scholarly journals Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

2021 ◽  
Vol 11 ◽  
Author(s):  
Seyed Mehdi Havaei ◽  
Marc G. Aucoin ◽  
Ali Jahanian-Najafabadi
Keyword(s):  
Cancer Cells ◽  
Antibody Fragment ◽  
Pseudomonas Exotoxin ◽  
Normal Cells ◽  
Protein Toxin ◽  
Fda Approval ◽  
Protein Toxins ◽  
Human Use ◽  
Almost All ◽  
Cancerous Cells

Cancer is one of the prominent causes of death worldwide. Despite the existence of various modalities for cancer treatment, many types of cancer remain uncured or develop resistance to therapeutic strategies. Furthermore, almost all chemotherapeutics cause a range of side effects because they affect normal cells in addition to malignant cells. Therefore, the development of novel therapeutic agents that are targeted specifically toward cancer cells is indispensable. Immunotoxins (ITs) are a class of tumor cell-targeted fusion proteins consisting of both a targeting moiety and a toxic moiety. The targeting moiety is usually an antibody/antibody fragment or a ligand of the immune system that can bind an antigen or receptor that is only expressed or overexpressed by cancer cells but not normal cells. The toxic moiety is usually a protein toxin (or derivative) of animal, plant, insect, or bacterial origin. To date, three ITs have gained Food and Drug Administration (FDA) approval for human use, including denileukin diftitox (FDA approval: 1999), tagraxofusp (FDA approval: 2018), and moxetumomab pasudotox (FDA approval: 2018). All of these ITs take advantage of bacterial protein toxins. The toxic moiety of the first two ITs is a truncated form of diphtheria toxin, and the third is a derivative of Pseudomonas exotoxin (PE). There is a growing list of ITs using PE, or its derivatives, being evaluated preclinically or clinically. Here, we will review these ITs to highlight the advances in PE-based anticancer strategies, as well as review the targeting moieties that are used to reduce the non-specific destruction of non-cancerous cells. Although we tried to be as comprehensive as possible, we have limited our review to those ITs that have proceeded to clinical trials and are still under active clinical evaluation.

scholarly journals The Expression of Antioxidant Genes and Cytotoxicity of Biosynthesized Cerium Oxide Nanoparticles Against Hepatic Carcinoma Cell Line

2019 ◽  
Vol 7 (1) ◽  
pp. 16-20 ◽  
Author(s):  
Ali Es-haghi ◽  
Fatemeh Javadi ◽  
Mohammad Ehsan Taghavizadeh Yazdi ◽  
Mohammad Sadegh Amiri
Keyword(s):  
Cancer Cells ◽  
Cell Line ◽  
Cerium Oxide ◽  
Carcinoma Cell ◽  
Cerium Oxide Nanoparticles ◽  
Oxide Nanoparticles ◽  
Hepatic Carcinoma ◽  
Normal Cells ◽  
Antioxidant Genes ◽  
Cancerous Cells

Background: Drug resistance due to genetic variations renders many therapeutic methods such as surgery, radiotherapy, chemotherapy, and hormone therapy unsuccessful in eradicating cancerous cells. Nowadays, application of nanoparticles (NPs) has been promising in destroying cancerous cells without side effects on normal cells. Objectives: This study aimed to investigate the antioxidant and anticancer effects of biosynthesized cerium oxide nanoparticles (CeO2 -NPs) on a hepatic carcinoma cell line. Methods: MTT assay was used to determine the cytotoxicity of CeO2 -NPs in concentrations of 0, 15.6, 31.2, 62.5, 125, and 250 μg/mL after 24, 48, and 72 hours of incubation. Moreover, the expression levels of catalase (CAT) and superoxide dismutase (SOD) (the antioxidant genes) were investigated at different concentrations of CeO2 -NPs using real-time polymerase chain reaction (PCR). Results: Our results showed a significant toxicity of the synthesized NPs against the cancerous liver cells. The IC50 calculated for CeO2 -NPs was 500 μg/mL at 24 hours of incubation. In addition, the expression levels of CAT and SOD significantly (P<0.05) increased upon the treatment of cells with CeO2 -NPs (500 µg /mL) compared to the untreated cells. Conclusion: Considering the minimal effects of the biosynthesized CeO2 -NPs on normal cells and on the other hand their considerable toxicity against hepatic cancer cells, these NPs could be utilized in medicine and in the development of new drugs for cancer cells.

