The Impact of Microenvironmental Heterogeneity on the Evolution of Drug Resistance in Cancer Cells

Therapeutic resistance arises as a result of evolutionary processes driven by dynamic feedback between a heterogeneous cell population and environmental selective pressures. Previous studies have suggested that mutations conferring resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in non-small-cell lung cancer (NSCLC) cells lower the fitness of resistant cells relative to drug-sensitive cells in a drug-free environment. Here, we hypothesize that the local tumor microenvironment could influence the magnitude and directionality of the selective effect, both in the presence and absence of a drug. Using a combined experimental and computational approach, we developed a mathematical model of preexisting drug resistance describing multiple cellular compartments, each representing a specific tumor environmental niche. This model was parameterized using a novel experimental dataset derived from the HCC827 erlotinib-sensitive and -resistant NSCLC cell lines. We found that, in contrast to in the drug-free environment, resistant cells may hold a fitness advantage compared to parental cells in microenvironments deficient in oxygen and nutrients. We then utilized the model to predict the impact of drug and nutrient gradients on tumor composition and recurrence times, demonstrating that these endpoints are strongly dependent on the microenvironment. Our interdisciplinary approach provides a model system to quantitatively investigate the impact of microenvironmental effects on the evolutionary dynamics of tumor cells.

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Use of kinase inhibitors against schistosomes to improve and broaden praziquantel efficacy

Parasitology ◽

10.1017/s0031182020001250 ◽

2020 ◽

Vol 147 (13) ◽

pp. 1488-1498

Author(s):

Sujeevi S. K. Nawaratna ◽

Donald P. McManus ◽

Robin B. Gasser ◽

Paul J. Brindley ◽

Glen M. Boyle ◽

...

Keyword(s):

Drug Resistance ◽

Kinase Inhibitors ◽

Lethal Dose ◽

Alternative Therapies ◽

Potential Drug ◽

Dependent Protein Kinase ◽

Drug Of Choice ◽

Dependent Protein ◽

The Impact

AbstractPraziquantel (PZQ) is the drug of choice for schistosomiasis. The potential drug resistance necessitates the search for adjunct or alternative therapies to PZQ. Previous functional genomics has shown that RNAi inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) gene in Schistosoma adult worms significantly improved the effectiveness of PZQ. Here we tested the in vitro efficacy of 15 selective and non-selective CaMK inhibitors against Schistosoma mansoni and showed that PZQ efficacy was improved against refractory juvenile parasites when combined with these CaMK inhibitors. By measuring CaMK activity and the mobility of adult S. mansoni, we identified two non-selective CaMK inhibitors, Staurosporine (STSP) and 1Naphthyl PP1 (1NAPP1), as promising candidates for further study. The impact of STSP and 1NAPP1 was investigated in mice infected with S. mansoni in the presence or absence of a sub-lethal dose of PZQ against 2- and 7-day-old schistosomula and adults. Treatment with STSP/PZQ induced a significant (47–68%) liver egg burden reduction compared with mice treated with PZQ alone. The findings indicate that the combination of STSP and PZQ dosages significantly improved anti-schistosomal activity compared to PZQ alone, demonstrating the potential of selective and non-selective CaMK/kinase inhibitors as a combination therapy with PZQ in treating schistosomiasis.

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The Impact of Extracellular Ca2+ and Nanosecond Electric Pulses on Sensitive and Drug-Resistant Human Breast and Colon Cancer Cells

Cancers ◽

10.3390/cancers13133216 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3216

Author(s):

Julita Kulbacka ◽

Nina Rembiałkowska ◽

Anna Szewczyk ◽

Helena Moreira ◽

Anna Szyjka ◽

...

Keyword(s):

