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Hydroxychloroquine inhibits autophagy. 449 / 453
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"CQ or HCQ, which are quinoline based drugs, are known as anti-malarial drugs and inhibit late autophagy by interfering with fusion between the autophagosome and lysosome by increasing lysosome pH. In recent years, quinoline based drugs have used as anti-inflammatory agents for rheumatoid arthritis, lupus erythematous, cancer, and sarcoidosis as well as some dermatologic conditions."
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"Herein, we describe our current understanding of the core components of the autophagy machinery and the functional relevance of autophagy within the tumor microenvironment, and we outline how this knowledge has informed preclinical investigations combining the autophagy inhibitor hydroxychloroquine (HCQ) with chemotherapy, targeted therapy, and immunotherapy."
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"Despite this, we acknowledge that multiple immune cells play roles in orchestrating the immune response such that CQ can decrease the immunosuppressive infiltration of myeloid-derived suppressor cells and Treg cells [73] and HCQ inhibition of autophagy may synergize with dual anti-PD1 and anti-CTLA4 therapy [74]."
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"Inhibition of autophagy by hydroxychloroquine, a well tolerated autophagy inhibitor, reduced cell viability in both ETV6-RUNX1 positive cell lines and primary acute lymphoblastic leukemia samples, and selectively sensitized primary ETV6-RUNX1 positive leukemia samples to L-asparaginase."
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"As mentioned above, HCQ is known to inhibit autophagy and is capable of sensitizing various tumors to the effects of chemotherapy, however, the nonselective distribution in vivo and the low capability to cross the BBB restrict its clinical use as well as the co-delivery of HCQ and ZD6474 in the treatment of glioma."
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"The late-stage autophagy inhibitors, such as CQ, HCQ, bafilomycin A1, and lysosomal protease inhibitors, exert suppressive effects on downstream of autophagosome formation, including inhibition of autophagosome and lysosome fusion and/or blocking degradation of autophagic cargo inside autolysosomes [14]."
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"Pharmacological suppression of autophagy by chloroquine (CQ) and its derivant hydroxychloroquine (HCQ) results in reactive oxygen species (ROS) upregulation, DNA impairment, and mitochondria dysfunction, ultimately inhibiting cell growth in vitro as well as in xenografts (Yang et al., 2011, 2014)."
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"Therefore, in some cancer cells, autophagy inhibition exerts anticancer effects; for example, chloroquine (CQ) and hydroxychloroquine (HCQ), which are inhibitors of autophagy that change lysosome acidification and inhibit autophagosome degradation by lysosomes, was combined with radiation and carmustine to treat glioblastoma in a phase III clinical trial [25]."
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"Furthermore, unfortunately, single proteasome inhibitor treatment has been proven unsatisfactory for solid tumors in clinical trials.5, 6 A recent clinical trial suggested that the anticancer effect of Bor is enhanced when it is combined with an autophagy inhibitor.7 To date, autophagy inhibitors including hydroxychloroquine (HCQ) and chloroquine (CQ) have been clinically viable."
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"100 Despite the promising effect of CQ, 100 a recent phase I/II clinical trial combining HCQ with TMZ and radiation therapy, in patients with newly diagnosed GBM showed that the maximum tolerated dose of HCQ was unable to consistently inhibit autophagy and that dose limiting toxicity prevented the possibility of moving to higher doses of HCQ."
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"HCQ was shown to successfully inhibit autophagy, as evidenced by the significant accumulation of autophagic vacuoles in peripheral blood mononuclear cells (mean autophagic vacuole counts : 2.19 at baseline, 2.45 after HCQ treatment, 3.84 after treatment with HCQ plus TMZ [difference between HCQ plus TMZ and baseline : p = 0.0007, difference between HCQ plus TMZ and HCQ only : p = 0.0034])."
eidos
"We also observed that the induction of apoptosis was greater with the combination of sorafenib and HCQ in only the S45F-mutated DT cell strains as compared to either treatments alone ( Fig. 5A ) , suggesting that autophagy blockade by HCQ enhances the antitumor activity of sorafenib in S45F-mutated DT cells ."