scholarly journals FURTHER EXPERIMENTS ON THE CAUSE OF SEQUENTIAL NEOPLASTIC CHANGES

1964 ◽  
Vol 120 (2) ◽  
pp. 197-222 ◽  
Author(s):  
James S. Henderson ◽  
Peyton Rous
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Benign Tumor ◽  
Benign Tumors ◽  
Tissue Fluid ◽  
Normal Cells ◽  
Negative Results ◽  
Malignant Changes ◽  
Favorable Conditions ◽  
Cancerous Cells

When crystalline 20-methylcholanthrene (MC) and the cells of tar-induced mouse papillomas (paps.) are injected together into the thigh muscles of mice the carcinogen exerts a marked promoting and chemotactic influence upon the cells while it is dissolving in the tissue fluid. Under such circumstances it strongly stimulates and attracts them, with result they surround and include the scattered crystals in small cysts that later coalesce to form a larger one from which the MC only very gradually escapes. Because of these findings intramuscular tests were made to learn whether MC would hasten the occurrence or increase the number of cancers that now and again derive from paps.; but the tests were repeatedly marred by the extraordinary behavior of such cancerous cells as happened to be already present in the implanted material. They responded far more actively to MC than did the pap. cells and soon took over the growths. Some carcinomas which failed to grow when transplanted alone, or only gradually formed small, regressing nodules, gave rise rapidly to huge growths of similar sort when exposed to MC. To exclude cancerous cells so far as possible from the later tests small grafts of pap. tissue with MC crystals adhering to them were implanted subcutaneously. The pap. cells promptly lined the graft pockets, encysting the crystals incidentally, and formed tumors that enlarged progressively by keratinizing inwards. While they did this their living layer of pap. tissue was continually bathed in dissolved MC throughout many weeks. Despite these apparently favorable conditions the carcinogen neither hastened the occurrence nor increased the number of visible epidermal cancers deriving from the paps. It also failed to bring about sequential malignant changes in the carcinomas. These negative results accord with those already obtained through long exposure of the benign pulmonary adenomas of mice to urethane or methylcholanthrene, agents which rapidly induce these benign tumors yet which were found to be incapable of furthering the cancerous changes to which such growths are prone. They accord also with another previous finding, namely that MC fails to bring on the malignant changes of discontinuous, sequential sort that mammary mouse carcinomas often undergo "spontaneously." Taken together these facts indicate that the change or changes whereby normal cells are converted into benign tumor cells differ in nature from those taking place when they become cancer cells, as also from those occurring when cancer cells undergo further, step-like, malignant changes. A study has been begun to learn whether the widely various carcinomas deriving from benign papillomas differ from these latter and from one and other in their chromosomal content.

Quantitative Freeze Fracture Studies of Gap Junctions in Somatic Cell Hybrids, Their Parents, and Revertants

1976 ◽  
Vol 34 ◽  
pp. 218-219
Author(s):  
W. J. Larsen ◽  
R. Azarnia ◽  
W. R. Loewenstein
Keyword(s):  
Gap Junctions ◽  
Striated Muscle ◽  
Freeze Fracture ◽  
Cell Movement ◽  
Dye Molecules ◽  
Somatic Cell Hybrids ◽  
Cell Coupling ◽  
Normal Cells ◽  
Mediate Cell ◽  
Almost All

Although the physiological significance of the gap junction remains unspecified, these membrane specializations are now recognized as common to almost all normal cells (excluding adult striated muscle and some nerve cells) and are found in organisms ranging from the coelenterates to man. Since it appears likely that these structures mediate the cell-to-cell movement of ions and small dye molecules in some electrical tissues, we undertook this study with the objective of determining whether gap junctions in inexcitable tissues also mediate cell-to-cell coupling.To test this hypothesis, a coupling, human Lesh-Nyhan (LN) cell was fused with a non-coupling, mouse cl-1D cell, and the hybrids, revertants, and parental cells were analysed for coupling with respect both to ions and fluorescein and for membrane junctions with the freeze fracture technique.

