scholarly journals Ancient hot and cold genes and chemotherapy resistance emergence

2015 ◽  
Vol 112 (33) ◽  
pp. 10467-10472 ◽  
Author(s):  
Amy Wu ◽  
Qiucen Zhang ◽  
Guillaume Lambert ◽  
Zayar Khin ◽  
Robert A. Gatenby ◽  
...  

We use a microfabricated ecology with a doxorubicin gradient and population fragmentation to produce a strong Darwinian selective pressure that drives forward the rapid emergence of doxorubicin resistance in multiple myeloma (MM) cancer cells. RNA sequencing of the resistant cells was used to examine (i) emergence of genes with high de novo substitution densities (i.e., hot genes) and (ii) genes never substituted (i.e., cold genes). The set of cold genes, which were 21% of the genes sequenced, were further winnowed down by examining excess expression levels. Both the most highly substituted genes and the most highly expressed never-substituted genes were biased in age toward the most ancient of genes. This would support the model that cancer represents a revision back to ancient forms of life adapted to high fitness under extreme stress, and suggests that these ancient genes may be targets for cancer therapy.

2021 ◽  
Vol 17 (1) ◽  
pp. 104-120
Author(s):  
N. Ivanenko

Relevance. Treatment of solid tumors and biofilm-derived infections face a common problem: drugs often fail to reach and kill cancer cells and microbial pathogens because of local microenvironment heterogeneities. There are remarkable challenges for current and prospective anticancer and antibiofilm agents to target and maintain activity in the microenvironments where cancer cells and microbial pathogens survive and cause the onset of disease. Bacterial infections in cancer formation will increase in the coming years. Collection of approaches such as ROS modulation in cells, the tumor is promoted by microbe’s inflammation can be a strategy to target cancer and bacteria. Besides that, bacteria may take the advantage of oxygen tension and permissive carbon sources, therefore the tumor microenvironment (TM) becomes a potential refuge for bacteria. It is noteworthy that the relationship between cancer and bacteria is intertwined. Objective: To analyze similarities between biofilm and tumor milieu that is produced against stress conditions and heterogeneous microenvironment for a combination of approaches the bacteriotherapy with chemotherapy which can help in defeating the tumor heterogeneity accompanied with malignancy, drug-resistance, and metastasis. Method: An analytical review of the literature on keywords from the scientometric databases PubMed, Wiley. Results: Bacteria evade antimicrobial treatment is mainly due to persistence that has become dormant during the stationary phase and tolerance. Drug-tolerant persisters and cellular dormancy are crucial in the development of cancer, especially in understanding the development of metastases as a late relapse. Biofilms are formed by groups of cells in different states, growing or non-growing and metabolically active or inactive in variable fractions, depending on maturity and on chemical gradients (O2 and nutrients) of the biofilms producing physiological heterogeneity. Heterogeneity in the microenvironment of cancer can be described as a non-cell autonomous driver of cancer cell diversity; in a highly diverse microenvironment, different cellular phenotypes may be selected for or against in different regions of the tumor. Hypoxia, oxidative stress, and inflammation have been identified as positive regulators of metastatic potential, drug resistance, and tumorigenic properties in cancer. It is proven that, Escherichia coli (E. coli) and life-threatening infectious pathogens such as Staphylococcus aureus (SA) and Mycobacterium tuberculosis (Mtb) are noticeably sensitive to alterations in the intracellular oxidative environment.  An alternative emerging paradigm is that many cancers may be promoted by commensal microbiota, either by translocation and adherence of microbes to cancer cells or by the distant release of inflammation-activating microbial metabolites. Microbial factors such as F. nucleatum, B. fragilis, and Enterobacteriaceae members may contribute to disease onset in patients with a hereditary form of colorectal cancer (CRC); familial adenomatous polyposis (FAP). These findings are linked with the creation of new biomarkers and therapy for identifying and treating biofilm-associated cancers.  Currently,  about 20% of neoplasms globally can be caused by infections, with  approximately 1.2 million cases annually. Several antineoplastic drugs that exhibited activity against S. mutans, including tamoxifen, doxorubicin, and ponatinib, also possessed activity against other Gram-positive bacteria. Drug repurposing, also known as repositioning, has gained momentum, mostly due to its advantages over de novo drug discovery, including reduced risk to patients due to previously documented clinical trials, lower drug development costs, and faster benchtop-to-clinic transition. Although many bacteria are carcinogens and tumor promoters, some have shown great potential towards cancer therapy. Several species of bacteria have shown an impressive power to penetrate and colonize solid tumors, which has mainly led to neoplasm slower growth and   tumor clearance.  Different strains of Clostridia, Lactococcus, Bifidobacteria, Shigella, Vibrio, Listeria, Escherichia, and Salmonella have been evaluated against cancer in animal models.  Conclusion. Cancer is a multifactorial disease and the use of bacteria for cancer therapy as an immunostimulatory agent or as a vector for carrying the therapeutic cargo is a promising treatment method. Therefore, the world has turned to an alternative solution, which is the use of genetically engineered microorganisms; thus, the use of living bacteria targeting cancerous cells is the unique option to overcome these challenges. Bacterial therapies, whether used alone or combination with chemotherapy, give a positive effect to treat multiple conditions of cancer.


2020 ◽  
Author(s):  
Marica Rosaria Ippolito ◽  
Valentino Martis ◽  
Christy Hong ◽  
René Wardenaar ◽  
Johanna Zerbib ◽  
...  

