov 12, 2022
We have demonstrated increased autophagy which led to minimal apoptosis in β-thalassaemic erythroblasts. However, increased PS exposure occurring through other mechanisms in thalassaemic erythroblasts might cause rapid phagocytic removal by macrophages and consequently ineffective erythropoiesis in β-thalassaemia.
- |||||||||| Journal: Crosstalk between autophagy and the Keap1-Nrf2-ARE pathway regulates realgar-induced neurotoxicity. (Pubmed Central) - Nov 9, 2022
In summary, our study provides the first evidence that UT antagonism may represent a novel therapeutic approach for the treatment of fasting-induced skeletal muscle atrophy. This study revealed that autophagy, the Nrf2 pathway, and apoptosis are involved in realgar-induced central nervous system toxicity and identified p62 as the hub of the LC3-p62-Keap1-Nrf2 axis in the regulation of autophagy, the Nrf2 pathway, and apoptosis.
- |||||||||| Cotellic (cobimetinib) / Exelixis, Roche, Tecentriq (atezolizumab) / Roche
Trial completion date, Trial primary completion date, Combination therapy, Checkpoint inhibition, Checkpoint block, Metastases: MEKiAUTO: Study of Combination Therapy With the MEK Inhibitor, Cobimetinib, Immune Checkpoint Blockade, Atezolizumab, and the AUTOphagy Inhibitor, Hydroxychloroquine in KRAS-mutated Advanced Malignancies (clinicaltrials.gov) - Nov 9, 2022
P1/2, N=175, Recruiting,
These data indicate that ROC-325 is a promising novel agent for the treatment of PH that inhibits autophagy, downregulates HIF levels, and increases nitric oxide production. Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Sep 2022 --> Sep 2023
- |||||||||| Journal: Investigation of chemoresistance to first-line chemotherapy and its possible association with autophagy in high-risk neuroblastoma. (Pubmed Central) - Nov 8, 2022
The sensitivity of tumor cells to chemotherapy agents and apoptosis rate were observed after inhibiting autophagy by transfection of shRNA or chloroquine (CQ)...The chemoresistance rates of patients treated with cyclophosphamide + adriamycin + vincristine (CAV) alternating with etoposide + cisplatin (EP) (Group 1) and CAV alternating with etoposide + ifosfamide + cisplatin (VIP) (Group 2) was 61.5% and 39.9% (P = 0.0009), respectively...Our results suggest that increasing the chemotherapy intensity can overcome resistance to NB. Inhibition of autophagy is beneficial to increase the sensitivity of NB to chemotherapy agents.
- |||||||||| Journal: PIN1 protects auditory hair cells from senescence via autophagy. (Pubmed Central) - Nov 8, 2022
On the contrary, inhibiting PIN1 could increase the autophagy level of senescent cells and cochlear hair cells. PIN1 might regulate autophagy activity to induce the senescent of HEI-OC1cells and HCs, which will provide a theoretical support for the prevention and treatment of age-related hearing loss.
- |||||||||| Journal: ASPP2 promotes cell apoptosis in cervical cancer through inhibiting autophagy. (Pubmed Central) - Nov 8, 2022
Taken together, the results of the present study have shown that ASPP2 exerted antitumor effect in cervical cancer by inhibiting cell proliferation and promoting apoptosis partly through inhibiting autophagy. These findings may be useful for the provision of potential targets for cervical cancer therapy.
- |||||||||| Journal: Beclin1- and Atg13-dependent autophagy activation and morroniside have synergistic effect on osteoblastogenesis. (Pubmed Central) - Nov 8, 2022
The promotional effect of morroniside on bone microarchitecture, bone mass, and bone parameters (including trabecular bone area and OCN expression in trabecular bone) in ovariectomized (OVX) mice was enhanced by TAT-Beclin1 administration. In conclusion, the autophagy-enhancing drugs related to Beclin1 or Atg13 may be an effective adjuvant therapy in the treatment of osteoporosis with morroniside.
