scholarly journals Global analysis of a cancer model with drug resistance due to Lamarckian induction and microvesicle transfer

2020 ◽  
Author(s):  
Attila Dénes ◽  
Gergely Röst
Keyword(s):  
Drug Resistance ◽  
Global Analysis ◽  
Infectious Agent ◽  
Chemotherapeutic Agents ◽  
Darwinian Evolution ◽  
Acquired Drug Resistance ◽  
Dulac Function ◽  
Development Of Resistance ◽  
Existence And Stability ◽  
Resistance To Chemotherapy

AbstractDevelopment of resistance to chemotherapy in cancer patients strongly effects the outcome of the treatment. Due to chemotherapeutic agents, resistance can emerge by Darwinian evolution. Besides this, acquired drug resistance may arise via changes in gene expression. A recent discovery in cancer research uncovered a third possibility, indicating that this phenotype conversion can occur through the transfer of microvesicles from resistant to sensitive cells, a mechanism resembling the spread of an infectious agent. We present a model describing the evolution of sensitive and resistant tumour cells considering Darwinian selection, Lamarckian induction and microvesicle transfer. We identify three threshold parameters which determine the existence and stability of the three possible equilibria. Using a simple Dulac function, we give a complete description of the dynamics of the model depending on the three threshold parameters. We demonstrate the possible effects of increasing drug concentration, and characterize the possible bifurcation sequences. Our results show that the presence of microvesicle transfer cannot ruin a therapy that otherwise leads to extinction, however it may doom a partially successful therapy to failure.

scholarly journals The Role of the Receptor Tyrosine Kinase Axl in Carcinogenesis and Development of Therapeutic Resistance: An Overview of Molecular Mechanisms and Future Applications

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1521
Author(s):  
Martha Wium ◽  
Aderonke F. Ajayi-Smith ◽  
Juliano D. Paccez ◽  
Luiz F. Zerbini
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
Cancer Progression ◽  
Receptor Tyrosine Kinase ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Chemotherapeutic Agents ◽  
Mesenchymal Transition ◽  
Development Of Resistance

Resistance to chemotherapeutic agents by cancer cells has remained a major obstacle in the successful treatment of various cancers. Numerous factors such as DNA damage repair, cell death inhibition, epithelial–mesenchymal transition, and evasion of apoptosis have all been implicated in the promotion of chemoresistance. The receptor tyrosine kinase Axl, a member of the TAM family (which includes TYRO3 and MER), plays an important role in the regulation of cellular processes such as proliferation, motility, survival, and immunologic response. The overexpression of Axl is reported in several solid and hematological malignancies, including non-small cell lung, prostate, breast, liver and gastric cancers, and acute myeloid leukaemia. The overexpression of Axl is associated with poor prognosis and the development of resistance to therapy. Reports show that Axl overexpression confers drug resistance in lung cancer and advances the emergence of tolerant cells. Axl is, therefore, an important candidate as a prognostic biomarker and target for anticancer therapies. In this review, we discuss the consequence of Axl upregulation in cancers, provide evidence for its role in cancer progression and the development of drug resistance. We will also discuss the therapeutic potential of Axl in the treatment of cancer.

scholarly journals Polymeric Nanoparticle Delivery of Combination Therapy with Synergistic Effects in Ovarian Cancer

Nanomaterials ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 1048
Author(s):  
Shani L. Levit ◽  
Christina Tang
Keyword(s):  
Ovarian Cancer ◽  
Drug Resistance ◽  
Treatment Efficacy ◽  
Synergistic Effects ◽  
Chemotherapeutic Agents ◽  
Drug Combinations ◽  
Dosing Schedule ◽  
Acquired Drug Resistance