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"Rapamycin can inhibit the proliferation, induce apoptosis and autophagy of RPMI 8226, the hydroxychloroquine can inhibit autophagy and proliferation of RPMI 8226, and induce apoptosis, the 3-MA can inhibit autophagy of RPMI 8226, but hardly has any effects on proliferation and apoptosis of RPMI 8226 cells."
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"Autophagy inhibitors such as 3-MA (a class-III-PI3K inhibitor), bafilomycin A1, hydroxychloroquine and monensin (autophagosome-lysosome fusion inhibitors) have shown different efficacies in mitigating the effects of chemo- and radiotherapeutic anti-cancer treatments [XREF_BIBR], indicating the complexity with which this process is executed."
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"Consistent with this hypothesis, a cytoprotective role of autophagy in established tumors exposed to stressors like anticancer treatments is suggested in studies where autophagy inhibitors like hydroxychloroquine or 3-methyladenine (3-MA) sensitize cancer cells to treatments like tamoxifen treatment, radiation, DNA alkylating agents cylophosphamide and cisplatin, and tyrosine kinase receptor inhibitor imatinib."
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"The number and size of the autophagosomes (dark arrows) were progressively enhanced in control, bortezomib alone, HCQ alone, and combined treatment (Figure 5), indicative of the positive modulation of the autophagic pathway by bortezomib.Next, we asked whether the inhibition of proteasome by bortezomib and the blockade of autophagy by HCQ affected the proliferation (and viability) of PCs and ECs in MGUS and MM patients (Figure 6)."
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"Chloroquine (CQ) and hydroxychloroquine (HCQ) are known to inhibit autophagy and have been investigated in preclinical studies and in more than 30 clinical trials; however, the ocular toxicities and minimal single-agent anticancer efficacy of CQ or HCQ have restricted their clinical application."
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"Given that autophagy inhibitors including HCQ have shown efficacy against many different types of viruses including SARS-CoV-2 in CPE assays, we assessed the protective effect of a group of autophagy inhibitors including ROC-325, clomipramine, hycanthone, verteporfin, CQ, HCQ, and mefloquine in 384-well plates (XREF_FIG)."
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"Additionally, HCQ is nonspecific autophagy inhibitor, and development of more specific and/or more potent autophagy inhibitors might be required to inhibit autophagy in BM-located cells in CML patients.We conclude that catalytic mTOR inhibitors may be effective for patients with BCR-ABL-independent resistance and that pharmacological autophagy inhibition will further enhance their efficacy."
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"We have previously shown that autophagy is rapidly induced following TKI treatment in CML cells and pharmacological autophagy inhibition, using the nonspecific autophagy inhibitor hydroxychloroquine (HCQ; inhibits autophagy at a late stage by preventing the fusion of autophagosomes and lysosomes), enhances the effect of TKI treatment in CML cells, including primary CD34 + stem or progenitor cells."
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"Our previous work demonstrated that co-treatment with the autophagy inhibitor hydroxychloroquine (HCQ) could effectively block the last step of autophagy and enhance cell death induced by activation of p53 or treatment with alkylating chemotherapy in a model of Myc induced tumorigenesis."
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"Furthermore, because patients with Copa syndrome show an increase in autophagy with abnormal autophagosomes, hydroxychloroquine, which prevents autophagy by inhibiting lysosomal acidification and impairing fusion of the autophagosome with the lysosome, may also be useful for therapy for Copa syndrome."
