scholarly journals Development of a Novel Class of Self-Assembling dsRNA Cancer Therapeutics: a Proof of Concept Investigation

2020 ◽  
Author(s):  
Vishwaratn Asthana ◽  
Brett S. Stern ◽  
Yuqi Tang ◽  
Pallavi Bugga ◽  
Ang Li ◽  
...  
Keyword(s):  
Fusion Gene ◽  
Cancer Therapeutics ◽  
Treatment Modalities ◽  
Functional Coupling ◽  
Proof Of Concept ◽  
Cancer Resistance ◽  
Self Assembling ◽  
Modified Dna ◽  
Difficult Challenge ◽  
Sarcoma Cells

AbstractCancer has proven to be an extremely difficult challenge to treat. Several fundamental issues currently underlie cancer treatment including differentiating self from non-self, functional coupling of the recognition and therapeutic components of various therapies, and the propensity of cancerous cells to develop resistance to common treatment modalities via evolutionary pressure. Given these limitations, there is an increasing need to develop an all-encompassing therapeutic that can uniquely target malignant cells, decouple recognition from treatment, and overcome evolutionarily driven cancer resistance. We describe herein, a new class of programmable self-assembling dsRNA-based cancer therapeutics, that uniquely targets aberrant genetic sequences, and in a functionally decoupled manner, undergoes oncogenic RNA activated displacement (ORAD), initiating a therapeutic cascade that induces apoptosis and immune activation. As a proof-of-concept, we show that RNA strands targeting the EWS/Fli1 fusion gene in Ewing Sarcoma cells that are end-blocked with phosphorothioate bonds and additionally sealed with a 2’-U modified DNA protector can be used to induce specific and potent killing of cells containing the target oncogenic sequence, but not wildtype.

scholarly journals Development of a Novel Class of Self-Assembling dsRNA Cancer Therapeutics: A Proof-of-Concept Investigation

2020 ◽  
Vol 18 ◽  
pp. 419-431
Author(s):  
Vishwaratn Asthana ◽  
Brett S. Stern ◽  
Yuqi Tang ◽  
Pallavi Bugga ◽  
Ang Li ◽  
...  
Keyword(s):  
Cancer Therapeutics ◽  
Proof Of Concept ◽  
Self Assembling

Role of Phytochemicals in the Treatment of Breast Cancer: Natural Swords battling Cancer Cells

2021 ◽  
Vol 16 ◽  
Author(s):  
Rajni Sawanny ◽  
Sheersha Pramanik ◽  
Unnati Agarwal
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
Low Cost ◽  
Epigallocatechin Gallate ◽  
Cancer Therapeutics ◽  
Treatment Modalities ◽  
Breast Cancer Patients ◽  
Scientific Validity ◽  
Phytochemical Study ◽  
Treat Breast Cancer

: Breast cancer is the most common type of malignancy among ladies (around 30% of newly diagnosed patients every year). To date, various modern treatment modalities for breast cancer, such as radiotherapy, surgical method, hormonal therapy, and chemotherapeutic drug utilisation, are available. However, adverse drug reactions, therapeutic resistance, metastasis, or cancer reoccurrence chances remain the primary causes of mortality for breast cancer patients. To overcome all the potential drawbacks, we need to investigate novel techniques and strategies previously not considered and treat breast cancer effectively with safety and efficacy. For centuries, we utilise phytochemicals to treat various diseases because of their safety, low-cost & least or no side effects. Recently, naturally produced phytochemicals gain immense attention as potential breast cancer therapeutics because of their ideal characteristics; for instance, they operate via modulating molecular pathways associated with cancer growth and progression. The primary mechanism involves inhibition of cell proliferation, angiogenesis, migration, invasion, increasing anti-oxidant status, initiation of the arrest of the cell cycle, and apoptosis. Remedial viability gets effectively enhanced when phytochemicals work as adjuvants with chemotherapeutic drugs. This comprehensive review revolves around the latest chemopreventive, chemotherapeutic, and chemoprotective treatments with their molecular mechanisms to treat breast cancer by utilising phytochemicals such as vinca alkaloids, resveratrol, curcumin, paclitaxel, silibinin, quercetin, genistein and epigallocatechin gallate. The authors wish to extend the field of phytochemical study for its scientific validity and its druggability.

scholarly journals Potent pro-apoptotic combination therapy is highly effective in a broad range of cancers

