scholarly journals Recent Advances in the Delivery Carriers and Chemical Conjugation Strategies for Nucleic Acid Drugs

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3881
Author(s):  
Shota Oyama ◽  
Tsuyoshi Yamamoto ◽  
Asako Yamayoshi
Keyword(s):  
Nucleic Acid ◽  
Cancer Therapy ◽  
Cancer Treatment ◽  
Target Genes ◽  
Loss Of Function ◽  
Ligand Modification ◽  
Chemical Conjugation ◽  
The Future ◽  
Small Chemical ◽  
Nucleic Acid Drug

With the development of new anticancer medicines, novel modalities are being explored for cancer treatment. For many years, conventional modalities, such as small chemical drugs and antibody drugs, have worked by “inhibiting the function” of target proteins. In recent years, however, nucleic acid drugs, such as ASOs and siRNAs, have attracted attention as a new modality for cancer treatment because nucleic acid drugs can directly promote the “loss of function” of target genes. Recently, nucleic acid drugs for use in cancer therapy have been extensively developed and some of them have currently been under investigation in clinical trials. To develop novel nucleic acid drugs for cancer treatment, it is imperative that cancer researchers, including ourselves, cover and understand those latest findings. In this review, we introduce and provide an overview of various DDSs and ligand modification technologies that are being employed to improve the success and development of nucleic acid drugs, then we also discuss the future of nucleic acid drug developments for cancer therapy. It is our belief this review will increase the awareness of nucleic acid drugs worldwide and build momentum for the future development of new cancer-targeted versions of these drugs.

scholarly journals Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer

2022 ◽  
Author(s):  
Shengliang Zhang ◽  
Lindsey Carlsen ◽  
Liz Hernandez Borrero ◽  
Attila A. Seyhan ◽  
Xiaobing Tian ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Target Genes ◽  
P53 Protein ◽  
Suppressor Gene ◽  
Functional Restoration ◽  
Mutant P53 ◽  
Combination Therapies ◽  
Loss Of Function ◽  
Wild Type ◽  
Promising Target

TP53 is a tumor suppressor gene that encodes a sequence-specific DNA-binding transcription factor activated by stressful stimuli and upregulates target genes involved in growth suppression, cell death, DNA repair, metabolism, among others. P53 is the most frequently mutated gene in tumors with mutations not only leading to loss-of-function (LOF), but also gain-of-function (GOF) which promotes tumor progression, and metastasis. The tumor-specific status of mutant p53 protein has suggested it is a promising target for cancer therapy. We summarize the current progress of targeting wild-type and mutant p53 for cancer therapy through biotherapeutic and biopharmaceutical methods for 1) boosting p53 activity in cancer, 2) p53-dependent and p53-independent strategies for targeting p53 pathway functional restoration in p53-mutated cancer, 3) targeting p53 in immunotherapy, and 4) combination therapies targeting p53, p53 checkpoints, or mutant p53 for cancer therapy.

scholarly journals Targeting Myc Interacting Proteins as a Winding Path in Cancer Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Yihui Zhou ◽  
Xiaomeng Gao ◽  
Meng Yuan ◽  
Bo Yang ◽  
Qiaojun He ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Cancer Treatment ◽  
Half Life ◽  
Target Genes ◽  
Interacting Proteins ◽  
Hematologic Neoplasms ◽  
Invasion And Metastasis ◽  
Post Translational Modifications ◽  
The Stability ◽  
Low Expression

MYC, as a well-known oncogene, plays essential roles in promoting tumor occurrence, development, invasion and metastasis in many kinds of solid tumors and hematologic neoplasms. In tumors, the low expression and the short half-life of Myc are reversed, cause tumorigenesis. And proteins that directly interact with different Myc domains have exerted a significant impact in the process of Myc-driven carcinogenesis. Apart from affecting the transcription of Myc target genes, Myc interaction proteins also regulate the stability of Myc through acetylation, methylation, phosphorylation and other post-translational modifications, as well as competitive combination with Myc. In this review, we summarize a series of Myc interacting proteins and recent advances in the related inhibitors, hoping that can provide new opportunities for Myc-driven cancer treatment.

Utilizing Cancer - Functional Gene Set - Compound Networks to Identify Putative Drugs for Breast Cancer

2018 ◽  
Vol 21 (2) ◽  
pp. 74-83
Author(s):  
Tzu-Hung Hsiao ◽  
Yu-Chiao Chiu ◽  
Yu-Heng Chen ◽  
Yu-Ching Hsu ◽  
Hung-I Harry Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Therapy ◽  
Cancer Treatment ◽  
Cancer Survival ◽  
Expression Profiles ◽  
Functional Gene ◽  
Gene Set Enrichment Analysis ◽  
Gene Set ◽  
Gene Sets