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"Based on the different types of inhibitory analyses, 10mM of the autophagy inhibitor 3-methyladenine (3-MA, Sigma-Aldrich Co., St. Louis, MO, USA), 100nM of the autophagy inhibitor bafilomycin A1 (ba A1, Sigma-Aldrich Co., St. Louis, MO, USA), 50muM of the autophagy inhibitor hydroxychloroquine (Selleck Chemicals, Houston, TX, USA), 5muM of the AKT inhibitor triciribine (Selleck Chemicals, Houston, TX, USA), 5muM of the PI3K agonist insulin like growth factors-1 (IGF-1, R&D Systems, Inc., Minneapolis, USA), 5muM of the PI3K inhibitor LY294002 (Selleck Chemicals, Houston, TX, USA), and 1muM of the mTOR inhibitor rapamycin (Rapa, Selleck Chemicals, Houston, TX, USA) were added to the culture medium together with HSYA for 4h."
eidos
"This has generated significant interest in autophagy inhibition as a therapeutic strategy in cancer ; recently , anti-malarials , such as hydroxychloroquine ( HCQ ) , which impair autophagy by disrupting lysosomal function , have been repurposed as autophagy inhibitors in multiple clinical trials for the treatment of advanced cancers ( Chude and Amaravadi , 2017 ) ."
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"To differentiate this, we treated the MCL cell line Mino with palbociclib and the downstream autophagy inhibitor hydroxychloroquine which inhibits the acidification of lysosomes, completely blocks autophagy in its final step and therefore leads to the accumulation of autophagosomes [XREF_BIBR]."
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"Regrettably, due to the lack of tubule-specific agonists of the autophagy-lysosomal pathway, we could not prove that rescue of the autophagy-lysosomal pathway decreases the susceptibility to AKI in the mice with proteinuric LN and HCQ preadministration, which should be performed in the future.As mentioned above, we found that a long-term therapeutic dose of HCQ for LN may disrupt autophagy and promote senescence in PTECs to increase the susceptibility to AKI."
| PMC
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"The replication of PEDV in the IPEC-J2 cells was measured by IFA with the monoclonal antibody (mAb) 3A6 anti-PEDV N protein (prepared in our laboratory) as the primary antibody, and the FITC-conjugated goat anti-mouse IgG (Abcam, China) as the secondary antibody.Rapamycin and its analogs are strong inducers of autophagy by inhibiting mTOR activity (Ravikumar et al., 2004; Russo et al., 2018) , and hydroxychloroquine can inhibit autophagy by blocking the fusion of autophagosomes with lysosomes (Yang et al., 2013) ."
| PMC
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"The majority of chemotherapy agents and targeted therapeutics have been found to induce protective autophagy, resulting in reduced sensitivity to antitumor drugs, including traditional chemotherapy drugs (e.g., platinum compounds, 9 fluorouracil, 10 and etoposide 11) and molecular targeted agents As a consequence, autophagy inhibitors such as CQ (chloroquine) and HCQ (hydroxychloroquine) have been extensively investigated to potentiate the sensitivity to antitumor drugs."
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"An ongoing trial being conducted by M.D. Anderson Cancer Center is testing the autophagy inhibitor hydroxychloroquine along with the MEK inhibitor binimetinib for the treatment of patients with KRAS mutant metastatic pancreatic cancer (Clinicaltrials.gov Identifier : NCT04132505 (accessed on 24 February 2021))."
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"CQ and HCQ inhibit autophagy and promote apoptosis of cancer cells, but they also work by affecting CXCR4-CXCL12 signaling, Toll-like receptor 9, and p53 in cancer cells, and tumor-associated fibroblasts and vessels as well immune responses in the tumor microenvironment retinopathy [76]."
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"These findings are currently under clinical investigation with several studies examining whether pharmacologic inhibition of autophagy with the anti-malaria and non specific autophagy inhibitor hydroxychloroquine augments the efficacy of standard anticancer regimens [XREF_BIBR - XREF_BIBR]."
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"In light of the sensitizing effect of autophagy inhibition on chemotherapy induced cell death, a number of clinical trials have been launched combining the first generation autophagy inhibitor hydroxychloroquine (HCQ) with individual chemotherapeutic agents in patients with solid tumors."
