scholarly journals Angiogenesis and chemotherapy resistance: optimizing chemotherapy scheduling using mathematical modeling

2021 ◽  
Author(s):  
Mariusz Bodzioch ◽  
Piotr Bajger ◽  
Urszula Foryś
Keyword(s):  
Mathematical Modeling ◽  
Drug Resistance ◽  
Chemotherapy Resistance ◽  
Maximum Tolerated Dose ◽  
Attractive Alternative ◽  
Acquired Drug Resistance ◽  
Control Techniques ◽  
Drug Doses ◽  
Metronomic Therapy

AbstractChemotherapy remains a widely used cancer treatment. Acquired drug resistance may greatly reduce the efficacy of treatment and means to overcome it are a topic of active discussion among researchers. One of the proposed solutions is to shift the therapeutic paradigm from complete eradication of cancer to maintenance, i.e., to treat it as a chronic disease. A concept of metronomic therapy (low chemotherapy doses applied continuously) emerged in early 2000s and was henceforth shown to offer a number of benefits, including targeting endothelial cells and reducing acquired drug resistance. Using mathematical modeling and optimal control techniques, we investigate the hypothesis that lower doses of chemotherapy are beneficial for patients. Our analysis of a mathematical model of tumor growth under angiogenic signaling proposed by Hahnfeldt et al. adapted to heterogeneous tumors treated by combined anti-angiogenic agent and chemotherapy offers insights into the effects of metronomic therapy. Firstly, assuming constant long-term drug delivery, the model suggests that the longest survival time is achieved for intermediate drug doses. Secondly, by formalizing the notion of the therapeutic target being maintenance rather than eradication, we show that in the short term, optimal chemotherapy scheduling consists mainly of a drug applied at a low dose. In conclusion, we suggest that metronomic therapy is an attractive alternative to maximum tolerated dose therapies to be investigated in experimental settings and clinical trials.

scholarly journals Midkine Mediates Intercellular Crosstalk between Drug-Resistant and Drug-Sensitive Neuroblastoma Cells In Vitro and In Vivo

ISRN Oncology ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-12
Author(s):  
Fei Chu ◽  
Jessica A. Naiditch ◽  
Sandra Clark ◽  
Yi-Yong Qiu ◽  
Xin Zheng ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Chemotherapy Resistance ◽  
Neuroblastoma Cells ◽  
Cytotoxic Agents ◽  
Drug Resistant ◽  
Wild Type ◽  
Cytoprotective Effect ◽  
Acquired Drug Resistance

Resistance to cytotoxic agents has long been known to be a major limitation in the treatment of human cancers. Although many mechanisms of drug resistance have been identified, chemotherapies targeting known mechanisms have failed to lead to effective reversal of drug resistance, suggesting that alternative mechanisms remain undiscovered. Previous work identified midkine (MK) as a novel putative survival molecule responsible for cytoprotective signaling between drug-resistant and drug-sensitive neuroblastoma, osteosarcoma and breast carcinoma cells in vitro. In the present study, we provide further in vitro and in vivo studies supporting the role of MK in neuroblastoma cytoprotection. MK overexpressing wild type neuroblastoma cells exhibit a cytoprotective effect on wild type cells when grown in a co-culture system, similar to that seen with doxorubicin resistant cells. siRNA knockdown of MK expression in doxorubicin resistant neuroblastoma and osteosarcoma cells ameliorates this protective effect. Overexpression of MK in wild type neuroblastoma cells leads to acquired drug resistance to doxorubicin and to the related drug etoposide. Mouse studies injecting various ratios of doxorubicin resistant or MK transfected cells with GFP transfected wild type cells confirm this cytoprotective effect in vivo. These findings provide additional evidence for the existence of intercellular cytoprotective signals mediated by MK which contribute to chemotherapy resistance in neuroblastoma.

scholarly journals The Long-Term DEHP Exposure Confers Multidrug Resistance of Triple-Negative Breast Cancer Cells through ABC Transporters and Intracellular ROS

