The Dual Role of Autophagy in Crizotinib-Treated ALK+ ALCL: From the Lymphoma Cells Drug Resistance to Their Demise

Espinos, Estelle; Lai, Raymond; Giuriato, Sylvie

doi:10.3390/cells10102517

Cited by 5 publications

(2 citation statements)

References 129 publications

(149 reference statements)

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“…Cytoprotective autophagy is an undesired side effect often induced by antineoplastic treatment; thus, it is considered a therapeutic target to overcome tumor resistance and execute cell death. However, autophagy in cancer is recognized as a double-edged sword, as some medications may exert a direct cytotoxic effect via an autophagic cell death pathway, despite the pro-survival face of this phenomenon [37][38][39].…”

Section: Discussionmentioning

confidence: 99%

Autophagy Inhibition with Chloroquine Increased Pro-Apoptotic Potential of New Aziridine-Hydrazide Hydrazone Derivatives against Glioblastoma Cells

Witusik-Perkowska,

Głowacka,

Pieczonka

et al. 2023

Cells

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Tumor therapy escape due to undesired side effects induced by treatment, such as prosurvival autophagy or cellular senescence, is one of the key mechanisms of resistance that eventually leads to tumor dormancy and recurrence. Glioblastoma is the most frequent and practically incurable neoplasm of the central nervous system; thus, new treatment modalities have been investigated to find a solution more effective than the currently applied standards based on temozolomide. The present study examined the newly synthesized compounds of aziridine–hydrazide hydrazone derivatives to determine their antineoplastic potential against glioblastoma cells in vitro. Although the output of our investigation clearly demonstrates their proapoptotic activity, the cytotoxic effect appeared to be blocked by treatment-induced autophagy, the phenomenon also detected in the case of temozolomide action. The addition of an autophagy inhibitor, chloroquine, resulted in a significant increase in apoptosis triggered by the tested compounds, as well as temozolomide. The new aziridine–hydrazide hydrazone derivatives, which present cytotoxic potential against glioblastoma cells comparable to or even higher than that of temozolomide, show promising results and, thus, should be further investigated as antineoplastic agents. Moreover, our findings suggest that the combination of an apoptosis inducer with an autophagy inhibitor could optimize chemotherapeutic efficiency, and the addition of an autophagy inhibitor should be considered as an optional adjunctive therapy minimizing the risk of tumor escape from treatment.

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Section: Discussionmentioning

confidence: 99%

Autophagy Inhibition with Chloroquine Increased Pro-Apoptotic Potential of New Aziridine-Hydrazide Hydrazone Derivatives against Glioblastoma Cells

Witusik-Perkowska,

Głowacka,

Pieczonka

et al. 2023

Cells

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“…It could exert either prosurvival or prodeath functions in anaplastic large cell lymphoma. Differences in autophagy activity lead to differences in treatment efficacy in cancers [ 37 ]. In our RNA-seq analysis with ARGs, crizotinib was found to play a role in the antitumor effect in PRCC-TFE3 fusion tRCC organoids.…”

Section: Discussionmentioning

confidence: 99%

Phenotypical screening on metastatic PRCC-TFE3 fusion translocation renal cell carcinoma organoids reveals potential therapeutic agents

Cao

Lan²,

Shang

et al. 2022

Clin Transl Oncol

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Purpose Translocation renal cell carcinoma (tRCC) is a subtype that occurs predominantly in children and young individuals. Metastatic tRCC occurring in young patients is more aggressive than that occurring in older patients, and there are still no effective therapies. Organoids can mimic original tissues and be assessed by high-throughput screening (HTS). We aimed to utilize patient-derived organoids and HTS to screen drugs that can be repurposed for metastatic tRCC with PRCC-TFE3 fusion. Methods Tumor tissues were obtained from treatment-naïve metastatic tRCC patients who underwent surgery. Histopathology and fluorescence in situ hybridization (FISH) confirmed the tRCC. Organoids derived from the dissected tissues were cultured and verified by FISH and RNA-seq. HTS was performed to seek promising drugs, and potential mechanisms were explored by RNA-seq and cell-based studies. Results We successfully established a metastatic tRCC organoid with PRCC-TFE3 fusion, a common fusion subtype, and its characteristics were verified by histopathology, FISH, and RNA-seq. An HTS assay was developed, and the robustness was confirmed. A compound library of 1816 drugs was screened. Eventually, axitinib, crizotinib, and JQ-1 were selected for further validation and were found to induce cell cycle arrest and apoptosis. RNA-seq analyses of posttreatment organoids indicated that crizotinib induced significant changes in autophagy-related genes, consistent with the potential pathogenesis of tRCC. Conclusions We established and validated organoids derived from tissues dissected from a patient with metastatic tRCC with PRCC-TFE3 fusion and achieved the HTS process for the first time. Crizotinib might be a targeted therapy worthy of exploration in the clinic for metastatic tRCC with PRCC-TFE3 fusion. Such organoid and HTS assays may represent a promising model system in translational research assisting in the development of clinical strategies.

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Role of Autophagy and Mitophagy in Neurodegenerative Disorders

Kapil

Kumar

Kaur

et al. 2024

CNSNDDT

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Autophagy is a self-destructive cellular process that removes essential metabolites and waste from inside the cell to maintain cellular health. Mitophagy is the process by which autophagy causes disruption inside mitochondria and the total removal of damaged or stressed mitochondria, hence enhancing cellular health. The mitochondria are the powerhouses of the cell, performing essential functions such as ATP (adenosine triphosphate) generation, metabolism, Ca2+ buffering, and signal transduction. Many different mechanisms, including endosomal and autophagosomal transport, bring these substrates to lysosomes for processing. Autophagy and endocytic processes each have distinct compartments, and they interact dynamically with one another to complete digestion. Since mitophagy is essential for maintaining cellular health and using genetics, cell biology, and proteomics techniques, it is necessary to understand its beginning, particularly in ubiquitin and receptor-dependent signalling in injured mitochondria. Despite their similar symptoms and emerging genetic foundations, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) have all been linked to abnormalities in autophagy and endolysosomal pathways associated with neuronal dysfunction. Mitophagy is responsible for normal mitochondrial turnover and, under certain physiological or pathological situations, may drive the elimination of faulty mitochondria. Due to their high energy requirements and post-mitotic origin, neurons are especially susceptible to autophagic and mitochondrial malfunction. This article focused on the importance of autophagy and mitophagy in neurodegenerative illnesses and how they might be used to create novel therapeutic approaches for treating a wide range of neurological disorders.

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The Dual Role of Autophagy in Crizotinib-Treated ALK+ ALCL: From the Lymphoma Cells Drug Resistance to Their Demise

Cited by 5 publications

References 129 publications

Autophagy Inhibition with Chloroquine Increased Pro-Apoptotic Potential of New Aziridine-Hydrazide Hydrazone Derivatives against Glioblastoma Cells

Autophagy Inhibition with Chloroquine Increased Pro-Apoptotic Potential of New Aziridine-Hydrazide Hydrazone Derivatives against Glioblastoma Cells

Phenotypical screening on metastatic PRCC-TFE3 fusion translocation renal cell carcinoma organoids reveals potential therapeutic agents

Role of Autophagy and Mitophagy in Neurodegenerative Disorders

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