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13 pages, 4419 KiB

Open AccessArticle

Distinct Classes of Flavonoids and Epigallocatechin Gallate, Polyphenol Affects an Oncogenic Mutant p53 Protein, Cell Growth and Invasion in a TNBC Breast Cancer Cell Line

by Madhu Kollareddy and Luis A. Martinez

Cells 2021, 10(4), 797; https://doi.org/10.3390/cells10040797 - 2 Apr 2021

Cited by 6 | Viewed by 3339

Abstract

Mutant p53(s) are widely considered as oncogenes and promote several gain-of-function oncogenic activities. p53 mutations correlate with higher rates of metastasis and poor survival; therefore, it is paramount to inhibit mutant p53 protein either directly or indirectly. Although some compounds have been developed, [...] Read more.

Mutant p53(s) are widely considered as oncogenes and promote several gain-of-function oncogenic activities. p53 mutations correlate with higher rates of metastasis and poor survival; therefore, it is paramount to inhibit mutant p53 protein either directly or indirectly. Although some compounds have been developed, none of them have achieved a desirable level of specificity. Some of these compounds only targeted specific mutations. In search of less-toxic compounds, we tested plant-derived compounds on mutant p53 triple-negative breast cancer cell lines. Here, we show that the compounds tested reduced the protein levels of one of the more frequent oncogenic p53 mutants (R249S; hot spot mutation), and its important targets that promote invasion and metastasis, including GMPS and IMPDH1. All compounds tested perturbed the invasion potential of the breast cancer cell line. These compounds downregulated several nucleotide metabolism genes (NMGs) which are essential for cell cycle progression. We observed S-phase arrest correlating to reduced cell proliferation and increased replication stress. Moreover, we also show a reduction of key ETS transcription family members including ETS2, ETS1, ETV1, and ETV4, which are involved in invasion and metastasis. We propose that these compounds may inhibit invasion by interfering with multiple pathways. Our findings exemplify that these tested compounds could inhibit invasion and cell growth in TNBC in a nucleotide-dependent manner. Full article

(This article belongs to the Special Issue Studying Drug Resistance Using Cancer Cell Lines)

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15 pages, 4026 KiB

Open AccessArticle

Constitutive Cell Proliferation Regulating Inhibitor of Protein Phosphatase 2A (CIP2A) Mediates Drug Resistance to Erlotinib in an EGFR Activating Mutated NSCLC Cell Line

by Hisham Saafan, Ahmad Alahdab, Robin Michelet, Linus Gohlke, Janine Ziemann, Stefan Holdenrieder, Katie-May McLaughlin, Mark N. Wass, Jindrich Cinatl, Jr., Martin Michaelis, Charlotte Kloft and Christoph A Ritter

Cells 2021, 10(4), 716; https://doi.org/10.3390/cells10040716 - 24 Mar 2021

Cited by 8 | Viewed by 3990

Abstract

Exploring mechanisms of drug resistance to targeted small molecule drugs is critical for an extended clinical benefit in the treatment of non-small cell lung cancer (NSCLC) patients carrying activating epidermal growth factor receptor (EGFR) mutations. Here, we identified constitutive cell proliferation regulating inhibitor [...] Read more.

Exploring mechanisms of drug resistance to targeted small molecule drugs is critical for an extended clinical benefit in the treatment of non-small cell lung cancer (NSCLC) patients carrying activating epidermal growth factor receptor (EGFR) mutations. Here, we identified constitutive cell proliferation regulating inhibitor of protein phosphatase 2A (CIP2A) in the HCC4006rErlo0.5 NSCLC cell line adapted to erlotinib as a model of acquired drug resistance. Constitutive CIP2A resulted in a constitutive activation of Akt signaling. The proteasome inhibitor bortezomib was able to reduce CIP2A levels, which resulted in an activation of protein phosphatase 2A and deactivation of Akt. Combination experiments with erlotinib and bortezomib revealed a lack of interaction between the two drugs. However, the effect size of bortezomib was higher in HCC4006rErlo0.5, compared to the erlotinib-sensitive HCC4006 cells, as indicated by an increase in Emax (0.911 (95%CI 0.867–0.954) vs. 0.585 (95%CI 0.568–0.622), respectively) and decrease in EC50 (52.4 µM (95%CI 46.1–58.8 µM) vs. 73.0 µM (95%CI 60.4–111 µM), respectively) in the concentration–effect model, an earlier onset of cell death induction, and a reduced colony surviving fraction (0.38 ± 0.18 vs. 0.95 ± 0.25, respectively, n = 3, p < 0.05). Therefore, modulation of CIP2A with bortezomib could be an interesting approach to overcome drug resistance to erlotinib treatment in NSCLC. Full article