Breast Cancer ◽

Colon Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Calcium Ions ◽

Colon Cancer Cells ◽

Human Breast ◽

The Impact ◽

Mcf 7 ◽

Resistant Cells

(1) Background: Calcium electroporation (CaEP) is based on the application of electrical pulses to permeabilize cells (electroporation) and allow cytotoxic doses of calcium to enter the cell. (2) Methods: In this work, we have used doxorubicin-resistant (DX) and non-resistant models of human breast cancer (MCF-7/DX, MCF-7/WT) and colon cancer cells (LoVo, LoVo/DX), and investigated the susceptibility of the cells to extracellular Ca2+ and electric fields in the 20 ns–900 ns pulse duration range. (3) Results: We have observed that colon cancer cells were less susceptible to PEF than breast cancer cells. An extracellular Ca2+ (2 mM) with PEF was more disruptive for DX-resistant cells. The expression of glycoprotein P (MDR1, P-gp) as a drug resistance marker was detected by the immunofluorescent (CLSM) method and rhodamine-123 efflux as an MDR1 activity. MDR1 expression was not significantly modified by nanosecond electroporation in multidrug-resistant cells, but a combination with calcium ions significantly inhibited MDR1 activity and cell viability. (4) Conclusions: We believe that PEF with calcium ions can reduce drug resistance by inhibiting drug efflux activity. This phenomenon of MDR mechanism disruption seems promising in anticancer protocols.

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The miR-185/PAK6 axis predicts therapy response and regulates survival of drug-resistant leukemic stem cells in CML

Blood ◽

10.1182/blood.2019003636 ◽

2020 ◽

Vol 136 (5) ◽

pp. 596-609 ◽

Cited By ~ 1

Author(s):

Hanyang Lin ◽

Katharina Rothe ◽

Min Chen ◽

Andrew Wu ◽

Artem Babaian ◽

...

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Kinase Inhibitors ◽

Mapk Pathway ◽

Therapy Response ◽

Predictive Biomarker ◽

Mitochondrial Activity ◽

Drug Resistant ◽

Resistant Cells

Abstract Overcoming drug resistance and targeting cancer stem cells remain challenges for curative cancer treatment. To investigate the role of microRNAs (miRNAs) in regulating drug resistance and leukemic stem cell (LSC) fate, we performed global transcriptome profiling in treatment-naive chronic myeloid leukemia (CML) stem/progenitor cells and identified that miR-185 levels anticipate their response to ABL tyrosine kinase inhibitors (TKIs). miR-185 functions as a tumor suppressor: its restored expression impaired survival of drug-resistant cells, sensitized them to TKIs in vitro, and markedly eliminated long-term repopulating LSCs and infiltrating blast cells, conferring a survival advantage in preclinical xenotransplantation models. Integrative analysis with mRNA profiles uncovered PAK6 as a crucial target of miR-185, and pharmacological inhibition of PAK6 perturbed the RAS/MAPK pathway and mitochondrial activity, sensitizing therapy-resistant cells to TKIs. Thus, miR-185 presents as a potential predictive biomarker, and dual targeting of miR-185-mediated PAK6 activity and BCR-ABL1 may provide a valuable strategy for overcoming drug resistance in patients.

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Use of Multi-Anionic Sodium Tripolyphosphate to Enhance Dispersion of Concentrated Kaolin Slurries in Seawater

Metals ◽

10.3390/met11071085 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1085

Author(s):

Williams Leiva ◽

Norman Toro ◽

Pedro Robles ◽

Edelmira Gálvez ◽

Ricardo Ivan Jeldres

Keyword(s):

Rheological Properties ◽

Fine Particles ◽

Sodium Tripolyphosphate ◽

Mining Industry ◽

Chord Length ◽

Water Recovery ◽

Reflectance Measurement ◽

Anionic Charge ◽

Free Environment ◽

The Impact

This research aims to analyze the impact of sodium tripolyphosphate (STPP) as a rheological modifier of concentrated kaolin slurries in seawater at pH 8, which is characteristic of copper sulfide processing operations. The dispersion phenomenon was analyzed through chord length measurements using the focused beam reflectance measurement (FBRM) technique, complementing size distributions in unweighted and square-weighted modes. The reduction of the rheological properties was significant, decreasing from 231 Pa in a reagent-free environment to 80 Pa after the application of STPP. A frequency sweep in a linear viscoelastic regime indicated that by applying a characteristic dosage of 0.53 kg/t of STPP, the pulp before yielding increases its phase angle, which increases its liquid-like character. Measurements of the chord length verified the dispersion of particles, which showed an apparent increase in the proportion of fine particles and a reduction of the coarser aggregates when STPP was applied. Measurements of the zeta potential suggested that the high anionic charge of the reagent (pentavalent) increases the electrostatic repulsions between particles, overcoming the effect of cations in seawater. The results are relevant for the mining industry, especially when the deposits have high contents of complex gangues, such as clays, that increase the rheological properties. This increases the energy costs and water consumption needed for pumping the tailings from thickeners to the tailing storages facilities. The strategies that allow for the improvement of the fluidity and deformation of the tailings generate slack in order to maximize water recovery in the thickening stages.