- |||||||||| hydroxychloroquine / Generic mfg.
Journal: Enhanced Sensitivity of Tumor Cells to Autophagy Inhibitors Using Fasting-Mimicking Diet and Targeted Lysosomal Delivery Nanoplatform. (Pubmed Central) - Nov 8, 2022
Herein, we report a nanoplatform for tumor-site-targeted delivery of hydroxychloroquine (HCQ) using insulin-like growth factors 2 receptor (IGF2R)-targeted liposomes (iLipo-H)...In vivo studies demonstrate that iLipo-H nanoparticles efficiently inhibit 4T1 tumor growth without obvious side effects, especially under FMD condition. This study provides a promising strategy to increase the sensitivity of tumor cells to autophagy inhibitors for effective cancer therapy.
- |||||||||| TRPML1 in muscle biogenesis and disease (Virtual platform and E-Posters only) - Nov 5, 2022 - Abstract #WMS2022WMS_492;
This further inhibits autophagosome-lysosome fusion, compromising muscle biogenesis. We predict that TRPML1 antagonists could be therapeutic drugs for XLMTM.
- |||||||||| Review, Journal: SGLT2 inhibitors protect cardiomyocytes from myocardial infarction: a direct mechanism? (Pubmed Central) - Nov 5, 2022
Preclinical experiments have shown that SGLT2 inhibitors could hinder the progression of myocardial infarction and alleviate cardiac remodeling by mechanisms of metabolism influence, autophagy induction, inflammation attenuation and fibrosis reduction. Here we summarize the direct mechanism of SGLT2 inhibitors on myocardial infarction and investigate whether it could be applied to the clinic in improving cardiac function and healing after myocardial infarction.
- |||||||||| Cerdelga (eliglustat tartrate) / Sanofi
Journal: Targeting UGCG overcomes resistance to lysosomal autophagy inhibition. (Pubmed Central) - Nov 5, 2022
The FDA-approved UGCG inhibitor eliglustat combined with LAI significantly inhibited tumor growth and improved survival in syngeneic tumors and a therapy-resistant patient-derived xenograft. These findings nominate UGCG as a new cancer target, and clinical trials testing UGCG inhibition in combination with LAI are warranted.
- |||||||||| etomoxir (MIQ-001) - Meta / IQ
Lipophagy As a Mechanism of Resistance in T-ALL Following Energetic Crisis Induced By Oxphos/MCT1 Blockade: Strategies to Eradicate Residual Disease (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_5784;
Concomitant administration of Atorvastatin as well as other inhibitors with both OxPhos/MCT-i significantly reduced cell viability and induced apoptosis, supporting the key role of lipid metabolism in the resistance of T-ALL to dual inhibition. In summary, these results demonstrate that OxPhos/MCT1 inhibition forces switch to lipophagy, sensitizing cells to inhibitors of lipid metabolism, uncovering metabolic checkpoints that can ultimately translate into successful therapies in T-ALL and OxPhos-dependent malignancies.
- |||||||||| belnacasan (VX-765) / Vertex
RIPK3 Deficiency Caused By DNA Hypermethylation Blocks R-2-Hydroxyglutarate Induced Necroptosis in AML with IDH Mutation (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_5723;
Interestingly, Necrostatin-1(Nec-1), a necroptosis inhibitor, could significantly prevent cell death induced by R-2HG in AML cell lines, but not Ferrostatin-1 (a ferroptosis inhibitor), Z-VAD (an apoptosis inhibitor), 3-MA (an autophagy inhibitor) and VX-765 (a pyroptosis inhibitor), suggesting that necroptosis contributed to the anti-leukemia activity of R-2HG...Primary cells from IDH-mutant AML patients were more sensitive to decitabine than those from IDH wild-type AML patients...IDH-mutant AML cells were more sensitive to DNMT inhibitor. These results implicate that restoring RIPK3 activity is a promising way to reverse R-2HG-resistant in AML cells with IDH mutation.
