Mechanistic study of the superior anti-cancer properties of a first-in-class small molecule targeting PCNA.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14636-e14636
Author(s):  
Long Gu ◽  
Robert Lingeman ◽  
Min Li ◽  
Robert Hickey ◽  
Yilun Liu ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Clinical Investigation ◽  
Antigenic Site ◽  
Nuclear Antigen ◽  
Mechanistic Study ◽  
Drug Candidate ◽  
Malignant Cells ◽  
Significant Toxicity ◽  
Anti Cancer

e14636 Background: Proliferating cell nuclear antigen (PCNA), through its interaction with various proteins involved in DNA synthesis, cell cycle regulation, and DNA repair, plays a central role in maintaining genome stability. We previously reported a novel cancer associated PCNA isoform (dubbed caPCNA), which was predominantly expressed in a broad range of cancer cells and tumor tissues, but not significantly in non-malignant cells. We found that the caPCNA-specific antigenic site lies between L126 and Y133, a region within the interdomain connector loop of PCNA that is known to be a major binding site for many of PCNA’s interacting proteins. A cell permeable peptide harboring the L126-Y133 sequence inhibited PCNA function in cancer cells and selectively kills cancer cells and xenograft tumors. Methods: Based on these observations, we sought small molecules targeting this peptide region of PCNA as potential broad-spectrum anti-cancer agents. Results: Our effort led to a drug candidate, AOH1996, which selectively kills a broad range of cancer cells at high nanomolar concentrations, but is not associated with significant toxicity to non-malignant cells. It also works synergistically with DNA damaging chemotherapeutic drugs, such as cisplatin and irinotecan, to selectively kill cancer cells. This compound is orally available to animals and suppresses tumor growth in a dosage form compatible to clinical applications. Importantly, it doesn’t cause significant toxicity at 2.5 times its effective dose. Mechanistically, AOH1996 competes with T3, a known PCNA ligand, for binding to PCNA. However, the mechanism by which AOH1996 exerts its effect on cancer cells may not be identical to what have been reported for the T3 analogs. In particular, we found that AOH1996 interferes with the association of PCNA and MCM7 to euchromatin, leading to DNA replication stress, blockade of homologous recombination-mediated DNA repair, and induction of apoptosis in cancer cells. Conclusions: These findings demonstrated the potential of this compound as a novel therapeutic agent warranting clinical investigation for cancer treatment. We have started planning a phase 1 clinical study for this compound.

scholarly journals Overcoming the problem of the lack of an immune response to cancer: A possible haptogenic approach to cancer immunotherapy

2021 ◽  
Vol 5 (1) ◽  
pp. 01-04
Author(s):  
Patrick Riley
Keyword(s):  
Immune Response ◽  
Cancer Cells ◽  
Cancer Immunotherapy ◽  
Immunological Response ◽  
Gene Products ◽  
Malignant Cells ◽  
Deviant Behaviour ◽  
Anti Cancer ◽  
Immune Response To Cancer ◽  
Normal Gene

Cancer cells possess a number of unusual features, most of which are explicable in the light of the theory of epigenetic carcinogenesis. This includes the remarkable failure of malignant cells to evoke an immunological response from the host which is ascribed to their deviant behaviour resulting from anomalous expression of normal gene products. Given this background a possible approach to eliciting a specific anti-cancer immune response is proposed which involves selective haptenation of an identifiable target protein.

scholarly journals Furanoic Lipid F-6, A Novel Anti-Cancer Compound that Kills Cancer Cells by Suppressing Proliferation and Inducing Apoptosis

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 960 ◽  
Author(s):  
Jassim M. Al-Hassan ◽  
Yuan Fang Liu ◽  
Meraj A. Khan ◽  
Peiying Yang ◽  
Rui Guan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Neutrophil Extracellular Trap ◽  
Cancer Drug ◽  
Drug Candidate ◽  
Cell Recovery ◽  
Network Analyses ◽  
Anti Cancer