(This article belongs to the Special Issue Studying Drug Resistance Using Cancer Cell Lines)

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14 pages, 2979 KiB

Open AccessArticle

Pre-Clinical Evaluation of the Proteasome Inhibitor Ixazomib against Bortezomib-Resistant Leukemia Cells and Primary Acute Leukemia Cells

by Margot S.F. Roeten, Johan van Meerloo, Zinia J. Kwidama, Giovanna ter Huizen, Wouter H. Segerink, Sonja Zweegman, Gertjan J.L. Kaspers, Gerrit Jansen and Jacqueline Cloos

Cells 2021, 10(3), 665; https://doi.org/10.3390/cells10030665 - 17 Mar 2021

Cited by 9 | Viewed by 3385

Abstract

At present, 20–30% of children with acute leukemia still relapse from current chemotherapy protocols, underscoring the unmet need for new treatment options, such as proteasome inhibition. Ixazomib (IXA) is an orally available proteasome inhibitor, with an improved safety profile compared to Bortezomib (BTZ). [...] Read more.

At present, 20–30% of children with acute leukemia still relapse from current chemotherapy protocols, underscoring the unmet need for new treatment options, such as proteasome inhibition. Ixazomib (IXA) is an orally available proteasome inhibitor, with an improved safety profile compared to Bortezomib (BTZ). The mechanism of action (proteasome subunit inhibition, apoptosis induction) and growth inhibitory potential of IXA vs. BTZ were tested in vitro in human (BTZ-resistant) leukemia cell lines. Ex vivo activity of IXA vs. BTZ was analyzed in 15 acute lymphoblastic leukemia (ALL) and 9 acute myeloid leukemia (AML) primary pediatric patient samples. BTZ demonstrated more potent inhibitory effects on constitutive β5 and immunoproteasome β5i proteasome subunit activity; however, IXA more potently inhibited β1i subunit than BTZ (70% vs. 29% at 2.5 nM). In ALL/AML cell lines, IXA conveyed 50% growth inhibition at low nanomolar concentrations, but was ~10-fold less potent than BTZ. BTZ-resistant cells (150–160 fold) displayed similar (100-fold) cross-resistance to IXA. Finally, IXA and BTZ exhibited anti-leukemic effects for primary ex vivo ALL and AML cells; mean LC₅₀ (nM) for IXA: 24 ± 11 and 30 ± 8, respectively, and mean LC₅₀ for BTZ: 4.5 ± 1 and 11 ± 4, respectively. IXA has overlapping mechanisms of action with BTZ and showed anti-leukemic activity in primary leukemic cells, encouraging further pre-clinical in vivo evaluation. Full article

(This article belongs to the Special Issue Studying Drug Resistance Using Cancer Cell Lines)

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15 pages, 2515 KiB

Open AccessArticle

Inhibition of HER Receptors Reveals Distinct Mechanisms of Compensatory Upregulation of Other HER Family Members: Basis for Acquired Resistance and for Combination Therapy

by Daniela Gutsch, Robert Jenke, Thomas Büch and Achim Aigner

Cells 2021, 10(2), 272; https://doi.org/10.3390/cells10020272 - 29 Jan 2021

Cited by 7 | Viewed by 2671

Abstract

Overexpression of members of the HER/erbB transmembrane tyrosine kinase family like HER2/erbB2/neu is associated with various cancers. Some heterodimers, especially HER2/HER3 heterodimers, are particularly potent inducers of oncogenic signaling. Still, from a clinical viewpoint their inhibition has yielded only moderate success so far, [...] Read more.