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"Analysis showed that chloroquine/hydroxychloroquine inhibits autophagy in initial phases, causing accumulation of acidic vesicular organelles and break/discontinue autophagosome-lysosome fusions, but they do not alter the ability of lysosomes to digest target macromolecules as conventionally accepted."
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"We also observed that the induction of apoptosis was greater with the combination of sorafenib and HCQ in only the S45F-mutated DT cell strains as compared to either treatments alone (Fig. 5A), suggesting that autophagy blockade by HCQ enhances the antitumor activity of sorafenib in S45F-mutated DT cells."
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"A meta-analysis concluded that autophagy inhibitors, such as CQ and HCQ, combined with other anticancer agents, could significantly increase overall response rate (ORR), 1-year overall survival (OS) rate, and 6-month progression-free survival (PFS) rate, improving survival of patients with cancer XREF_BIBR."
| PMC
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"We recently determined that concurrent inhibition of ERK1/2 and autophagy synergistically suppressed the growth of KRAS-mutant PDAC, leading to our initiation of clinical trials to evaluate the combination of MEK or ERK inhibitor together with the autophagy inhibitor hydroxychloroquine."
eidos
"This has generated significant interest in autophagy inhibition as a therapeutic strategy in cancer ; recently , anti-malarials , such as hydroxychloroquine ( HCQ ) , which impair autophagy by disrupting lysosomal function , have been repurposed as autophagy inhibitors in multiple clinical trials for the treatment of advanced cancers ( Chude and Amaravadi , 2017 ) ."
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"However, despite the ability of HCQ to inhibit autophagy in patients, as evidenced by autophagosome accumulation on peripheral blood mononuclear and tumor cells [XREF_BIBR], its application in the clinical setting is limited by poor pharmacokinetics and frequent side effects [XREF_BIBR]."
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"Furthermore, selective triple knockdown of the autophagy genes ATG7, ATG5 and ATG3, and pre-treatment with the autophagy inhibitor hydroxychloroquine, efficiently overcame the resistance to Akt and mTOR inhibitors in this model, leading to the activation of the mitochondrial apoptotic pathway."
eidos
"Introduction Hydroxychloroquine ( Plaquenil ) is an aminoquinoline that is commonly used to treat malaria and a variety of rheumatic and dermatologic diseases , including systemic lupus erythematosus , rheumatoid arthritis , Sjogren syndrome , and porphyria cutanea tarda.1 ,2 In addition to its immunomodulatory effects , hydroxychloroquine has been noted to inhibit cellular autophagy ."
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"Ongoing and planned studies will further address the possibility of better elucidating and fingerprinting autophagy marker levels in a dynamic fashion to accurately assess changes during the different steps of the autophagy process in any given biological setting.Overall, our data show that while combination treatment with bortezomib and HCQ significantly downregulates autophagy in myeloma PCs promoting PC death, it also positively modulates autophagy in ECs, supporting their survival."
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"Further based on preclinical studies, we provide evidences that i) hydroxychloroquine impairs autophagy, which leads to accumulation of damaged and oxidized cytoplasmic constituents and interferes with cellular homeostasis, ii) this impaired autophagy in part reduces antigen processing and presentation to immune cells and iii) inhibition of endosome-lysosome system acidification by hydroxychloroquine not only impairs the phagocytosis process, but also potentially alters pulmonary surfactant in the lungs."
| PMC
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"Since bafilomycin A1 could have non-autophagy-related activities, we performed confirmatory experiments with additional autophagy inhibitors including hydroxychloroquine sulfate (lysosomal acidification inhibitor), 3-methyladenine (3-MA, PI3K inhibitor), and MHY1485 (mTOR agonist)."
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"Given the divergent conclusions of published studies regarding autophagy protein markers and autophagosome formation, the utility of autophagy inhibitors (lysosomotropic agents) such as chloroquine (CQ) or hydroxychloroquine (HCQ) in clinical trials for melanoma (either alone or as a combination therapy) supports conclusions in the literature that autophagy is a pro survival feature of melanomas, and so inhibiting the process pharmacologically is not only of clinical relevance, but a priority [XREF_BIBR, XREF_BIBR, XREF_BIBR]."