Identifying novel anti-cancer drugs is important for devising better cancer treatment options. In a series of studies designed to identify novel therapeutic compounds, we recently showed that a C-20 fatty acid (12,15-epoxy-13,14-dimethyleicosa-12,14-dienoic acid, a furanoic acid or F-6) present in the lipid fraction of the secretions of the Arabian Gulf catfish skin (Arius bilineatus Val.; AGCS) robustly induces neutrophil extracellular trap formation. Here, we demonstrate that a lipid mix (Ft-3) extracted from AGCS and F-6, a component of Ft-3, dose dependently kill two cancer cell lines (leukemic K-562 and breast MDA MB-231). Pure F-6 is approximately 3.5 to 16 times more effective than Ft-3 in killing these cancer cells, respectively. Multiplex assays and network analyses show that F-6 promotes the activation of MAPKs such as Erk, JNK, and p38, and specifically suppresses JNK-mediated c-Jun activation necessary for AP-1-mediated cell survival pathways. In both cell lines, F-6 suppresses PI3K-Akt-mTOR pathway specific proteins, indicating that cell proliferation and Akt-mediated protection of mitochondrial stability are compromised by this treatment. Western blot analyses of cleaved caspase 3 (cCasp3) and poly ADP ribose polymerase (PARP) confirmed that F-6 dose-dependently induced apoptosis in both of these cell lines. In 14-day cell recovery experiments, cells treated with increasing doses of F-6 and Ft-3 fail to recover after subsequent drug washout. In summary, this study demonstrates that C-20 furanoic acid F-6, suppresses cancer cell proliferation and promotes apoptotic cell death in leukemic and breast cancer cells, and prevents cell recovery. Therefore, F-6 is a potential anti-cancer drug candidate.

scholarly journals Anti-cancer efficacy and mechanisms of usnic acid

2019 ◽  
Vol 7 (03) ◽  
pp. 1-4 ◽  
Author(s):  
Kunal Kumar ◽  
Jai PN Mishra ◽  
Rana P Singh
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Therapeutic Potential ◽  
Biological Activities ◽  
Usnic Acid ◽  
Nuclear Antigen ◽  
Jnk Pathway ◽  
Anti Cancer ◽  
Clonogenic Potential ◽  
Apoptotic Pathways

Cancer is the second deadly disease after cardiovascular diseases. The presently available therapeutic strategies of cancer are insufficient for the cure and betterment of cancer patients. Herein, we have reviewed the therapeutic potential of a lichenic secondary metabolite, the usnic acid, with special emphasis on its anti-cancer efficacy and associated mechanisms. Usnic acid has various biological activities that have been explored and it is utilized by humans from ancient times throughout the globe. A summary of the anti-cancer properties of usnic acid in different cancer types and models is presented. Usnic acid has shown to inhibit the cancer cell proliferation by suppressing the clonogenic potential, decreasing the expression of PCNA (proliferating cell nuclear antigen), and activating the tumor suppressor genes. Primarily, usnic acid induces reactive oxygen species (ROS) in cancer cells that lead to DNA damage, further causing the activation of DNA damage response that finally initiates the apoptotic pathways. The ROS induction was found to activate the JNK pathway. It also depolarizes the mitochondrial membrane, induces the release of cytochrome-c, and activates the caspase cascade and cleavage of PARP that ultimately results in programmed cell death of cancer cells. Overall, this lichen metabolite has a strong efficacy against cancer cells, which warrants further investigation for its potential clinical uses.

scholarly journals Leukocyte immunoglobulin-like receptor subfamily B: therapeutic targets in cancer

2021 ◽  
Vol 4 (1) ◽  
pp. 16-33
Author(s):  
Mi Deng ◽  
Heyu Chen ◽  
Xiaoye Liu ◽  
Ryan Huang ◽  
Yubo He ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Immune Evasion ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Cancer Biology ◽  
Cancer Development ◽  
Malignant Cells ◽  
Dual Roles ◽  
Anti Cancer ◽  
Therapeutic Development