AbstractMitotic errors lead to aneuploidy, a condition of karyotype imbalance, frequently found in cancer cells. Alterations in chromosome copy number induce a wide variety of cellular stresses, including genome instability. Here, we show that cancer cells might exploit aneuploidy-induced genome instability to survive under conditions of selective pressure, such as chemotherapy. Resistance to chemotherapeutic drugs was dictated by the acquisition of recurrent karyotypes, indicating that gene dosage, together with mutational burden, might play a role in driving chemoresistance. Thus, our study establishes a causal link between aneuploidy-driven genome instability and chemoresistance and might explain why some chemotherapies fail to succeed.


Author(s):  
Menghan Gao ◽  
Hong Deng ◽  
Weiqi Zhang

: Hyaluronan (HA) is a natural linear polysaccharide that has excellent hydrophilicity, biocompatibility, biodegradability, and low immunogenicity, making it one of the most attractive biopolymers used for biomedical researches and applications. Due to the multiple functional sites on HA and its intrinsic affinity for CD44, a receptor highly expressed on various cancer cells, HA has been widely engineered to construct different drug-loading nanoparticles (NPs) for CD44- targeted anti-tumor therapy. When a cocktail of drugs is co-loaded in HA NP, a multifunctional nano-carriers could be obtained, which features as a highly effective and self-targeting strategy to combat the cancers with CD44 overexpression. The HA-based multidrug nano-carriers can be a combination of different drugs, various therapeutic modalities, or the integration of therapy and diagnostics (theranostics). Up to now, there are many types of HA-based multidrug nano-carriers constructed by different formulation strategies including drug co-conjugates, micelles, nano-gels and hybrid NP of HA and so on. This multidrug nano-carrier takes the full advantages of HA as NP matrix, drug carriers and targeting ligand, representing a simplified and biocompatible platform to realize the targeted and synergistic combination therapy against the cancers. In this review, recent progresses about HA-based multidrug nano-carriers for combination cancer therapy are summarized and its potential challenges for translational applications have been discussed.


Cell Cycle ◽  
2014 ◽  
Vol 13 (15) ◽  
pp. 2415-2430 ◽  
Author(s):  
Lakshmi Reddy Bollu ◽  
Jiangong Ren ◽  
Alicia Marie Blessing ◽  
Rajasekhara Reddy Katreddy ◽  
Guang Gao ◽  
...  

Nanoscale ◽  
2020 ◽  
Vol 12 (18) ◽  
pp. 10189-10195 ◽  
Author(s):  
Xin Zhao ◽  
Dongyang Tang ◽  
Ying Wu ◽  
Shaoqing Chen ◽  
Cheng Wang

The artifical cell system for the gene therapy of cancer might be a promising approach for the reversal of neoplastic progress of cancer cells.


Author(s):  
Xiao Lei ◽  
Kun Cao ◽  
Yuanyuan Chen ◽  
Hui Shen ◽  
Zhe Liu ◽  
...  

Abstract Background To block repairs of DNA damages, especially the DNA double strand break (DSB) repair, can be used to induce cancer cell death. DSB repair depends on a sequential activation of DNA repair factors that may be potentially targeted for clinical cancer therapy. Up to now, many protein components of DSB repair complex remain unclear or poorly characterized. In this study, we discovered that Transglutaminase 2 (TG2) acted as a new component of DSB repair complex. Methods A bioinformatic analysis was performed to identify DNA damage relative genes from dataset from The Cancer Genome Atlas. Immunofluorescence and confocal microscopy were used to monitor the protein localization and recruitment kinetics. Furthermore, immunoprecipitation and mass spectrometry analysis were performed to determine protein interaction of both full-length and fragments or mutants in distinct domain. In situ lung cancer model was used to study the effects cancer therapy in vivo. Results After DSB induction, cytoplasmic TG2 was extensively mobilized and translocated into nucleus after phosphorylated at T162 site by DNA-PKcs. Nuclear TG2 quickly accumulated at DSB sites and directly interacting with Topoisomerase IIα (TOPOIIα) with its TGase domain to promote DSB repair. TG2 deficient cells lost capacity of DSB repair and become susceptible to ionizing radiation. Specific inhibition of TG2-TOPOIIα interaction by glucosamine also significantly inhibited DSB repair, which increased sensitivity in lung cancer cells and engrafted lung cancers. Conclusions These findings elucidate new mechanism of TG2 in DSB repair trough directly interacting with TOPOIIα, inhibition of which provided potential target for overcoming cancer resistance.


2021 ◽  
Vol 11 (3) ◽  
pp. 1259
Author(s):  
Qiong Wu ◽  
Bo Zhao ◽  
Guangchao Sui ◽  
Jinming Shi

Aberrant metabolism is one of the hallmarks of cancers. The contributions of dysregulated metabolism to cancer development, such as tumor cell survival, metastasis and drug resistance, have been extensively characterized. “Reprogrammed” metabolic pathways in cancer cells are mainly represented by excessive glucose consumption and hyperactive de novo lipogenesis. Natural compounds with anticancer activities are constantly being demonstrated to target metabolic processes, such as glucose transport, aerobic glycolysis, fatty acid synthesis and desaturation. However, their molecular targets and underlying anticancer mechanisms remain largely unclear or controversial. Mounting evidence indicated that these natural compounds could modulate the expression of key regulatory enzymes in various metabolic pathways at transcriptional and translational levels. Meanwhile, natural compounds could also inhibit the activities of these enzymes by acting as substrate analogs or altering their protein conformations. The actions of natural compounds in the crosstalk between metabolism modulation and cancer cell destiny have become increasingly attractive. In this review, we summarize the activities of natural small molecules in inhibiting key enzymes of metabolic pathways. We illustrate the structural characteristics of these compounds at the molecular level as either inhibitor of various enzymes or regulators of metabolic pathways in cancer cells. Our ultimate goal is to both facilitate the clinical application of natural compounds in cancer therapies and promote the development of novel anticancer therapeutics.


Sign in / Sign up

Export Citation Format

Share Document