Treatment of ovarian cancer is challenging due to late stage diagnosis, acquired drug resistance mechanisms, and systemic toxicity of chemotherapeutic agents. Combination chemotherapy has the potential to enhance treatment efficacy by activation of multiple downstream pathways to overcome drug resistance and reducing required dosages. Sequence of delivery and the dosing schedule can further enhance treatment efficacy. Formulation of drug combinations into nanoparticles can further enhance treatment efficacy. Due to their versatility, polymer-based nanoparticles are an especially promising tool for clinical translation of combination therapies with tunable dosing schedules. We review polymer nanoparticle (e.g., micelles, dendrimers, and lipid nanoparticles) carriers of drug combinations formulated to treat ovarian cancer. In particular, the focus on this review is combinations of platinum and taxane agents (commonly used first line treatments for ovarian cancer) combined with other small molecule therapeutic agents. In vitro and in vivo drug potency are discussed with a focus on quantifiable synergistic effects. The effect of drug sequence and dosing schedule is examined. Computational approaches as a tool to predict synergistic drug combinations and dosing schedules as a tool for future nanoparticle design are also briefly discussed.

scholarly journals Proteomic Reveals Reasons for Acquired Drug Resistance in Lung Cancer Derived Brain Metastasis Based on a Newly Established Multi-Organ Microfluidic Chip Model

2020 ◽  
Vol 8 ◽  
Author(s):  
Mingxin Xu ◽  
Yingyan Wang ◽  
Wenzhe Duan ◽  
Shengkai Xia ◽  
Song Wei ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Brain Metastasis ◽  
Microfluidic Chip ◽  
Kinase Inhibitors ◽  
Primary Lung Cancer ◽  
Chemotherapeutic Agents ◽  
Preclinical Model ◽  
Acquired Drug Resistance ◽  
Gsh Metabolism

Anti-tumor drugs can effectively shrink the lesions of primary lung cancer; however, it has limited therapeutic effect on patients with brain metastasis (BM). A BM preclinical model based on a multi-organ microfluidic chip has been established proficiently in our previous work. In this study, the BM subpopulation (PC9-Br) derived from the parental PC9 cell line was isolated from the chip model and found to develop obvious resistance to antineoplastic drugs including chemotherapeutic agents (cisplatin, carboplatin, pemetrexed) and tyrosine kinase inhibitors (TKIs) which target epidermal growth factor receptor (EGFR); this suggested that the acquisition of drug-resistance by brain metastatic cells was attributable to the intrinsic changes in PC9-Br. Hence, we performed proteomic and revealed a greatly altered spectrum of BM protein expression compared with primary lung cancer cells. We identified the hyperactive glutathione (GSH) metabolism pathway with the overexpression of various GSH metabolism-related enzymes (GPX4, RRM2, GCLC, GPX1, GSTM4, GSTM1). Aldehyde dehydrogenases (ALDH1A1, ALDH3A1) were also found to be upregulated in BM. What's more, loss of EGFR and phosphorylated EGFR in PC9-Br gave reasons for the TKIs resistance. Collectively, our findings indicated potential mechanisms for the acquirement of drug resistance occurred in BM, providing new strategies to overcome therapeutic resistance in lung cancer BM.

scholarly journals Tumour Microenvironment Stress Promotes the Development of Drug Resistance

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1801
Author(s):  
Nicole A. Seebacher ◽  
Maria Krchniakova ◽  
Alexandra E. Stacy ◽  
Jan Skoda ◽  
Patric J. Jansson
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Hypoxia Inducible Factor ◽  
Tumour Microenvironment ◽  
Chemotherapeutic Agents ◽  
Multi Drug Resistance ◽  
Therapeutic Success ◽  
Major Barrier ◽  
Development Of Resistance

Multi-drug resistance (MDR) is a leading cause of cancer-related death, and it continues to be a major barrier to cancer treatment. The tumour microenvironment (TME) has proven to play an essential role in not only cancer progression and metastasis, but also the development of resistance to chemotherapy. Despite the significant advances in the efficacy of anti-cancer therapies, the development of drug resistance remains a major impediment to therapeutic success. This review highlights the interplay between various factors within the TME that collectively initiate or propagate MDR. The key TME-mediated mechanisms of MDR regulation that will be discussed herein include (1) altered metabolic processing and the reactive oxygen species (ROS)-hypoxia inducible factor (HIF) axis; (2) changes in stromal cells; (3) increased cancer cell survival via autophagy and failure of apoptosis; (4) altered drug delivery, uptake, or efflux and (5) the induction of a cancer stem cell (CSC) phenotype. The review also discusses thought-provoking ideas that may assist in overcoming the TME-induced MDR. We conclude that stressors from the TME and exposure to chemotherapeutic agents are strongly linked to the development of MDR in cancer cells. Therefore, there remains a vast area for potential research to further elicit the interplay between factors existing both within and outside the TME. Elucidating the mechanisms within this network is essential for developing new therapeutic strategies that are less prone to failure due to the development of resistance in cancer cells.