- |||||||||| erastin - Whitehead Institute for Biomedical Research, Dana / Farber Cancer Institute, Columbia University, Prolexys
AT56 Exerts Anti-Tumor Effects in Peripheral T Cell Lymphoma By Regulating HMOX1-Mediated Ferroptosis (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_4864;
AT56 exerted potent anti-tumor effects in PTCL via promoting ferroptosis process, which was mediated by HMOX1 and partly dependent on autophagy. Our in vitro and in vivo study revealed the synergistic effect and mechanism of AT56 and sorafenib, providing a novel AT56-based treatment paradigm for PTCL patients.
- |||||||||| An Ancient Transcriptional Hub Couples Developmentally Regulated Gene Expression with Metabolism during Erythropoiesis (ENMCC - Hall E) - Nov 4, 2022 - Abstract #ASH2022ASH_3604;
Thus, we conclude that the genomic contact hub Nprl3 shares with a-globin and its enhancers bestows the erythroid-specific transcriptional upregulation required for Nprl3 to perform its important erythropoietic role. This finding suggests that the deep evolutionary coupling of these two genes has enabled the a-globin enhancers to control metabolism, as well as a-globin production, in developing erythroid cells.
- |||||||||| Xospata (gilteritinib) / Astellas, crenolanib (ARO-002) / AROG, Vanflyta (quizartinib) / Daiichi Sankyo
Translatome Proteomics Identifies Autophagy As a Resistance Mechanism to on-Target FLT3 Inhibitors in Acute Myeloid Leukemia (Hall D (Ernest N. Morial Convention Center)) - Nov 4, 2022 - Abstract #ASH2022ASH_2172;
In immunodeficient mice xenografted with human FLT3-ITD+ AML cells, oral co-treatment with gilteritinib and autophagy inhibitor ROC-325 synergistically impaired leukemia progression and extended overall survival. Our findings show the utility of functional translatome proteomics to systematically investigate cell-autonomous therapy resistance mechanisms, identify a molecular mechanism responsible for primary on-target FLT3i treatment resistance and demonstrate the pre-clinical efficacy of a rational combination treatment strategy targeting both FLT3 and autophagy induction.
- |||||||||| chloroquine phosphate / Generic mfg.
Autophagy Plays a Role in the Maintenance of Acute Myeloid Leukemia Stem Cells in the Hypoxic Bone Marrow Microenvironment (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_2072;
Lys05 is a promising chloroquine derivative with increased potency and therapeutic potential...We have also shown that autophagy inhibition impacts AML LSCs, reducing their ability to repopulate disease upon transplantation. These results suggest autophagy plays a key role in the maintenance of AML LSCs and suggests that inhibition of autophagy by pharmacological agents such as Lys05 may be a viable therapeutic method of eliminating LSCs.
- |||||||||| sirolimus / Generic mfg.
Autophagy Facilitates Cancer-Intrinsic Evasion of CAR T Cell-Mediated Cytotoxicity in B-Cell Malignancies (ENMCC - La Nouvelle Orleans Ballroom C) - Nov 4, 2022 - Abstract #ASH2022ASH_1657;
The addition of autophagy inhibitor (autophinib) during the co-culture with B cell malignancy cells significantly enhanced the killing effect of CD19 CAR T cells, whereas the addition of autophagy inducer (rapamycin) demonstrated the opposite effects...In conclusion, this study offered a novel mechanism in which autophagy mediates cancer-intrinsic biology contributing to observed therapeutic failure during CAR T cell therapy, wherein both STAT1/IRF1-induced chemokine signaling activation and TNF-a induced apoptosis are involved (Figure 1). Our findings promote better understanding of the role of autophagy in cancer cell resistance to CAR T cells, which will help to identify crucial areas requiring further research to improve patient outcomes.
|