Aim and Objective: The number of anticancer drugs available currently is limited, and some of them have low treatment response rates. Moreover, developing a new drug for cancer therapy is labor intensive and sometimes cost prohibitive. Therefore, “repositioning” of known cancer treatment compounds can speed up the development time and potentially increase the response rate of cancer therapy. This study proposes a systems biology method for identifying new compound candidates for cancer treatment in two separate procedures. Materials and Methods: First, a “gene set–compound” network was constructed by conducting gene set enrichment analysis on the expression profile of responses to a compound. Second, survival analyses were applied to gene expression profiles derived from four breast cancer patient cohorts to identify gene sets that are associated with cancer survival. A “cancer–functional gene set– compound” network was constructed, and candidate anticancer compounds were identified. Through the use of breast cancer as an example, 162 breast cancer survival-associated gene sets and 172 putative compounds were obtained. Results: We demonstrated how to utilize the clinical relevance of previous studies through gene sets and then connect it to candidate compounds by using gene expression data from the Connectivity Map. Specifically, we chose a gene set derived from a stem cell study to demonstrate its association with breast cancer prognosis and discussed six new compounds that can increase the expression of the gene set after the treatment. Conclusion: Our method can effectively identify compounds with a potential to be “repositioned” for cancer treatment according to their active mechanisms and their association with patients’ survival time.

scholarly journals Chemical conjugation of nucleic acid aptamers and synthetic polymers

2021 ◽  
Author(s):  
Maria Nerantzaki ◽  
Capucine Loth ◽  
Jean-Francois Lutz
Keyword(s):  
Nucleic Acid ◽  
Synthetic Polymers ◽  
Specific Sequence ◽  
Biological Targets ◽  
Nucleic Acid Aptamers ◽  
Chemical Conjugation ◽  
Sequence Dependent

Nucleic acid aptamers are chemically-synthesized single-stranded oligonucleotides that fold into specific sequence-dependent configurations. Due to their exceptional recognition properties towards a variety of biological targets, they find applications in many...

scholarly journals Photocontrolled apoptosis induction using precursor miR-664a and an RNA carrier-conjugated with photosensitizer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kazunori Watanabe ◽  
Tomoko Nawachi ◽  
Ruriko Okutani ◽  
Takashi Ohtsuki
Keyword(s):  
Cancer Therapy ◽  
Cell Types ◽  
Drug Candidate ◽  
Apoptosis Induction ◽  
Delivery Method ◽  
Apoptotic Pathway ◽  
Photochemical Internalization ◽  
Therapeutic Uses ◽  
Induction Of Apoptosis ◽  
Nucleic Acid Drug

AbstractMethods to spatially induce apoptosis are useful for cancer therapy. To control the induction of apoptosis, methods using light, such as photochemical internalization (PCI), have been developed. We hypothesized that photoinduced delivery of microRNAs (miRNAs) that regulate apoptosis could spatially induce apoptosis. In this study, we identified pre-miR-664a as a novel apoptosis-inducing miRNA via mitochondrial apoptotic pathway. Further, we demonstrated the utility of photoinduced cytosolic dispersion of RNA (PCDR), which is an intracellular RNA delivery method based on PCI. Indeed, apoptosis is spatially regulated by pre-miR-664a and PCDR. In addition, we found that apoptosis induced by pre-miR-664a delivered by PCDR was more rapid than that by lipofection. These results suggest that pre-miR-664a is a nucleic acid drug candidate for cancer therapy and PCDR and pre-miR-664a-based strategies have potential therapeutic uses for diseases affecting various cell types.

scholarly journals Increased presence of nuclear DNAJA3 and upregulation of cytosolic STAT1 and of nucleic acid sensors trigger innate immunity in the ClpP-null mouse

Neurogenetics ◽  
2021 ◽  
Author(s):  
Antonia Maletzko ◽  
Jana Key ◽  
Ilka Wittig ◽  
Suzana Gispert ◽  
Gabriele Koepf ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Nucleic Acid ◽  
Inflammatory Responses ◽  
Subcellular Fractionation ◽  
Inflammatory Factors ◽  
Null Mouse ◽  
Loss Of Function ◽  
Response Factors ◽  
Perrault Syndrome ◽  
Acid Sensors

AbstractMitochondrial dysfunction may activate innate immunity, e.g. upon abnormal handling of mitochondrial DNA in TFAM mutants or in altered mitophagy. Recent reports showed that also deletion of mitochondrial matrix peptidase ClpP in mice triggers transcriptional upregulation of inflammatory factors. Here, we studied ClpP-null mouse brain at two ages and mouse embryonal fibroblasts, to identify which signaling pathways are responsible, employing mass spectrometry, subcellular fractionation, immunoblots, and reverse transcriptase polymerase chain reaction. Several mitochondrial unfolded protein response factors showed accumulation and altered migration in blue-native gels, prominently the co-chaperone DNAJA3. Its mitochondrial dysregulation increased also its extra-mitochondrial abundance in the nucleus, a relevant observation given that DNAJA3 modulates innate immunity. Similar observations were made for STAT1, a putative DNAJA3 interactor. Elevated expression was observed not only for the transcription factors Stat1/2, but also for two interferon-stimulated genes (Ifi44, Gbp3). Inflammatory responses were strongest for the RLR pattern recognition receptors (Ddx58, Ifih1, Oasl2, Trim25) and several cytosolic nucleic acid sensors (Ifit1, Ifit3, Oas1b, Ifi204, Mnda). The consistent dysregulation of these factors from an early age might influence also human Perrault syndrome, where ClpP loss-of-function leads to early infertility and deafness, with subsequent widespread neurodegeneration.