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The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma

Scientific Reports ◽

10.1038/s41598-021-84117-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hiroaki Kanzaki ◽

Tetsuhiro Chiba ◽

Junjie Ao ◽

Keisuke Koroki ◽

Kengo Kanayama ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Mechanisms ◽

Kinase Inhibitors ◽

Progression Free Survival ◽

Erk Signaling ◽

Enzyme Linked Immunosorbent Assay ◽

Antitumor Effects ◽

The Impact

AbstractFGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.

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The Impact of Longer Consultation Time: A Simulation-Based Approach

Applied Clinical Informatics ◽

10.1055/s-0040-1721320 ◽

2020 ◽

Vol 11 (05) ◽

pp. 857-864

Author(s):

Abdulrahman M. Jabour

Keyword(s):

Waiting Time ◽

Quality Care ◽

Working Hours ◽

Discrete Events ◽

Simulation Based ◽

Patient Waiting Time ◽

Free Environment ◽

The Impact ◽

Consultation Time ◽

Patient Waiting

Abstract Background Maintaining a sufficient consultation length in primary health care (PHC) is a fundamental part of providing quality care that results in patient safety and satisfaction. Many facilities have limited capacity and increasing consultation time could result in a longer waiting time for patients and longer working hours for physicians. The use of simulation can be practical for quantifying the impact of workflow scenarios and guide the decision-making. Objective To examine the impact of increasing consultation time on patient waiting time and physician working hours. Methods Using discrete events simulation, we modeled the existing workflow and tested five different scenarios with a longer consultation time. In each scenario, we examined the impact of consultation time on patient waiting time, physician hours, and rate of staff utilization. Results At baseline scenarios (5-minute consultation time), the average waiting time was 9.87 minutes and gradually increased to 89.93 minutes in scenario five (10 minutes consultation time). However, the impact of increasing consultation time on patients waiting time did not impact all patients evenly where patients who arrive later tend to wait longer. Scenarios with a longer consultation time were more sensitive to the patients' order of arrival than those with a shorter consultation time. Conclusion By using simulation, we assessed the impact of increasing the consultation time in a risk-free environment. The increase in patients waiting time was somewhat gradual, and patients who arrive later in the day are more likely to wait longer than those who arrive earlier in the day. Increasing consultation time was more sensitive to the patients' order of arrival than those with a shorter consultation time.

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The impact of fusion genes on cancer stem cells and drug resistance

Molecular and Cellular Biochemistry ◽

10.1007/s11010-021-04203-4 ◽

2021 ◽

Author(s):

Saurav Panicker ◽

Sivaramakrishnan Venkatabalasubramanian ◽

Surajit Pathak ◽

Satish Ramalingam

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Fusion Genes ◽

The Impact

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Evolutionary Genetics of Mycobacterium tuberculosis and HIV-1: “The Tortoise and the Hare”

Microorganisms ◽

10.3390/microorganisms9010147 ◽

2021 ◽

Vol 9 (1) ◽

pp. 147

Author(s):

Ana Santos-Pereira ◽

Carlos Magalhães ◽

Pedro M. M. Araújo ◽

Nuno S. Osório

Keyword(s):

Genetic Diversity ◽

Drug Resistance ◽

Mycobacterium Tuberculosis ◽

Evolutionary Dynamics ◽

Evolutionary Genetics ◽

Host Cells ◽

Whole Genome Sequencing Data ◽

Host Immune System ◽

Viral Mutant ◽

Hiv 1

The already enormous burden caused by Mycobacterium tuberculosis and Human Immunodeficiency Virus type 1 (HIV-1) alone is aggravated by co-infection. Despite obvious differences in the rate of evolution comparing these two human pathogens, genetic diversity plays an important role in the success of both. The extreme evolutionary dynamics of HIV-1 is in the basis of a robust capacity to evade immune responses, to generate drug-resistance and to diversify the population-level reservoir of M group viral subtypes. Compared to HIV-1 and other retroviruses, M. tuberculosis generates minute levels of genetic diversity within the host. However, emerging whole-genome sequencing data show that the M. tuberculosis complex contains at least nine human-adapted phylogenetic lineages. This level of genetic diversity results in differences in M. tuberculosis interactions with the host immune system, virulence and drug resistance propensity. In co-infected individuals, HIV-1 and M. tuberculosis are likely to co-colonize host cells. However, the evolutionary impact of the interaction between the host, the slowly evolving M. tuberculosis bacteria and the HIV-1 viral “mutant cloud” is poorly understood. These evolutionary dynamics, at the cellular niche of monocytes/macrophages, are also discussed and proposed as a relevant future research topic in the context of single-cell sequencing.

