ArticleInternational journal of hematology2019
An mTORC1/2 dual inhibitor, AZD2014, acts as a lysosomal function activator and enhances gemtuzumab ozogamicin-induced apoptosis in primary human leukemia cells.
Article in International journal of hematology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 20 citations in OpenAlex.
- Machine learning-based integration develops a novel lysosome-related prognostic signature associated with prognosis and immune infiltration landscape in acute myeloid leukemia.Discover oncology · 2026Article
- Overcoming resistance to antibody-drug conjugates: mechanisms and emerging strategies.The oncologist · 2026Review
- A zebrafish xenotransplant model of anaplastic thyroid cancer to study tumor microenvironment and innate immune cell interactions in vivo.Endocrine-related cancer · 2024Article
- Kinase-independent role of mTOR and on-/off-target effects of an mTOR kinase inhibitor.Leukemia · 2023Article
- A novel prognostic model of methylation-associated genes in acute myeloid leukemia.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2023Article
- Article
- New Perspectives in Treating Acute Myeloid Leukemia: Driving towards a Patient-Tailored Strategy.International journal of molecular sciences · 2022Review
- Lysosomes in Stem Cell Quiescence: A Potential Therapeutic Target in Acute Myeloid Leukemia.Cancers · 2022Review
- Lysosome-mediated chemoresistance in acute myeloid leukemia.Cancer drug resistance (Alhambra, Calif.) · 2022Review
- Establishment and validation of a carbohydrate metabolism-related gene signature for prognostic model and immune response in acute myeloid leukemia.Frontiers in immunology · 2022Article
- Review
- Review
- [Antitumor effects of AZD2014, a dual mTORC1/2 inhibitor, against human hepatocellular carcinoma xenograft in nude mice].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2021Article
- Dual Kinase Targeting in Leukemia.Cancers · 2021Review
- Targeting autophagy to overcome drug resistance: further developments.Journal of hematology & oncology · 2020Review
- Overexpression of annexin A5 might guide the gemtuzumab ozogamicin treatment choice in patients with pediatric acute myeloid leukemia.Therapeutic advances in medical oncology · 2020Article
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Gemtuzumab ozogamicin (GO), an anti-CD33 antibody linked to calicheamicin via an acid-labile linker, is the first antibody-drug conjugate (ADC). The acidic environment inside lysosomes of target cells is an important intracellular determinant of the cytocidal action of GO, as the linker is hydrolyzed under acidic conditions. However, lysosomal activity in acute myeloid leukemia (AML) blasts in GO therapy has been insufficiently evaluated. It has been suggested that lysosome activity is suppressed in AML due to hyperactivation of the phosphoinositide 3-kinase/Akt pathway. We therefore hypothesized that agents which activate lysosomal function would potentiate the cytotoxicity of GO. Here, we found that a clinically useful mTORC1/2 dual inhibitor, AZD2014, reduced pH in the acidic organelles, including lysosomes, as shown by increased LysoTracker fluorescent intensity, and synergistically enhanced the cytotoxic effect of GO in primary leukemia cells. GO-induced cytotoxicity appeared to be enhanced with the increase in lysosomal activity by AZD2014. These results indicate that AZD2014 activated lysosomal function in primary leukemia cells, which in turn enhanced the cytotoxicity of GO. Enhancement of lysosomal activity may represent a new therapeutic strategy in the treatment of GO and other ADCs, particularly in cases with low lysosomal activity.
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