Coconut-shell-derived activated carbon for NIR photo-activated synergistic photothermal-chemodynamic cancer therapy

2021 ◽  
Author(s):  
Gang Wu ◽  
Bao Jiang ◽  
Lin Zhou ◽  
Ao Wang ◽  
Shaohua Wei
Keyword(s):  
Activated Carbon ◽  
Cancer Therapy ◽  
Cancer Treatment ◽  
Photothermal Therapy ◽  
Carbon Nanoparticles ◽  
Coconut Shell ◽  
Photothermal Conversion

Activated carbon nanoparticles (ANs) were synthesized from coconut shell. ANs show peroxidase and photothermal conversion activities, allowing synergistic cancer treatment via chemodynamic therapy (CDT) and photothermal therapy (PTT).

scholarly journals Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Julia M. Kempf ◽  
Sabrina Weser ◽  
Michael D. Bartoschek ◽  
Klaus H. Metzeler ◽  
Binje Vick ◽  
...  
Keyword(s):  
Target Genes ◽  
Chemotherapeutic Agent ◽  
Chemotherapy Resistance ◽  
Xenograft Model ◽  
Histone Methyltransferase ◽  
Loss Of Function ◽  
Resistance Development ◽  
Selective Growth Advantage ◽  
Patient Derived Xenograft ◽  
Transmembrane Transporter

AbstractChemotherapy resistance is the main impediment in the treatment of acute myeloid leukaemia (AML). Despite rapid advances, the various mechanisms inducing resistance development remain to be defined in detail. Here we report that loss-of-function mutations (LOF) in the histone methyltransferase EZH2 have the potential to confer resistance against the chemotherapeutic agent cytarabine. We identify seven distinct EZH2 mutations leading to loss of H3K27 trimethylation via multiple mechanisms. Analysis of matched diagnosis and relapse samples reveal a heterogenous regulation of EZH2 and a loss of EZH2 in 50% of patients. We confirm that loss of EZH2 induces resistance against cytarabine in the cell lines HEK293T and K562 as well as in a patient-derived xenograft model. Proteomics and transcriptomics analysis reveal that resistance is conferred by upregulation of multiple direct and indirect EZH2 target genes that are involved in apoptosis evasion, augmentation of proliferation and alteration of transmembrane transporter function. Our data indicate that loss of EZH2 results in upregulation of its target genes, providing the cell with a selective growth advantage, which mediates chemotherapy resistance.

scholarly journals DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ruixue Huang ◽  
Ping-Kun Zhou
Keyword(s):  
Dna Damage ◽  
Cancer Therapy ◽  
Cancer Treatment ◽  
Dna Damage Response ◽  
Dna Damage Repair ◽  
Therapeutic Effects ◽  
Targeted Cancer Therapy ◽  
Baseline Drift ◽  
Damage Repair ◽  
Damage Response

AbstractGenomic instability is the hallmark of various cancers with the increasing accumulation of DNA damage. The application of radiotherapy and chemotherapy in cancer treatment is typically based on this property of cancers. However, the adverse effects including normal tissues injury are also accompanied by the radiotherapy and chemotherapy. Targeted cancer therapy has the potential to suppress cancer cells’ DNA damage response through tailoring therapy to cancer patients lacking specific DNA damage response functions. Obviously, understanding the broader role of DNA damage repair in cancers has became a basic and attractive strategy for targeted cancer therapy, in particular, raising novel hypothesis or theory in this field on the basis of previous scientists’ findings would be important for future promising druggable emerging targets. In this review, we first illustrate the timeline steps for the understanding the roles of DNA damage repair in the promotion of cancer and cancer therapy developed, then we summarize the mechanisms regarding DNA damage repair associated with targeted cancer therapy, highlighting the specific proteins behind targeting DNA damage repair that initiate functioning abnormally duo to extrinsic harm by environmental DNA damage factors, also, the DNA damage baseline drift leads to the harmful intrinsic targeted cancer therapy. In addition, clinical therapeutic drugs for DNA damage and repair including therapeutic effects, as well as the strategy and scheme of relative clinical trials were intensive discussed. Based on this background, we suggest two hypotheses, namely “environmental gear selection” to describe DNA damage repair pathway evolution, and “DNA damage baseline drift”, which may play a magnified role in mediating repair during cancer treatment. This two new hypothesis would shed new light on targeted cancer therapy, provide a much better or more comprehensive holistic view and also promote the development of new research direction and new overcoming strategies for patients.

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