Plaquenil vs. chloroquine phosphate rezension

In some cases, stable disease has even been achieved. Despite the success of hydroxychloroquine in early clinical trials, more potent lysosomotropic agents are under development to address potential toxicity issues. Although studies are limited to in vitro characterization and mouse models, several lysosome-targeted compounds have shown improved potency over hydroxychloroquine.

As the autophagy field continues to expand in both breadth and depth of knowledge within cancer, small molecule inhibitors of key autophagy enzymes are under investigation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Open acess. National Center for Biotechnology Information , U. Future Med Chem. Author information Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Abstract The search for a single silver bullet for the treatment of cancer has now been overshadowed by the identification of multiple therapeutic targets unique to each malignancy and even to each patient. The rise of autophagy as a therapeutic target Cancer is the second leading cause of death in the USA by a minute margin expected to close within the next decade [ 1 ].

Open in a separate window. Figure 1. The stages of autophagy. Antimalarial drugs as autophagy inhibitors The first compounds termed autophagy inhibitors were not designed as such, but were rather repurposed from their initial use as antimalarial agents.

Figure 2. Key events in the history of hydroxychloroquine. Hydroxychloroquine in cancer clinical trials The biomedical research field was slow to translate the observations of lysosomotropic agents out of the malaria research field. Table 1. Hydroxychloroquine success in clinical trials. Study identifier Disease context Treatment regimen Major findings Ref. Improving autophagy inhibition at the lysosome As both preclinical and clinical trials of hydroxychloroquine continue, a parallel movement has begun to investigate and develop more potent lysosomotropic agents.

Figure 3. Structures of prominent lysosomotropic agents.

Novel therapeutic targets in the autophagy pathway Potential therapeutic targets of autophagy inhibitors can seemingly be divided into two categories: key molecules associated with autophagy and major steps within the process. Table 2. Therapeutic potential of essential autophagy machinery. Autophagy-associated proteins Role in process Potential for therapeutic targeting Ref.

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Figure 4. Current therapeutic targets in the autophagy pathway. Future perspective The early successes of both lysosomotropic agents and small molecule inhibitors of the autophagy pathway have poised the field for rapid growth and development.

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Key terms. Executive summary. The rise of autophagy as a therapeutic target Autophagy has emerged as a valid therapeutic target across multiple malignancies. Antimalarial drugs as autophagy inhibitors The first autophagy inhibitors were born out of antimalarial research. Hydroxychloroquine in cancer clinical trials The path to clinical trials for hydroxychloroquine was expedited due to its prior FDA approval and extensive characterization in the treatment of both malaria and inflammatory diseases.

Improving autophagy inhibition at the lysosome Despite the success of hydroxychloroquine in early clinical trials, more potent lysosomotropic agents are under development to address potential toxicity issues. Novel therapeutic targets in the autophagy pathway As the autophagy field continues to expand in both breadth and depth of knowledge within cancer, small molecule inhibitors of key autophagy enzymes are under investigation.

Leading causes of death. Cancer statistics, CA Cancer J.

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• The rise of autophagy as a therapeutic target.

Duffy MJ. The war on cancer: are we winning? Tumour Biol. Mills GB. An emerging toolkit for targeted cancer therapies. Genome Res. Cancer genome landscapes. Workman P, Al-Lazikani B. Drugging cancer genomes. Drug Discov. Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Clonal evolution in breast cancer revealed by single nucleus genome sequencing. Mccormick F.

KRAS as a therapeutic target. Cancer Res. Autophagy in malignant transformation and cancer progression. EMBO J. Guo JY, White E.



Humana Press, Inc. Cooper RG, Magwere T. Indian J. Hiraki K, Kimura I. Studies on the treatment of malignant tumors with fibroblast-inhibiting agent.

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Effects of chloroquine on human cancers. Acta Med. Bielicky T, Zak M. Hepatic response to lysosomal effects of hypoxia, neutral red and chloroquine. Abraham R, Hendy RJ. Irreversible lysosomal damage induced by chloroquine in the retinae of pigmented and albino rats. Lie SO, Schofield B. Inactivation of lysosomal function in normal cultured human fibroblasts by chloroquine.

Wibo M, Poole B.



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Protein degradation in cultured cells. The uptake of chloroquine by rat fibroblasts and the inhibition of cellular protein degradation and cathepsin B1. Cell Biol. Ascoli M, Puett D. Inhibition of the degradation of receptor-bound human choriogonadotropin by lysosomotropic agents, protease inhibitors, and metabolic inhibitors. Foley M, Tilley L. Quinoline antimalarials: mechanisms of action and resistance and prospects for new agents. Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Synthesis of improved lysomotropic autophagy inhibitors.

Cell Res. Hughes GRV. Lupus: The Facts. Inhibition of macroautophagy triggers apoptosis.