Abstract The degradation of denatured globin in reticulocyte lysates is markedly stimulated by ATP. This system has now been resolved into two components, designated fractions I and II, in the order of their elution from DEAE-cellulose. Fraction II has a neutral protease activity but is stimulated only slightly by ATP, whereas fraction I has no proteolytic activity but restores ATP-dependent proteolysis when combined with fraction II. The active principle of fraction I is remarkably heat-stable, but it is non-dialysable, precipitable with ammonium sulfate and it is destroyed by treatment with proteolytic enzymes. In gel filtration on Sephadex-G-75, it behaves as a single component with a molecular weight of approximately 9,000.

A heat-stable polypeptide component of an ATP-Dependent Proteolytic System from reticullocytes

Candidate drugs against SARS-CoV-2 and COVID-19.

Ever present hurdles for the discovery of new drugs for cancer therapy have necessitated the development of the alternative strategy of drug repurposing, the development of old drugs for new therapeutic purposes. This strategy with a cost-effective way offers a rare opportunity for the treatment of human neoplastic disease, facilitating rapid clinical translation. With an increased understanding of the hallmarks of cancer and the development of various data-driven approaches, drug repurposing further promotes the holistic productivity of drug discovery and reasonably focuses on target-defined antineoplastic compounds. The “treasure trove” of non-oncology drugs should not be ignored since they could target not only known but also hitherto unknown vulnerabilities of cancer. Indeed, different from targeted drugs, these old generic drugs, usually used in a multi-target strategy may bring benefit to patients. In this review, aiming to demonstrate the full potential of drug repurposing, we present various promising repurposed non-oncology drugs for clinical cancer management and classify these candidates into their proposed administration for either mono- or drug combination therapy. We also summarize approaches used for drug repurposing and discuss the main barriers to its uptake.

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Overcoming cancer therapeutic bottleneck by drug repurposing

Proteasome inhibitors are rapidly evolving as potent treatment options in cancer therapy. One of the most promising drug candidates of this type is salinosporamide A from the bacterium Salinispora tropica. This marine natural product possesses a complex, densely functionalized γ-lactam-β-lactone pharmacophore, which is responsible for its irreversible binding to its target, the β subunit of the 20S proteasome. Salinosporamide A entered phase I clinical trials for the treatment of multiple myeloma only three years after its discovery. The strong biological activity and the challenging structure of this compound have fueled intense academic and industrial research in recent years, which has led to the development of more than ten syntheses, the elucidation of its biosynthetic pathway, and the generation of promising structure–activity relationships and oncological data. Salinosporamide A thus serves as an intriguing example of the successful interplay of modern drug discovery and biomedical research, medicinal chemistry and pharmacology, natural product synthesis and analysis, as well as biosynthesis and bioengineering.

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Salinosporamide natural products: Potent 20 S proteasome inhibitors as promising cancer chemotherapeutics.

Naringin and naringenin as anticancer agents and adjuvants in cancer combination therapy: Efficacy and molecular mechanisms of action, a comprehensive narrative review

Cancer stem cells (CSCs) constitute a subpopulation of tumor cells that possess self-renewal and tumor initiation capacity, and the ability to give rise to the heterogeneous lineages of cancer cells that comprise the tumor. CSCs exhibit intrinsic mechanisms of resistance to virtually all conventional cancer therapeutics, allowing them to survive current cancer therapies and to initiate tumor recurrence and metastasis. Different pathways and mechanisms that confer resistance and survival of CSCs, including activation of the Wnt/β- catenin, Sonic Hedgehog, Notch, PI3K/Akt/mTOR and STAT3 signaling pathways, expression of aldehyde dehydrogenase 1 (ALDH1) and oncogenic microRNAs, and acquisition of epithelial-mesenchymal transition (EMT), have been identified recently. Certain phytochemicals, in particular curcumin, epigallocatechin-3-gallate (EGCG), sulforaphane, resveratrol and genistein have been shown to interfere with these intrinsic CSC pathways in vitro and in human xenograft mice, leading to elimination of CSCs. Moreover, recent clinical trials have demonstrated the therapeutic efficacy of five phytochemicals, alone or in combination with modern cancer therapeutics, and in various types of cancer. Since current cancer therapies fail to eradicate CSCs, leading to cancer recurrence and progression, targeting of CSCs with phytochemicals such as curcumin, EGCG, sulforaphane, resveratrol and genistein, combined with each other and/or in combination with conventional cytotoxic drugs and novel cancer therapeutics, may offer a novel therapeutic strategy against cancer.

The "Big Five" Phytochemicals Targeting Cancer Stem Cells: Curcumin, EGCG, Sulforaphane, Resveratrol and Genistein

Das Ubiquitin-Proteasom-System ist eines der wichtigsten zellularen Regulationssysteme. In weniger als 25 Jahren wurde es systematisch und vollstandig charakterisiert. Heute bietet es eine umfassende molekulare Basis fur die Therapie bosartiger, entzundlicher und immunologischer Erkrankungen.

Cord Naujokat

Papers

The "Big Five" Phytochemicals Targeting Cancer Stem Cells: Curcumin, EGCG, Sulforaphane, Resveratrol and Genistein

Das Ubiquitin‐Proteasom‐System. Konsequente Erforschung und therapeutische Nutzung