Typical and Atypical Inducers of Lysosomal Cell Death: A Promising Anticancer Strategy

Domagała, Antoni; Fidyt, Klaudyna; Bobrowicz, Małgorzata; Stachura, Joanna; Szczygiel, Kacper; Firczuk, Małgorzata

doi:10.3390/ijms19082256

Cited by 69 publications

(56 citation statements)

References 111 publications

(128 reference statements)

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“…Chemotherapy resistance in patients with recurrent and advanced disease (3) and strong systemic toxicity, especially in elderly (4), have raised concerns over the progress of cancer therapy, making it necessary to change the paradigm in the search for new treatments, more effective and with milder adverse effects. Thus, alternative cell death pathways capable of killing apoptosisand therapy resistant cancer cells, have gained vast interest among cancer researchers, leading to the identification of autophagy and lysosomal cell death programs as attractive means to circumvent therapy resistance (5)(6)(7)(8). Lysosomal activation is common in aggressive cancers, where lysosomes promote disease progression and treatment resistance (9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Psychotropic Drugs Show Anticancer Activity by Disrupting Mitochondrial and Lysosomal Function

et al. 2020

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Background and Purpose: Drug repositioning is a promising strategy for discovering new therapeutic strategies for cancer therapy. We investigated psychotropic drugs for their antitumor activity because of several epidemiological studies reporting lower cancer incidence in individuals receiving long term drug treatment. Experimental Approach: We investigated 27 psychotropic drugs for their cytotoxic activity in colorectal carcinoma, glioblastoma and breast cancer cell lines. Consistent with the cationic amphiphilic structure of the most cytotoxic compounds, we investigated their effect on mitochondrial and lysosomal compartments. Results: Penfluridol, ebastine, pimozide and fluoxetine, fluspirilene and nefazodone showed significant cytotoxicity, in the low micromolar range, in all cell lines tested. In MCF7 cells these drugs caused mitochondrial membrane depolarization, increased the acidic vesicular compartments and induced phospholipidosis. Both penfluridol and spiperone induced AMPK activation and autophagy. Neither caspase nor autophagy inhibitors rescued cells from death induced by ebastine, fluoxetine, fluspirilene and nefazodone. Treatment with 3-methyladenine partially rescued cell death induced by pimozide and spiperone, whereas enhanced the cytotoxic activity of penfluridol. Conversely, inhibition of lysosomal cathepsins significantly reduced cell death induced by ebastin, penfluridol, pimozide, spiperone and mildly in fluoxetine treated cells. Lastly, Spiperone cytotoxicity was restricted to colorectal cancer and breast cancer and caused apoptotic cell death in MCF7 cells. Conclusions: The cytotoxicity of psychotropic drugs with cationic amphiphilic structures relied on simultaneous mitochondrial and lysosomal disruption and induction of cell death that not necessarily requires apoptosis. Since dual targeting of lysosomes and mitochondria constitutes a new promising therapeutic approach for cancer, particularly those in which the apoptotic machinery is defective, these data further support their clinical development for cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Psychotropic Drugs Show Anticancer Activity by Disrupting Mitochondrial and Lysosomal Function

et al. 2020

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“…This high dependence on the lysosomal pathway paired with decreased stability of cancer cell lysosomes (e.g. by degradation of LAMP1 and LAMP2), as reported by several studies, makes lysosomes a particularly suitable target for cancer therapy [62,63].…”

Section: Discussionmentioning

confidence: 87%

Autophagy activation, lipotoxicity and lysosomal membrane permeabilization synergize to promote pimozide- and loperamide-induced glioma cell death

Meyer

Henkel

Linder

et al. 2020

Preprint

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Increasing evidence suggests that induction of lethal autophagy carries potential significance for the treatment of glioblastoma (GBM). In continuation of previous work, we demonstrate that pimozide and loperamide trigger an ATG5- and ATG7-dependent type of cell death that is significantly inhibited with the cathepsin inhibitors E64D/Pepstatin A and the lipid ROS scavenger α-tocopherol in MZ-54 GBM cells. Global proteomic analysis after treatment with both drugs also revealed an increase of proteins related to lipid and cholesterol metabolic processes. These changes were accompanied by AKT1 (AKT serine/threonine kinase 1) inhibition and a massive accumulation of cholesterol and other lipids in the lysosomal compartment, indicative of impaired lipid transport/degradation. In line with these observations, pimozide and loperamide treatment were associated with a pronounced increase of bioactive sphingolipids including ceramides, glucosylceramides and sphingoid bases measured by targeted lipidomic analysis. Furthermore, pimozide and loperamide inhibited the activity of acid sphingomyelinase (ASM), increased lipid-ROS levels and promoted induction of lysosomal membrane permeabilization (LMP), as well as release of cathepsin B into the cytosol in MZ-54 wt cells. While LMP and cell death were significantly attenuated in ATG5/7 KO cells, both events were enhanced by depletion of the lysophagy receptor VCP (valosin containing protein), supporting a pro-survival function of lysophagy under these conditions. Collectively, our data suggest that pimozide and loperamide-driven autophagy and lipotoxicity synergize to induce LMP and lysosomal cell death. The results also support the notion that simultaneous overactivation of autophagy and induction of LMP represents a promising approach for the treatment of GBM.

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“…22 Third, the lysosomal pathological features lay a foundation for precise drug release. 23 Given the evidence discussed above, lysosomal targeting and destruction could represent potential pharmacological delivery strategies.…”

Section: Lysosomal Accumulationmentioning

confidence: 99%

Precise design strategies of nanomedicine for improving cancer therapeutic efficacy using subcellular targeting

Shi

et al. 2020

Sig Transduct Target Ther

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Therapeutic efficacy against cancer relies heavily on the ability of the therapeutic agents to reach their final targets. The optimal targets of most cancer therapeutic agents are usually biological macromolecules at the subcellular level, which play a key role in carcinogenesis. Therefore, to improve the therapeutic efficiency of drugs, researchers need to focus on delivering not only the therapeutic agents to the target tissues and cells but also the drugs to the relevant subcellular structures. In this review, we discuss the most recent construction strategies and release patterns of various cancer cell subcellular-targeting nanoformulations, aiming at providing guidance in the overall design of precise nanomedicine. Additionally, future challenges and potential perspectives are illustrated in the hope of enhancing anticancer efficacy and accelerating the translational progress of precise nanomedicine.

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Typical and Atypical Inducers of Lysosomal Cell Death: A Promising Anticancer Strategy

Cited by 69 publications

References 111 publications

Psychotropic Drugs Show Anticancer Activity by Disrupting Mitochondrial and Lysosomal Function

Psychotropic Drugs Show Anticancer Activity by Disrupting Mitochondrial and Lysosomal Function

Autophagy activation, lipotoxicity and lysosomal membrane permeabilization synergize to promote pimozide- and loperamide-induced glioma cell death

Precise design strategies of nanomedicine for improving cancer therapeutic efficacy using subcellular targeting

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