2021 ◽  
Author(s):  
Antonella Montinaro ◽  
Itziar Areso Zubiaur ◽  
Julia Saggau ◽  
Anna-Laura Kretz ◽  
Rute M. M. Ferreira ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Cancer Cells ◽  
Standard Of Care ◽  
Therapy Resistance ◽  
Treatment Modalities ◽  
Cancer Resistance ◽  
Therapeutic Approaches ◽  
Highly Effective ◽  
Drastic Increase ◽  
New Treatment

AbstractPrimary or acquired therapy resistance is a major obstacle to the effective treatment of cancer. Resistance to apoptosis has long been thought to contribute to therapy resistance. We show here that recombinant TRAIL and CDK9 inhibition cooperate in killing cells derived from a broad range of cancers, importantly without inducing detectable adverse events. Remarkably, the combination of TRAIL with CDK9 inhibition was also highly effective on cancers resistant to both, standard-of-care chemotherapy and various targeted therapeutic approaches. Dynamic BH3 profiling revealed that, mechanistically, combining TRAIL with CDK9 inhibition induced a drastic increase in the mitochondrial priming of cancer cells. Intriguingly, this increase occurred irrespective of whether the cancer cells were sensitive or resistant to chemo- or targeted therapy. We conclude that this pro-apoptotic combination therapy has the potential to serve as a highly effective new treatment option for a variety of different cancers. Notably, this includes cancers that are resistant to currently available treatment modalities.

scholarly journals A Self-Assembling Whole-Cell Vaccine Antigen Presentation Platform

2018 ◽  
Vol 200 (15) ◽  
Author(s):  
Julie Liao ◽  
Daniel R. Smith ◽  
Jóhanna Brynjarsdóttir ◽  
Paula I. Watnick
Keyword(s):  
Vibrio Cholerae ◽  
Bacterial Biofilm ◽  
Cell Vaccine ◽  
Secreted Protein ◽  
Proof Of Concept ◽  
Whole Cell ◽  
Content Type ◽  
Self Assembling ◽  
Whole Cell Vaccine ◽  
Common Infection

ABSTRACTDiarrhea is the most common infection in children under the age of 5 years worldwide. In spite of this, only a few vaccines to treat infectious diarrhea exist, and many of the available vaccines are sparingly and sporadically administered. Major obstacles to the development and widespread implementation of vaccination include the ease and cost of production, distribution, and delivery. Here we present a novel, customizable, and self-assembling vaccine platform that exploits theVibrio choleraebacterial biofilm matrix for antigen presentation. We use this technology to create a proof-of-concept, live-attenuated whole-cell vaccine that is boosted by spontaneous association of a secreted protein antigen with the cell surface. Sublingual administration of this live-attenuated vaccine to mice confers protection againstV. choleraechallenge and elicits the production of antigen-specific IgA in stool. The platform presented here enables the development of antigen-boosted vaccines that are simple to produce and deliver, addressing many of the obstacles to vaccination against diarrheal diseases. This may also serve as a paradigm for the development of broadly protective biofilm-based vaccines against other mucosal infections.IMPORTANCEDiarrheal disease is the most common infection afflicting children worldwide. In resource-poor settings, these infections are correlated with cognitive delay, stunted growth, and premature death. With the development of efficacious, affordable, and easily administered vaccines, such infections could be prevented. While a major focus of research on biofilms has been their elimination, here we harness the bacterial biofilm to create a customizable platform for cost-effective, whole-cell mucosal vaccines that self-incorporate secreted protein antigens. We use this platform to develop a sublingually administered live-attenuated prototype vaccine based onVibrio cholerae. This serves not only as a proof of concept for a multivalent vaccine against common bacterial enteric pathogens but also as a paradigm for vaccines utilizing other bacterial biofilms to target mucosal infections.

Pharmacogenomics, Pharmacokinetics, and Pharmacodynamics in the Era of Targeted Therapies

2016 ◽  
pp. e175-e184 ◽  
Author(s):  
Emiliano Calvo ◽  
Christine Walko ◽  
E. Claire Dees ◽  
Belén Valenzuela
Keyword(s):  
Targeted Therapies ◽  
Acquired Resistance ◽  
Cancer Therapeutics ◽  
Assessment Tools ◽  
Therapeutic Drug ◽  
Complex Nature ◽  
The Past ◽  
Negative Effect ◽  
Difficult Challenge ◽  
Treatment Tolerance