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"Fortuitously, the autophagy inhibitor hydroxychloroquine (a chloroquine derivative) has been used for many years in the management of patients with systemic lupus erythematosus, rheumatoid arthritis and malaria and therefore information about dosage, safety and side-effects has been available."
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"The latest reports have shown that the autophagy inhibitor hydroxychloroquine is tolerable and potentially effective in combination with the MTOR targeted agent temsirolimus XREF_BIBR and the proteasome inhibitor bortezomib XREF_BIBR in phase I trials and may be a valid complement to STAT3 targeted therapy."
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"The most recent reports have shown that the autophagy inhibitor hydroxychloroquine is tolerable and potentially effective in combination with the MTOR targeted agent temsirolimus [XREF_BIBR] and the proteasome inhibitor bortezomib [XREF_BIBR] in phase I trials (www.clinicaltrials.gov)."
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"Preclinical studies have demonstrated that HCQ, the widely used antimalarial and antirheumatic drug, is a potent inhibitor of autophagy in cancer and increases tumor cell death alone or through enhancing tumor killing in combination with cytotoxic chemotherapy or targeted agents, mostly in patients with solid tumors, with the exception of cervical cancer."
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"In a relevant clinical trial in dogs with non Hodgkin 's lymphoma, the combined treatment of autophagy inhibitor hydroxychloroquine (12.5 mg/kg/d) with a lower dose of doxorubicin (25 mg/m 2) has resulted in clinical benefit with superior overall response rate (93.3%) and comparable median progression-free interval (5 months) compared to standard single agent doxorubicin (30 mg/m 2) treatment [XREF_BIBR]."
eidos
"Lysosomotropic drugs like HCQ and CQ accumulate inside the lysosome and these drugs potentially increase the pH inside and disrupt lysosomal functions Fig. 3 : Inhibition of autophagy by HCQ and CQ triggers apoptosis : Autophagy is often utilized by cells as a survival mechanism to prevent apoptosis ."
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"Although some clinical successes have been noted with chloroquine, a phase I/II clinical trial with the autophagy inhibitor hydroxychloroquine administered in combination with standard and adjuvant chemoradiotherapy failed to show a significant benefit in patients with newly diagnosed GBM."
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"Appropriate interpretation of the outcomes of these trials would require knowledge as to whether the drugs or radiation utilized promote the cytoprotective form of autophagy in the tumor cells as well as whether the chloroquine or hydroxychloroquine actually inhibited the autophagy."
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"Indeed, numerous clinical trials utilizing HCQ in combination with cytotoxic and targeted therapies are under evaluation in various cancers; the first of these studies indicate that HCQ can be successfully employed to therapeutically inhibit autophagy in cancer patients with minimal dose limiting toxicities."
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"Another pathway U0126 has been shown to interact with is the mTOR and autophagy pathway [XREF_BIBR, XREF_BIBR], given that HCQ is known to inhibit autophagy, subsequent experiments to dissect out the specific mechanism through which U0126 is blocking the protective effects of HCQ should be explored."
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"Herein, we describe our current understanding of the core components of the autophagy machinery, the functional relevance of autophagy within the tumor microenvironment and outline how this knowledge has informed preclinical investigations combining the autophagy inhibitor hydroxychloroquine (HCQ) with chemotherapy, targeted therapy and immunotherapy."
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"Chloroquine (and its derivative hydroxychloroquine) inhibits autophagy, which is the proposed mechanism of its anti-ZIKV action since deficiency in an essential autophagy gene, Atg16l1, in mice limited ZIKV vertical transmission, placental and fetal damage, and improved placental and fetal outcomes overall."
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"Chi et al. reported a 40% response rate and a 84% disease control rate by simultaneously adding the autophagy inducer rapamycin and the autophagy inhibitor hydroxychloroquine in 25 patients with various tumor types presenting with intrinsic resistance to numerous MC regimens [XREF_BIBR]."