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 949
Author(s):  
Mahendra Jadhao ◽  
Eing-Mei Tsai ◽  
Ho-Chun Yang ◽  
Yih-Fung Chen ◽  
Shih-Shin Liang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Multidrug Resistance ◽  
Cancer Cells ◽  
Abc Transporters ◽  
Breast Cancer Cells ◽  
Acquired Drug Resistance ◽  
Intracellular Ros ◽  
Dehp Exposure

The characteristics of phthalates had been thought to be similar to endocrine disruptors, which increases cancer risk. The role of phthalates in acquired drug resistance remains unclear. In this study, we investigated the effect of di-(2-ethylhexyl) phthalate (DEHP) on acquired drug resistance in breast cancer. MCF7 and MDA-MB-231 breast cancer cells were exposed to long-term physiological concentration of DEHP for more than three months. Long-exposure DEHP permanently attenuated the anti-proliferative effect of doxorubicin with estrogen receptor-independent activity even after withdrawal of DEHP. Long term DEHP exposure significantly reduced ROS (O2−) level in MDA-MB-231 cells while increased in MCF7 cells. ATP-binding cassette (ABC) transporters possess a widely recognized mechanism of drug resistance and are considered a target for drug therapy. Upregulation of ABC family proteins, ABCB-1 and ABCC-1 observed in DEHP-exposed clones compared to doxorubicin-resistant (DoxR) and parental MDA-MB-231 cells. A viability assay showed enhanced multidrug resistance in DEHP-exposed clones against Dox, topotecan, and irinotecan. Inhibition of ABC transporters with tariquidar, enhanced drug cytotoxicity through increased drug accumulation reversing acquired multidrug resistance in MDA-MB-231 breast cancer cells. Tariquidar enhanced Dox cytotoxicity by increasing intracellular ROS production leading to caspase-3 mediated apoptosis. Activation of PI3K/Akt signaling enhanced proliferation and growth of DEHP-exposed MDA-MB-231 cells. Overall, long-term DEHP exposure resulted in acquired multidrug resistance by upregulating ABCB-1 and ABCC1; apart from proliferation PI3K/Akt may be responsible for acquired drug resistance through ABC transporter upregulation. Targeting ABCB1 and ABCC1 with tariquidar may be a promising strategy for reversing the acquired multidrug resistance of triple-negative breast cancer cells.

scholarly journals Long-term non-invasive drug treatments for adult zebrafish

2021 ◽  
Author(s):  
Yuting Lu ◽  
E. Elizabeth Patton
Keyword(s):  
Drug Resistance ◽  
Drug Efficacy ◽  
Drug Formulation ◽  
Tumour Regression ◽  
Adult Zebrafish ◽  
Zebrafish Model ◽  
Invasive Approach ◽  
Acquired Drug Resistance ◽  
Non Invasive

Zebrafish embryos are widely used for drug-discovery however administering drugs to adult zebrafish is limited by current protocols that can cause stress. Here, we develop a drug formulation and administration method for adult zebrafish by producing food-based drug pellets which are consumed voluntarily. We apply this to zebrafish with BRAF-mutant melanoma, a model that has significantly advanced our understanding of melanoma progression, but not of drug resistance due to the limitations of current treatment methods. Short-term, precise, and daily dosing with drug-pellets made with the BRAFV600E inhibitor, vemurafenib, led to tumour regression. On-target drug efficacy was determined by phospho-ERK staining. Continued drug treatment led to the emergence, for the first time in zebrafish, of acquired drug resistance and melanoma relapse, modelling the responses seen in melanoma patients. This method presents a controlled, non-invasive approach that permits long-term drug studies, and can be widely applied to any adult zebrafish model.

scholarly journals Long-term activation of SAPK/JNK, p38 kinase and fas-L expression by cisplatin is attenuated in human carcinoma cells that acquired drug resistance