Bexarotene prevents and reverses gemcitabine resistance in non-small-cell lung cancer cells by affecting gene amplification

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2057-2057 ◽  
Author(s):  
T. W. Hermann ◽  
W. Yen ◽  
P. Tooker ◽  
S. Ng ◽  
A. Negro-Vilar ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Gene Amplification ◽  
Gene Copy Number ◽  
Dna Amplification ◽  
Fold Increase ◽  
Gene Copy ◽  
Strong Increase ◽  
Combination Regimen ◽  
Acquired Drug Resistance ◽  
Development Of Resistance

2057 Background: Bexarotene (BEX) is a retinoid X receptor selective drug approved for treatment of CTCL and has activity in various cancers. Here we evaluate its effect on acquired drug resistance towards gemcitabine (GEM) in Calu3 NSCLC models. Methods: Parental or GEM-resistant Calu3 NSCLC cells were treated with BEX and GEM as single agents or in combination. Over the treatment course the cells were evaluated for molecular changes (RNA expression and DNA amplification), which were associated with resistance status. Results: Calu3 cells treated with repeated cycles of GEM alone gradually developed resistance to this drug. However, inclusion of BEX prevented the development of resistance and cells remained chemosensitive. Microarray analysis showed a strong increase of rrm1 (ribonucleotide reductase M1) expression in the resistant cells (Calu3-GemR), a gene known to be involved in GEM resistance. In addition, the expression of genes surrounding the chromosomal location of rrm1 was increased suggesting that resistance was due to gene amplification at the 11p15 locus. This was confirmed by analysis of genomic DNA, indicating a 20-fold increase of rrm1 gene copy number. To evaluate BEX’s activity on pre-existing GEM-resistance, Calu3-GemR cells were treated with ten 10-day cycles of vehicle, GEM, BEX, or GEM plus BEX. After 4 treatment cycles the cultures treated with the combination regimen showed a loss in cell numbers, which continued until the end of the 10th cycle. This indicated a re-sensitization of the Calu3-GemR cells to treatment. The cultures treated with the single drug regimens expanded as the vehicle controls. However, analysis of RNA and DNA samples collected over the treatment course revealed that rrm1 gene amplification was gradually reduced even in the cultures treated with BEX alone, reaching parental levels at the end of the study. As expected from these data, the BEX-treated Calu3-GemR cells were again sensitive to GEM. Conclusions: The data indicate that bexarotene can re-sensitize GEM-resistant tumor cells by reversing gene amplification. This suggests that bexarotene may have general clinical utility in cancers where drug-resistance by gene amplification is a major obstacle to successful therapy. [Table: see text]

scholarly journals The Inhibition of CDK8/19 Mediator Kinases Prevents the Development of Resistance to EGFR-Targeting Drugs

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 144
Author(s):  
Amanda C. Sharko ◽  
Chang-Uk Lim ◽  
Martina S. J. McDermott ◽  
Chuck Hennes ◽  
Kingsavanh P. Philavong ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Growth Factor Receptor ◽  
Tumor Resistance ◽  
Acquired Drug Resistance ◽  
Transcriptional Reprogramming ◽  
Development Of Resistance ◽  
Transcriptional Changes ◽  
Epidermal Growth

