The endoplasmic reticulum (ER) is a multifunctional organelle required for lipid biosynthesis, calcium storage, and protein folding and processing. A number of physiological and pathological conditions, as well as a variety of pharmacological agents, are able to disturb proper ER function and thereby cause ER stress, which severely impairs protein folding and therefore poses the risk of proteotoxicity. Specific triggers for ER stress include, for example, particular intracellular alterations (e.g., calcium or redox imbalances), certain microenvironmental conditions (e.g., hypoglycemia, hypoxia, and acidosis), high-fat and high-sugar diet, a variety of natural compounds (e.g., thapsigargin, tunicamycin, and geldanamycin), and several prescription drugs (e.g., bortezomib/Velcade, celecoxib/Celebrex, and nelfinavir/Viracept). The cell reacts to ER stress by initiating a defensive process, called the unfolded protein response (UPR), which is comprised of cellular mechanisms aimed at adaptation and safeguarding cellular survival or, in cases of excessively severe stress, at initiation of apoptosis and elimination of the faulty cell. In recent years, this dichotomic stress response system has been linked to several human diseases, and efforts are underway to develop approaches to exploit ER stress mechanisms for therapy. For example, obesity and type 2 diabetes have been linked to ER stress-induced failure of insulin-producing pancreatic beta cells, and current research efforts are aimed at developing drugs that ameliorate cellular stress and thereby protect beta cell function. Other studies seek to pharmacologically aggravate chronic ER stress in cancer cells in order to enhance apoptosis and achieve tumor cell death. In the following, these principles will be presented and discussed.

https://downloads.hindawi.com/journals/scientifica/2012/857516.pdf

Endoplasmic Reticulum Stress: Its Role in Disease and Novel Prospects for Therapy

A variety of organisms, such as bacteria, fungi, and plants, produce secondary metabolites, also known as natural products. Natural products have been a prolific source and an inspiration for numerous medical agents with widely divergent chemical structures and biological activities, including antimicrobial, immunosuppressive, anticancer, and anti-inflammatory activities, many of which have been developed as treatments and have potential therapeutic applications for human diseases. Aside from natural products, the recent development of recombinant DNA technology has sparked the development of a wide array of biopharmaceutical products, such as recombinant proteins, offering significant advances in treating a broad spectrum of medical illnesses and conditions. Herein, we will introduce the structures and diverse biological activities of natural products and recombinant proteins that have been exploited as valuable molecules in medicine, agriculture and insect control. In addition, we will explore past and ongoing efforts along with achievements in the development of robust and promising microorganisms as cell factories to produce biologically active molecules. Furthermore, we will review multi-disciplinary and comprehensive engineering approaches directed at improving yields of microbial production of natural products and proteins and generating novel molecules. Throughout this article, we will suggest ways in which microbial-derived biologically active molecular entities and their analogs could continue to inspire the development of new therapeutic agents in academia and industry.

/pdf/a-review-of-the-microbial-production-of-bioactive-natural-1gxj2rmzvz.pdf

A Review of the Microbial Production of Bioactive Natural Products and Biologics.

Novel hotspot mutant p53 gain-of-function mouse model shows that tumours depend on its sustained expression, and genetic and pharmacological approaches reveal mutant p53 as an actionable cancer drug target The tumour suppressor TP53 is one of the most frequently mutated genes in human cancer Although some genetic alterations cause its complete loss, many are gain-of-function mutations in which mutant p53 protein gains new properties that promote tumorigenesis Ute Moll and colleagues now demonstrate in a mouse model that expression of such a p53 mutant is needed not only for tumour initiation but also for tumour maintenance They further show that they can target mutant p53 indirectly by inhibiting a chaperone called Hsp90 which is needed to keep mutant p53 protein stable In a mouse model of lymphoma, this approach led to degradation of mutant p53 and reduced tumour growth Missense mutations in p53 generate aberrant proteins with abrogated tumour suppressor functions that can also acquire oncogenic gain-of-function activities that promote malignant progression, invasion, metastasis and chemoresistance1,2,3,4,5 Mutant p53 (mutp53) proteins undergo massive constitutive stabilization specifically in tumours, which is the key requisite for the acquisition of gain-of-functions activities6,7,8 Although currently 11 million patients worldwide live with tumours expressing highly stabilized mutp53, it is unknown whether mutp53 is a therapeutic target in vivo Here we use a novel mutp53 mouse model expressing an inactivatable R248Q hotspot mutation (floxQ) to show that tumours depend on sustained mutp53 expression Upon tamoxifen-induced mutp53 ablation, allotransplanted and autochthonous tumours curb their growth, thus extending animal survival by 37%, and advanced tumours undergo apoptosis and tumour regression or stagnation The HSP90/HDAC6 chaperone machinery, which is significantly upregulated in cancer compared with normal tissues, is a major determinant of mutp53 stabilization9,10,11,12 We show that long-term HSP90 inhibition significantly extends the survival of mutp53 Q/− (R248Q allele2) and H/H (R172H allele3) mice by 59% and 48%, respectively, but not their corresponding p53−/− littermates This mutp53-dependent drug effect occurs in H/H mice treated with 17DMAG+SAHA and in H/H and Q/− mice treated with the potent Hsp90 inhibitor ganetespib Notably, drug activity correlates with induction of mutp53 degradation, tumour apoptosis and prevention of T-cell lymphomagenesis These proof-of-principle data identify mutp53 as an actionable cancer-specific drug target

Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment

Pharmacological targeting of endoplasmic reticulum stress signaling in cancer.

The discovery of hypoxia-inducible factor-1 (HIF-1) has led to an increasing understanding of the mechanism of tumor hypoxia in the past two decades. As a key transcriptional regulator, HIF-1 plays a central role in the adaptation of tumor cells to hypoxia by activating the transcription of targeting genes, which regulate several biological processes including angiogenesis, cell proliferation, survival, glucose metabolism and migration. The inhibitors of HIF-1 in cancer have provided us a new clue for the targeting cancer therapy. This review will introduce the general knowledge of the biology characteristic of HIF-1 and mechanism of O(2)-dependent regulation. Moreover, a number of chemical inhibitors plus protein and nucleic acid inhibitors are included and classified mainly based on their different mechanism of inhibiting action. We also prefer to discuss the advantages of protein and nucleic acid inhibitors compared with chemical inhibitors.

Recent agents targeting HIF‐1α for cancer therapy

The Hsp90 molecule, one of the most abundant heat shock proteins in mammalian cells, maintains homeostasis and prevents stress-induced cellular damage. Hsp90 is expressed under normal conditions at a level of about 1-2 Percent of total proteins, while its expression increases 2-10 fold in cancer cells. The two main constitutively expressed isoforms of Hsp90 are known as Hsp90-alpha and Hsp90-beta, and their upregulation is associated with tumor progression, invasion and formation of metastases, as well as development of drug resistance. The Hsp90 is a key target for many newly established, potent anticancer agents containing Hsp90 N-terminal ATP binding inhibitors, such as geldanamycin, and its analogues 17AAG and 17DMAG. The therapeutic usage of geldanamycin has been limited due to its poor water solubility and severe hepatotoxicity. Therefore, its analogues, including 17AAG, 17DMAG, Tanespimycin and Retaspimycin hydrochloride, with improved pharmacokinetic profiles, have been developed.

https://iris.unipa.it/bitstream/10447/201057/1/gorska%202011.pdf

Alicja Sielicka-Dudzin

Papers

Geldanamycin and its derivatives as Hsp90 inhibitors.