Anticancer Immunotoxins, Challenges, and Approaches

2020 ◽  
Vol 26 ◽  
Author(s):  
Maryam Dashtiahangar ◽  
Leila Rahbarnia ◽  
Safar Farajnia ◽  
Arash Salmaninejad ◽  
Arezoo Gowhari Shabgah ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Antibody Fragment ◽  
Clinical Use ◽  
Multiple Cancer ◽  
Main Obstacle ◽  
Cancer Types ◽  
Recombinant Immunotoxins ◽  
Cancerous Cells ◽  
High Immunogenicity ◽  
Novel Therapeutic

: The development of recombinant immunotoxins (RITs) as a novel therapeutic strategy has made a revolution in the treatment of cancer. RITs are resulting from the fusion of antibodies to toxin proteins for targeting and eliminating cancerous cells by inhibiting protein synthesis. Despite indisputable outcomes of RITs regarding inhibiting multiple cancer types, high immunogenicity has been known as the main obstacle in the clinical use of RITs. Various strategies have been proposed to overcome these limitations, including immunosuppressive therapy, humanization of the antibody fragment moiety, generation of immunotoxins originated from endogenous human cytotoxic enzymes, and modification of the toxin moiety to escape the immune system. This paper devoted to reviewing recent advances in the design of immunotoxins with lower immunogenicity.

Tubulin Proteins in Cancer Resistance: A Review

2020 ◽  
Vol 21 (3) ◽  
pp. 178-185 ◽  
Author(s):  
Mohammad Amjad Kamal ◽  
Maryam Hassan Al-Zahrani ◽  
Salman Hasan Khan ◽  
Mateen Hasan Khan ◽  
Hani Awad Al-Subhi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
High Rate ◽  
Vinca Alkaloids ◽  
Cancer Resistance ◽  
New Approach ◽  
Natural Sources ◽  
Cell Cycle Genes ◽  
Cancerous Cells ◽  
Β Tubulin

Cancer cells are altered with cell cycle genes or they are mutated, leading to a high rate of proliferation compared to normal cells. Alteration in these genes leads to mitosis dysregulation and becomes the basis of tumor progression and resistance to many drugs. The drugs which act on the cell cycle fail to arrest the process, making cancer cell non-responsive to apoptosis or cell death. Vinca alkaloids and taxanes fall in this category and are referred to as antimitotic agents. Microtubule proteins play an important role in mitosis during cell division as a target site for vinca alkaloids and taxanes. These proteins are dynamic in nature and are composed of α-β-tubulin heterodimers. β-tubulin specially βΙΙΙ isotype is generally altered in expression within cancerous cells. Initially, these drugs were very effective in the treatment of cancer but failed to show their desired action after initial chemotherapy. The present review highlights some of the important targets and their mechanism of resistance offered by cancer cells with new promising drugs from natural sources that can lead to the development of a new approach to chemotherapy.