The complex nature of the pharmacologic aspects of cancer therapeutics has become more apparent in the past several years with the arrival of a cascade of target-based agents and the difficult challenge of bringing individualized precision medicine to oncology. Interpatient variability in drug action, singularly in novel agents, is in part caused by pharmacogenomic (PG), pharmacokinetic, and pharmacodynamic (PD) factors, and drug selection and dosing should take this into consideration to optimize the benefit for our patients in terms of antitumor activity and treatment tolerance. In this regard, somatic genetic evaluation of tumors is useful in not only predicting response to initial targeted therapies but also in anticipating and guiding therapy after the development of acquired resistance; therapeutic drug monitoring of novel small molecules and monoclonal antibodies must be incorporated in our day-to-day practice to minimize the negative effect on clinical outcome of interindividual variability on pharmacokinetic processes of these drugs for all patients, but especially for fragile patient populations and those with organ dysfunction or comorbidities. For these populations, incorporating frailty assessment tools into trials of newer agents and validating frailty-based dose adjustment should be an important part of further drug development.

scholarly journals Gene expression profile by blocking the SYT-SSX fusion gene in synovial sarcoma cells. Identification of XRCC4 as a putative SYT-SSX target gene

Oncogene ◽  
2003 ◽  
Vol 22 (48) ◽  
pp. 7628-7631 ◽  
Author(s):  
Yuntao Xie ◽  
Maria Törnkvist ◽  
Yan Aalto ◽  
Gunnar Nilsson ◽  
Leonard Girnita ◽  
...  
Keyword(s):  
Gene Expression ◽  
Synovial Sarcoma ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Target Gene ◽  
Fusion Gene ◽  
Sarcoma Cells

scholarly journals Folding Angle Regulation by Curved Crease Design for Self-Assembling Origami Propellers

2015 ◽  
Vol 7 (2) ◽  
Author(s):  
Shuhei Miyashita ◽  
Isabella DiDio ◽  
Ishwarya Ananthabhotla ◽  
Byoungkwon An ◽  
Cynthia Sung ◽  
...  
Keyword(s):  
Magnetic Field ◽  
Three Dimensional ◽  
Layered Materials ◽  
The Self ◽  
Proof Of Concept ◽  
Folding Process ◽  
Folding Angle ◽  
Curved Structures ◽  
Self Assembling ◽  
Uniform Heat

This paper describes a method for manufacturing complex three-dimensional curved structures by self-folding layered materials. Our main focus is to first show that the material can cope with curved crease self-folding and then to utilize the curvature to predict the folding angles. The self-folding process employs uniform heat to induce self-folding of the material and shows the successful generation of several types of propellers as a proof of concept. We further show the resulting device is functional by demonstrating its levitation in the presence of a magnetic field applied remotely.

scholarly journals Self-assembly of an anion receptor with metal-dependent kinase inhibition and potent in vitro anti-cancer properties

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Simon J. Allison ◽  
Jaroslaw Bryk ◽  
Christopher J. Clemett ◽  
Robert A. Faulkner ◽  
Michael Ginger ◽  
...  
Keyword(s):  
Self Assembly ◽  
Human Cancer ◽  
Cancer Therapeutics ◽  
Selective Inhibition ◽  
Human Cancer Cell Lines ◽  
Cellular Processes ◽  
Self Assembling ◽  
Anti Cancer ◽  
Anionic Species

AbstractOne topical area of supramolecular chemistry is the binding of anionic species but despite the importance of anions in diverse cellular processes and for cancer development, anion receptors or ‘binders’ have received little attention as potential anti-cancer therapeutics. Here we report self-assembling trimetallic cryptands (e.g. [L2(Metal)3]6+ where Metal = Cu2+, Zn2+ or Mn2+) which can encapsulate a range of anions and which show metal-dependent differences in chemical and biological reactivities. In cell studies, both [L2Cu3]6+ and [L2Zn3]6+ complexes are highly toxic to a range of human cancer cell lines and they show significant metal-dependent selective activity towards cancer cells compared to healthy, non-cancerous cells (by up to 2000-fold). The addition of different anions to the complexes (e.g. PO43ˉ, SO42ˉ or PhOPO32ˉ) further alters activity and selectivity allowing the activity to be modulated via a self-assembly process. The activity is attributed to the ability to either bind or hydrolyse phosphate esters and mechanistic studies show differential and selective inhibition of multiple kinases by both [L2Cu3]6+ and [L2Zn3]6+ complexes but via different mechanisms.

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