Abstract Inhibitory leukocyte immunoglobulin-like receptors (LILRBs 1–5) transduce signals via intracellular immunoreceptor tyrosine-based inhibitory motifs that recruit phosphatases to negatively regulate immune activation. The activation of LILRB signaling in immune cells may contribute to immune evasion. In addition, the expression and signaling of LILRBs in cancer cells especially in certain hematologic malignant cells directly support cancer development. Certain LILRBs thus have dual roles in cancer biology—as immune checkpoint molecules and tumor-supporting factors. Here, we review the expression, ligands, signaling, and functions of LILRBs, as well as therapeutic development targeting them. LILRBs may represent attractive targets for cancer treatment, and antagonizing LILRB signaling may prove to be effective anti-cancer strategies.

scholarly journals Pulmonary Complications and Critical Care in Cancer Patients

2018 ◽  
Vol 3 (12) ◽  
Author(s):  
Dr. B. A. Darmi, MD
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Critical Care ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Pulmonary Complications ◽  
Genetic Change ◽  
Malignant Cells ◽  
Normal Cells ◽  
Anti Cancer

Cancer refers to the condition where abnormal proliferation of cells occurs overriding the natural check of cell death.[1] As a normal physiological process, all cells of our body are programmed to die - called as apoptosis.[2] In cancer, the balance between cell proliferation and cell death is disrupted, resulting in uncontrolled division of cells.[3] Hence, apoptosis is an anti-cancer defense of body. In other words, carcinogenesis involves sequential genetic change that transforms normal cells to malignant cells. The cancer cells interfere with normal physiological functions and kill by invading various body organs vital for living. Cancer is a second leading cause of death worldwide, estimated to kill 9.6 million people in 2018.[4] Approximately, every sixth death is caused by cancer.[4] Globally, most common cancers are lung, breast, colorectal, prostate, skin and stomach cancers.

Cancer Treatment with Liposomes Based Drugs and Genes Co-delivery Systems

2018 ◽  
Vol 25 (28) ◽  
pp. 3319-3332 ◽  
Author(s):  
Chuanmin Zhang ◽  
Shubiao Zhang ◽  
Defu Zhi ◽  
Jingnan Cui
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Synergistic Effects ◽  
Resistance Mechanisms ◽  
Delivery Systems ◽  
Cell Cycle Checkpoints ◽  
Drug Efflux ◽  
Cancer Resistance ◽  
Cancer Models ◽  
Anti Cancer

There are several mechanisms by which cancer cells develop resistance to treatments, including increasing anti-apoptosis, increasing drug efflux, inducing angiogenesis, enhancing DNA repair and altering cell cycle checkpoints. The drugs are hard to reach curative effects due to these resistance mechanisms. It has been suggested that liposomes based co-delivery systems, which can deliver drugs and genes to the same tumor cells and exhibit synergistic anti-cancer effects, could be used to overcome the resistance of cancer cells. As the co-delivery systems could simultaneously block two or more pathways, this might promote the death of cancer cells by sensitizing cells to death stimuli. This article provides a brief review on the liposomes based co-delivery systems to overcome cancer resistance by the synergistic effects of drugs and genes. Particularly, the synergistic effects of combinatorial anticancer drugs and genes in various cancer models employing multifunctional liposomes based co-delivery systems have been discussed. This review also gives new insights into the challenges of liposomes based co-delivery systems in the field of cancer therapy, by which we hope to provide some suggestions on the development of liposomes based co-delivery systems.