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"To examine if palmitoylation regulates GNA13 protein stability through these systems, we tested whether the downregulation of the GNA13 C14/18S mutant could be rescued by treatment with the proteasomal inhibitor MG132, the autophagy inhibitors HCQ and ULK-101, and several caspase inhibitors."
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"The combination of the autophagy inhibitor hydroxychloroquine with different drugs (gemcitabine, paclitaxel, carboplatin, etc.) or with mTOR inhibitors (rapamycin, everolimus, temsirolimus) is already used in several types of cancers, such as non small cell lung cancer (NSCLC), pancreatic cancer, renal cell carcinoma, myeloma and squamous cell cancer (head and neck cancer) (XREF_TABLE)."
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"Although a number of studies have demonstrated that autophagy may sensitize certain tumor cells to chemotherapeutic agents [XREF_BIBR - XREF_BIBR], the clinical applications of autophagy inhibitors such as CQ and hydroxychloroquine have been limited by their efficacy and side effects [XREF_BIBR, XREF_BIBR]."
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"Further based on preclinical studies, we provide evidences that i) hydroxychloroquine impairs autophagy, which leads to accumulation of damaged and oxidized cytoplasmic constituents and interferes with cellular homeostasis, ii) this impaired autophagy in part reduces antigen processing and presentation to immune cells and iii) inhibition of endosome-lysosome system acidification by hydroxychloroquine not only impairs the phagocytosis process, but also potentially alters pulmonary surfactant in the lungs."
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"Hydroxychloroquine (HCQ) is an inhibitor of autophagy that has been studied in a randomized phase II trial in combination with gemcitabine and nab-paclitaxel; however, it showed no benefit compared to gemcitabine and nab-paclitaxel alone in terms of 12-month OS and median PFS (152)."
eidos
"As mentioned above , HCQ is known to inhibit autophagy and is capable of sensitizing various tumors to the effects of chemotherapy , however , the nonselective distribution in vivo and the low capability to cross the BBB restrict its clinical use as well as the co-delivery of HCQ and ZD6474 in the treatment of glioma ( Gustafson et al ., 2006 ; Rangwala et al ., 2014 ; Rosenfeld et al ., 2014 ) ."
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"Thus, autophagy inhibitors, such as HCQ, when used in association with bortezomib, may induce this response in resistant myeloma PCs, although an anti-angiogenic drug must be included to achieve a complete remission, as the simultaneous pro-angiogenic effect could, in fact, promote the proliferation of a small residual tumor PC clone to cause relapse.Accordingly, our study should be followed by further translational investigations of the role of therapeutic suppression in autophagy modulation."
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"Hypoxia induced resistance of lung tumor to cytolytic T lymphocyte (CTL)-mediated lysis was demonstrated to be associated with autophagy induction, and inhibition of autophagy by HCQ dramatically reduced tumor growth in B16-F10 tumor bearing mice and restored the susceptibility of hypoxic tumor cell to CTL mediated lysis [XREF_BIBR]."
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"More recently, two second generation autophagy inhibitors, Lys05 a highly potent lysosometric agent and PIK-III a selective inhibitor of VPS34, demonstrated synergistic effects with TKIs to reduce primary CML LSCs quiescence, compared to the first generation autophagy inhibitor Hydroxychloroquine [XREF_BIBR]."
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"Recently, preclinical studies demonstrated that autophagy inhibition by hydroxychloroquine augments the efficacy of the proteasome inhibitor bortezomib in myeloma, indicating that the combination of autophagy and proteasome inhibition might be clinically useful for improving the outcomes of this neoplasia [XREF_BIBR, XREF_BIBR]."
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"This has generated significant interest in autophagy inhibition as a therapeutic strategy in cancer; recently, anti-malarials, such as hydroxychloroquine (HCQ), which impair autophagy by disrupting lysosomal function, have been repurposed as autophagy inhibitors in multiple clinical trials for the treatment of advanced cancers."