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A microfluidic device enabling drug resistance analysis of leukemia cells via coupled dielectrophoretic detection and impedimetric counting

Scientific Reports ◽

10.1038/s41598-021-92647-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yağmur Demircan Yalçın ◽

Taylan Berkin Töral ◽

Sertan Sukas ◽

Ender Yıldırım ◽

Özge Zorlu ◽

...

Keyword(s):

Drug Resistance ◽

K562 Cells ◽

Leukemia Cells ◽

Drug Resistant ◽

Wild Type ◽

Gene Expressions ◽

Before And After ◽

The Difference ◽

Selection Of ◽

Resistant Cells

AbstractWe report the development of a lab-on-a-chip system, that facilitates coupled dielectrophoretic detection (DEP-D) and impedimetric counting (IM-C), for investigating drug resistance in K562 and CCRF-CEM leukemia cells without (immuno) labeling. Two IM-C units were placed upstream and downstream of the DEP-D unit for enumeration, respectively, before and after the cells were treated in DEP-D unit, where the difference in cell count gave the total number of trapped cells based on their DEP characteristics. Conductivity of the running buffer was matched the conductivity of cytoplasm of wild type K562 and CCRF-CEM cells. Results showed that DEP responses of drug resistant and wild type K562 cells were statistically discriminative (at p = 0.05 level) at 200 mS/m buffer conductivity and at 8.6 MHz working frequency of DEP-D unit. For CCRF-CEM cells, conductivity and frequency values were 160 mS/m and 6.2 MHz, respectively. Our approach enabled discrimination of resistant cells in a group by setting up a threshold provided by the conductivity of running buffer. Subsequent selection of drug resistant cells can be applied to investigate variations in gene expressions and occurrence of mutations related to drug resistance.

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Effect of Allium senescens Extract on Sorafenib Resistance in Hepatocarcinoma Cells

Applied Sciences ◽

10.3390/app11083696 ◽

2021 ◽

Vol 11 (8) ◽

pp. 3696

Author(s):

Sohyeon Park ◽

Yoonjin Park ◽

Heejong Shin ◽

Boyong Kim ◽

Seunggwan Lee

Keyword(s):

Drug Resistance ◽

Hepg2 Cells ◽

High Performance ◽

Quantitative Polymerase Chain Reaction ◽

Mitochondrial Apoptosis ◽

Coumaric Acid ◽

Allium Species ◽

Hepatocarcinoma Cells ◽

Polymerase Chain ◽

Resistant Cells

Although Allium species are involved in bioactivity, to the best of our knowledge, there is no research on the effects of Allium senescens on drug resistance in hepatocarcinoma. Ultra-high performance liquid chromatography was used to determine the concentration of several bioactive compounds in A. senescens extract; flow cytometry, reverse transcription–quantitative polymerase chain reaction, and siRNA-mediated knockdown to estimate the levels of different markers in HepG2 cells. The quantity of p-coumaric acid in the extract was 4.7291 ± 0.06 μg/mL, and the protein of relevant evolutionary and lymphoid interest (PRELI) in the resistant cells decreased 2.1 times in the presence of p-coumaric acid. The resistant cells strongly downregulated the efflux transporters (ABCB1, ABCC2, and ABCG2) when exposed to the extract or p-coumaric acid and when PRELI was knocked down, in contrast to the influx proteins (OCT-1). Additionally, the extract induced mitochondrial apoptosis and suppressed autophagy. Consequently, the extract and p-coumaric acid attenuated drug resistance of HepG2 cells through the downregulation of PRELI, a key protein associated with the modulation of drug transporter expression, the activation of autophagy, and mitochondrial apoptosis. Our results indicate that A. senescens extract is beneficial in protecting cancer cells against drug resistance and sustaining the efficacy of sorafenib against liver cancer.

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