2004 ◽  
Vol 112 (6) ◽  
pp. 974-985 ◽  
Author(s):  
Anamaria Brozovic ◽  
Gerhard Fritz ◽  
Markus Christmann ◽  
Jochen Zisowsky ◽  
Ulrich Jaehde ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Carcinoma Cells ◽  
P38 Kinase ◽  
Human Carcinoma ◽  
Acquired Drug Resistance ◽  
Fas L

scholarly journals miR-199a-5p Represses Protective Autophagy and Overcomes Chemoresistance by Directly Targeting DRAM1 in Acute Myeloid Leukemia

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Yang Li ◽  
Guojun Zhang ◽  
Bin Wu ◽  
Wei Yang ◽  
Zhuogang Liu
Keyword(s):  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Therapeutic Strategy ◽  
Chemotherapy Resistance ◽  
K562 Cells ◽  
Acquired Drug Resistance ◽  
Underlying Mechanisms ◽  
Posttranscriptional Level ◽  
Acute Myeloid

Chemotherapy resistance is still a primary clinical obstacle to the successful treatment of acute myeloid leukemia (AML). The underlying mechanisms of drug resistance are complicated and have not been fully understood. Here, we found that miR-199a-5p levels were significantly reduced in refractory/relapsed AML patients compared to those who achieved complete remission after chemotherapy. Consistently, miR-199a-5p was markedly decreased in Adriamycin-resistant AML K562/ADM cells in contrast with Adriamycin-sensitive K562 cells, and its decrement dramatically correlated with the chemoresistance of AML cells. Furthermore, we demonstrated that the basic and Adriamycin-induced autophagic activity in K562/ADM cells was higher than that in K562 cells. This inducible autophagy played a prosurvival role and contributed to the development of acquired drug resistance. Importantly, we investigated that miR-199a-5p could negatively regulate autophagy, at least in part, by inhibiting damage regulator autophagy modulator (DRAM1) expression at both the transcriptional and posttranscriptional level. miR-199a-5p bound directly to the 3′-UTR of DRAM1 mRNA which was a functional target of miR-199a-5p. Indeed, downregulation of DRAM1 gene by siRNA in K562/ADM cells resulted in autophagy suppression and chemosensitivity restoration. These results revealed that the miR-199a-5p/DRAM1/autophagy signaling represented a novel pathway regulating chemoresistance, indicating a potential therapeutic strategy for the intervention in drug-resistant AML.

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.

Application of the method of mathematical modeling for forecasting channel deformations at the underwater crossing of the main pipeline

2020 ◽  
Vol 10 (6) ◽  
pp. 599-609
Author(s):  
Valery А. Gruzdev ◽  
◽  
Georgy V. Mosolov ◽  
Ekaterina A. Sabayda ◽  
◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Mathematical Model ◽  
Roughness Coefficient ◽  
Computational Domain ◽  
Channel Deformations ◽  
Geological Surveys ◽  
Kuban River ◽  
The Stability ◽  
Protective Structures

In order to determine the possibility of using the method of mathematical modeling for making long-term forecasts of channel deformations of trunk line underwater crossing (TLUC) through water obstacles, a methodology for performing and analyzing the results of mathematical modeling of channel deformations in the TLUC zone across the Kuban River is considered. Within the framework of the work, the following tasks were solved: 1) the format and composition of the initial data necessary for mathematical modeling were determined; 2) the procedure for assigning the boundaries of the computational domain of the model was considered, the computational domain was broken down into the computational grid, the zoning of the computational domain was performed by the value of the roughness coefficient; 3) the analysis of the results of modeling the water flow was carried out without taking the bottom deformations into account, as well as modeling the bottom deformations, the specifics of the verification and calibration calculations were determined to build a reliable mathematical model; 4) considered the possibility of using the method of mathematical modeling to check the stability of the bottom in the area of TLUC in the presence of man-made dumping or protective structure. It has been established that modeling the flow hydraulics and structure of currents, making short-term forecasts of local high-altitude reshaping of the bottom, determining the tendencies of erosion and accumulation of sediments upstream and downstream of protective structures are applicable for predicting channel deformations in the zone of the TLUC. In all these cases, it is mandatory to have materials from engineering-hydro-meteorological and engineering-geological surveys in an amount sufficient to compile a reliable mathematical model.

Sign in / Sign up

Export Citation Format

Share Document