Recent Advances on Therapeutic Peptides for Breast Cancer Treatment

2020 ◽  
Vol 21 ◽  
Author(s):  
Samad Beheshtirouy ◽  
Farhad Mirzaei ◽  
Shirin Eyvazi ◽  
Vahideh Tarhriz
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Breast Cancer Cells ◽  
Specific Binding ◽  
High Specificity ◽  
The Novel ◽  
Anti Cancer ◽  
Therapeutic Peptides ◽  
Low Toxicity

: Breast cancer is a heterogeneous malignancy which is the second cause of mortality among women in the world. Increasing the resistance to anti-cancer drugs in breast cancer cells persuades researchers to search the novel therapies approaches for the treatment of the malignancy. Among the novel methods, therapeutic peptides which target and disrupt tumor cells have been of great interest. Therapeutic peptides are short amino acids monomer chains with high specificity to bind and modulate a protein interaction of interest. Several advantages of peptides such as specific binding on tumor cells surface, low molecular weight and low toxicity on normal cells make the peptides as an appealing therapeutic agents against solid tumors, particularly breast cancer. Also, National Institutes of Health (NIH) describes therapeutic peptides as suitable candidate for the treatment of drug-resistant breast cancer. In this review, we attempt to review the different therapeutic peptides against breast cancer cells which can be used in treatment and diagnosis of the malignancy. Meanwhile, we presented an overview of peptide vaccines which have been developed for the treatment of breast cancer.

Fanconi Anemia DNA Repair Pathway as a New Mechanism to Exploit Cancer Drug Resistance

2020 ◽  
Vol 20 (9) ◽  
pp. 779-787
Author(s):  
Kajal Ghosal ◽  
Christian Agatemor ◽  
Richard I. Han ◽  
Amy T. Ku ◽  
Sabu Thomas ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Cancer Drug ◽  
Drug Resistant ◽  
Cancer Drugs ◽  
Repair Pathway ◽  
Cancer Drug Resistance ◽  
Anti Cancer ◽  
Cancerous Cells

Chemotherapy employs anti-cancer drugs to stop the growth of cancerous cells, but one common obstacle to the success is the development of chemoresistance, which leads to failure of the previously effective anti-cancer drugs. Resistance arises from different mechanistic pathways, and in this critical review, we focus on the Fanconi Anemia (FA) pathway in chemoresistance. This pathway has yet to be intensively researched by mainstream cancer researchers. This review aims to inspire a new thrust toward the contribution of the FA pathway to drug resistance in cancer. We believe an indepth understanding of this pathway will open new frontiers to effectively treat drug-resistant cancer.

Potential of Mesenchymal Stem Cells in Anti-Cancer Therapies

2020 ◽  
Vol 15 (6) ◽  
pp. 482-491 ◽  
Author(s):  
Milena Kostadinova ◽  
Milena Mourdjeva
Keyword(s):  
Cancer Cells ◽  
Small Population ◽  
Tumor Formation ◽  
Bioactive Molecules ◽  
Cancer Therapies ◽  
New Methods ◽  
Cycle Arrest ◽  
Anti Cancer ◽  
Blocking Mechanisms

Mesenchymal stem/stromal cells (MSCs) are localized throughout the adult body as a small population in the stroma of the tissue concerned. In injury, tissue damage, or tumor formation, they are activated and leave their niche to migrate to the site of injury, where they release a plethora of growth factors, cytokines, and other bioactive molecules. With the accumulation of data about the interaction between MSCs and tumor cells, the dualistic role of MSCs remains unclear. However, a large number of studies have demonstrated the natural anti-tumor properties inherent in MSCs, so this is the basis for intensive research for new methods using MSCs as a tool to suppress cancer cell development. This review focuses specifically on advanced approaches in modifying MSCs to become a powerful, precision- targeted tool for killing cancer cells, but not normal healthy cells. Suppression of tumor growth by MSCs can be accomplished by inducing apoptosis or cell cycle arrest, suppressing tumor angiogenesis, or blocking mechanisms mediating metastasis. In addition, the chemosensitivity of cancer cells may be increased so that the dose of the chemotherapeutic agent used could be significantly reduced.

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