Molecular Studies on Novel Antitumor Bis 1,4-Dihydropyridine Derivatives Against Lung Carcinoma and their Limited Side Effects on Normal Melanocytes

2019 ◽  
Vol 18 (15) ◽  
pp. 2156-2168 ◽  
Author(s):  
Magda F. Mohamed ◽  
Nada S. Ibrahim ◽  
Ahmed H.M. Elwahy ◽  
Ismail A. Abdelhamid
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Cancer Cells ◽  
Cell Line ◽  
Lung Carcinoma ◽  
Carcinoma Cell ◽  
Normal Cells ◽  
Lung Carcinoma Cell Line ◽  
Molecular Studies ◽  
Dihydropyridine Derivatives

Background: Cancer is a complex genetic disease which is characterized by an abnormal cell growth, invasion and spreading to other parts of the body. There are several factors that lead to cancer by causing DNA damage and the impairment of its repair. Treatment of cancer using the chemotherapeutic drugs have adverse side effects such as toxicity as they lose their specificity toward cancer cells and affect also normal cells. Moreover, the cancer cells can resist the chemotherapeutic agents and make them ineffective. For these reasons, much attentions have been paid to develop new drugs with limited side effects on normal cells and to diminish cancer resistance to drug chemotherapy. Recently, some 1,4-dihydropyridine derivatives were reported to act as Multi-Drug Resistance (MDR) modulators that inhibit p-glycoprotein which is responsible for the inability of drugs to enter the cancer cells. Also 1,4-DHPs have antimutagenic properties against chemicals via modulating DNA repair when studied on drosophila. Objective: The objective of this study is the synthesis of bis 1,4-DHPs incorporating ester as well as ether linkages and evaluate the anticancer activity of new compounds for synergistic purpose. Different genetic tools were used in an attempt to know the mechanism of action of this compound against lung cancer. Method: An efficient one pot synthesis of bis 1,4-DHPs using 3-aminocrotononitrile and bis(aldehydes) has been developed. The cytotoxic effect against human cell lines MCF7, and A549 cell lines was evaluated. Results: All compounds exhibited better cytotoxicity toward lung carcinoma cells than breast cancer cells. With respect to lung carcinoma cell line (A549), compound 10 was the most active compound and the three other compounds 7, 8, and 9 showed comparable IC50 values. In case of breast cancer cell line (MCF7), the most active one was compound 7, while compound 8 recorded the least activity. Conclusion: we have developed an efficient method for the synthesis of novel bis 1,4-dihydropyridine derivatives incorporating ester or ether linkage. All compounds showed better cytotoxicity results against A549 than MCF7, so that lung carcinoma cell line was chosen to perform the molecular studies on it. The results showed that all compounds (7, 8, 9 and 10) caused cell cycle arrest at G1 phase. The molecular docking study on CDK2 confirmed the results of cell cycle assay which showed good binding energy between the compounds and the active site of enzyme indicating the inhibition of the enzyme.

scholarly journals Landscape of Chimeric RNAs in Non-Cancerous Cells

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 466
Author(s):  
Chen Chen ◽  
Samuel Haddox ◽  
Yue Tang ◽  
Fujun Qin ◽  
Hui Li
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Drug Targets ◽  
Neoplastic Cell ◽  
Multiple Cancer ◽  
Chimeric Rnas ◽  
Healthy Donors ◽  
Cancer Types ◽  
Chimeric Rna ◽  
Cancerous Cells

Gene fusions and their products (RNA and protein) have been traditionally recognized as unique features of cancer cells and are used as ideal biomarkers and drug targets for multiple cancer types. However, recent studies have demonstrated that chimeric RNAs generated by intergenic alternative splicing can also be found in normal cells and tissues. In this study, we aim to identify chimeric RNAs in different non-neoplastic cell lines and investigate the landscape and expression of these novel candidate chimeric RNAs. To do so, we used HEK-293T, HUVEC, and LO2 cell lines as models, performed paired-end RNA sequencing, and conducted analyses for chimeric RNA profiles. Several filtering criteria were applied, and the landscape of chimeric RNAs was characterized at multiple levels and from various angles. Further, we experimentally validated 17 chimeric RNAs from different classifications. Finally, we examined a number of validated chimeric RNAs in different cancer and non-cancer cells, including blood from healthy donors, and demonstrated their ubiquitous expression pattern.

scholarly journals Normal cells repel WWOX-negative or -dysfunctional cancer cells via WWOX cell surface epitope 286-299