Drug resistance is the main obstacle to achieving cures with both conventional and targeted anticancer drugs. The emergence of acquired drug resistance is initially mediated by non-genetic transcriptional changes, which occur at a much higher frequency than mutations and may involve population-scale transcriptomic adaptation. CDK8/19 kinases, through association with transcriptional Mediator complex, regulate transcriptional reprogramming by co-operating with different signal-responsive transcription factors. Here we tested if CDK8/19 inhibition could prevent adaptation to drugs acting on epidermal growth factor receptor (EGFR/ERBB1/HER1). The development of resistance was analyzed following long-term exposure of BT474 and SKBR3 breast cancer cells to EGFR-targeting small molecules (gefitinib, erlotinib) and of SW48 colon cancer cells to an anti-EGFR monoclonal antibody cetuximab. In all cases, treatment of small cell populations (~105 cells) with a single dose of the drug initially led to growth inhibition that was followed by the resumption of proliferation and development of drug resistance in the adapted populations. However, this adaptation was always prevented by the addition of selective CDK8/19 inhibitors, even though such inhibitors alone had only moderate or no effect on cell growth. These results indicate that combining EGFR-targeting drugs with CDK8/19 inhibitors may delay or prevent the development of tumor resistance to therapy.

Hybrid Compounds & Oxidative Stress Induced Apoptosis in Cancer Therapy

2020 ◽  
Vol 27 (13) ◽  
pp. 2118-2132 ◽  
Author(s):  
Aysegul Hanikoglu ◽  
Hakan Ozben ◽  
Ferhat Hanikoglu ◽  
Tomris Ozben
Keyword(s):  
Oxidative Stress ◽  
Drug Resistance ◽  
Side Effects ◽  
Cancer Therapy ◽  
Tumor Cells ◽  
Anticancer Drugs ◽  
Chemotherapeutic Agents ◽  
Oxidation Reactions ◽  
Hybrid Compounds ◽  
Induced Apoptosis

: Elevated Reactive Oxygen Species (ROS) generated by the conventional cancer therapies and the endogenous production of ROS have been observed in various types of cancers. In contrast to the harmful effects of oxidative stress in different pathologies other than cancer, ROS can speed anti-tumorigenic signaling and cause apoptosis of tumor cells via oxidative stress as demonstrated in several studies. The primary actions of antioxidants in cells are to provide a redox balance between reduction-oxidation reactions. Antioxidants in tumor cells can scavenge excess ROS, causing resistance to ROS induced apoptosis. Various chemotherapeutic drugs, in their clinical use, have evoked drug resistance and serious side effects. Consequently, drugs having single-targets are not able to provide an effective cancer therapy. Recently, developed hybrid anticancer drugs promise great therapeutic advantages due to their capacity to overcome the limitations encountered with conventional chemotherapeutic agents. Hybrid compounds have advantages in comparison to the single cancer drugs which have usually low solubility, adverse side effects, and drug resistance. This review addresses two important treatments strategies in cancer therapy: oxidative stress induced apoptosis and hybrid anticancer drugs.

Genetic and Epigenetic Modulation of Drug Resistance in Cancer: Challenges and Opportunities

2020 ◽  
Vol 20 (14) ◽  
pp. 1114-1131 ◽  
Author(s):  
Kanisha Shah ◽  
Rakesh M. Rawal
Keyword(s):  
Drug Resistance ◽  
Drug Targets ◽  
Complex Disease ◽  
Cancer Therapies ◽  
Altered Expression ◽  
Acquired Drug Resistance ◽  
Challenges And Opportunities ◽  
Chemotherapeutic Treatment ◽  
Epigenetic Modulation ◽  
Targeted Drug Therapies

Cancer is a complex disease that has the ability to develop resistance to traditional therapies. The current chemotherapeutic treatment has become increasingly sophisticated, yet it is not 100% effective against disseminated tumours. Anticancer drugs resistance is an intricate process that ascends from modifications in the drug targets suggesting the need for better targeted therapies in the therapeutic arsenal. Advances in the modern techniques such as DNA microarray, proteomics along with the development of newer targeted drug therapies might provide better strategies to overcome drug resistance. This drug resistance in tumours can be attributed to an individual’s genetic differences, especially in tumoral somatic cells but acquired drug resistance is due to different mechanisms, such as cell death inhibition (apoptosis suppression) altered expression of drug transporters, alteration in drug metabolism epigenetic and drug targets, enhancing DNA repair and gene amplification. This review also focusses on the epigenetic modifications and microRNAs, which induce drug resistance and contributes to the formation of tumour progenitor cells that are not destroyed by conventional cancer therapies. Lastly, this review highlights different means to prevent the formation of drug resistant tumours and provides future directions for better treatment of these resistant tumours.

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