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Yu-An Chen ◽  
Yong-Da Sie ◽  
Tsung-Yun Liu ◽  
Hsiang-Ling Kuo ◽  
Pei-Yi Chou ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cancer Cells ◽  
Room Temperature ◽  
Metastatic Cancer ◽  
Normal Cells ◽  
Tgfβ Receptor ◽  
Membrane Type ◽  
Cell Invasiveness ◽  
And Control ◽  
Metastatic Cancer Cells

AbstractMetastatic cancer cells are frequently deficient in WWOX protein or express dysfunctional WWOX (designated WWOXd). Here, we determined that functional WWOX-expressing (WWOXf) cells migrate collectively and expel the individually migrating WWOXd cells. For return, WWOXd cells induces apoptosis of WWOXf cells from a remote distance. Survival of WWOXd from the cell-to-cell encounter is due to activation of the survival IκBα/ERK/WWOX signaling. Mechanistically, cell surface epitope WWOX286-299 (repl) in WWOXf repels the invading WWOXd to undergo retrograde migration. However, when epitope WWOX7-21 (gre) is exposed, WWOXf greets WWOXd to migrate forward for merge. WWOX binds membrane type II TGFβ receptor (TβRII), and TβRII IgG-pretreated WWOXf greet WWOXd to migrate forward and merge with each other. In contrast, TβRII IgG-pretreated WWOXd loses recognition by WWOXf, and WWOXf mediates apoptosis of WWOXd. The observatons suggest that normal cells can be activated to attack metastatic cancer cells. WWOXd cells are less efficient in generating Ca2+ influx and undergo non-apoptotic explosion in response to UV irradiation in room temperature. WWOXf cells exhibit bubbling cell death and Ca2+ influx effectively caused by UV or apoptotic stress. Together, membrane WWOX/TβRII complex is needed for cell-to-cell recognition, maintaining the efficacy of Ca2+ influx, and control of cell invasiveness.

scholarly journals Quantum Dots as a Good Carriers of Unsymmetrical Bisacridines for Modulating Cellular Uptake and the Biological Response in Lung and Colon Cancer Cells

Nanomaterials ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 462 ◽  
Author(s):  
Joanna Pilch ◽  
Patrycja Kowalik ◽  
Piotr Bujak ◽  
Anna M. Nowicka ◽  
Ewa Augustin
Keyword(s):  
Quantum Dots ◽  
Cancer Cells ◽  
Cellular Uptake ◽  
Laser Scanning ◽  
Biological Response ◽  
Drug Carriers ◽  
Confocal Laser ◽  
Normal Cells ◽  
H460 Cells ◽  
Hct116 Cells

Nanotechnology-based drug delivery provides a promising area for improving the efficacy of cancer treatments. Therefore, we investigate the potential of using quantum dots (QDs) as drug carriers for antitumor unsymmetrical bisacridine derivatives (UAs) to cancer cells. We examine the influence of QD–UA hybrids on the cellular uptake, internalization (Confocal Laser Scanning Microscope), and the biological response (flow cytometry and light microscopy) in lung H460 and colon HCT116 cancer cells. We show the time-dependent cellular uptake of QD–UA hybrids, which were more efficiently retained inside the cells compared to UAs alone, especially in H460 cells, which could be due to multiple endocytosis pathways. In contrast, in HCT116 cells, the hybrids were taken up only by one endocytosis mechanism. Both UAs and their hybrids induced apoptosis in H460 and HCT116 cells (to a greater extent in H460). Cells which did not die underwent senescence more efficiently following QDs–UAs treatment, compared to UAs alone. Cellular senescence was not observed in HCT116 cells following treatment with both UAs and their hybrids. Importantly, QDgreen/red themselves did not provoke toxic responses in cancer or normal cells. In conclusion, QDs are good candidates for targeted UA delivery carriers to cancer cells while protecting normal cells from toxic drug activities.

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