Overexpression of members of the HER/erbB transmembrane tyrosine kinase family like HER2/erbB2/neu is associated with various cancers. Some heterodimers, especially HER2/HER3 heterodimers, are particularly potent inducers of oncogenic signaling. Still, from a clinical viewpoint their inhibition has yielded only moderate success so far, despite promising data from cell cultures. This suggests acquired resistance upon inhibitor therapy as one putative issue, requiring further studies in cell culture also aiming at rational combination therapies. In this paper, we demonstrate in ovarian carcinoma cells that the RNAi-mediated single knockdown of HER2 or HER3 leads to the rapid counter-upregulation of the respective other HER family member, thus providing a rational basis for combinatorial inhibition. Concomitantly, combined knockdown of HER2/HER3 exerts stronger anti-tumor effects as compared to single inhibition. In a tumor cell line xenograft mouse model, therapeutic intervention with nanoscale complexes based on polyethylenimine (PEI) for siRNA delivery, again reveals HER3 upregulation upon HER2 single knockdown and a therapeutic benefit from combination therapy. On the mechanistic side, we demonstrate that HER2 knockdown or inhibition reduces miR-143 levels with subsequent de-repression of HER3 expression, and validates HER3 as a direct target of miR-143. HER3 knockdown or inhibition, in turn, increases HER2 expression through the upregulation of the transcriptional regulator SATB1. These counter-upregulation processes of HER family members are thus based on distinct molecular mechanisms and may provide the basis for the rational combination of inhibitors. Full article

(This article belongs to the Special Issue Studying Drug Resistance Using Cancer Cell Lines)

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19 pages, 7578 KiB

Open AccessEditor’s ChoiceArticle

Artesunate Impairs Growth in Cisplatin-Resistant Bladder Cancer Cells by Cell Cycle Arrest, Apoptosis and Autophagy Induction

by Fuguang Zhao, Olesya Vakhrusheva, Sascha D. Markowitsch, Kimberly S. Slade, Igor Tsaur, Jindrich Cinatl, Jr., Martin Michaelis, Thomas Efferth, Axel Haferkamp and Eva Juengel

Cells 2020, 9(12), 2643; https://doi.org/10.3390/cells9122643 - 9 Dec 2020

Cited by 87 | Viewed by 6534

Abstract

Cisplatin, which induces DNA damage, is standard chemotherapy for advanced bladder cancer (BCa). However, efficacy is limited due to resistance development. Since artesunate (ART), a derivative of artemisinin originating from Traditional Chinese Medicine, has been shown to exhibit anti-tumor activity, and to inhibit [...] Read more.

Cisplatin, which induces DNA damage, is standard chemotherapy for advanced bladder cancer (BCa). However, efficacy is limited due to resistance development. Since artesunate (ART), a derivative of artemisinin originating from Traditional Chinese Medicine, has been shown to exhibit anti-tumor activity, and to inhibit DNA damage repair, the impact of artesunate on cisplatin-resistant BCa was evaluated. Cisplatin-sensitive (parental) and cisplatin-resistant BCa cells, RT4, RT112, T24, and TCCSup, were treated with ART (1–100 µM). Cell growth, proliferation, and cell cycle phases were investigated, as were apoptosis, necrosis, ferroptosis, autophagy, metabolic activity, and protein expression. Exposure to ART induced a time- and dose-dependent significant inhibition of tumor cell growth and proliferation of parental and cisplatin-resistant BCa cells. This inhibition was accompanied by a G0/G1 phase arrest and modulation of cell cycle regulating proteins. ART induced apoptos is by enhancing DNA damage, especially in the resistant cells. ART did not induce ferroptosis, but led to a disturbance of mitochondrial respiration and ATP generation. This impairment correlated with autophagy accompanied by a decrease in LC3B-I and an increase in LC3B-II. Since ART significantly inhibits proliferative and metabolic aspects of cisplatin-sensitive and cisplatin-resistant BCa cells, it may hold potential in treating advanced and therapy-resistant BCa. Full article

(This article belongs to the Special Issue Studying Drug Resistance Using Cancer Cell Lines)

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Review

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14 pages, 1498 KiB

Open AccessReview

Ellagic Acid and Schisandrins: Natural Biaryl Polyphenols with Therapeutic Potential to Overcome Multidrug Resistance in Cancer

by Sabesan Yoganathan, Anushan Alagaratnam, Nikita Acharekar and Jing Kong

Cells 2021, 10(2), 458; https://doi.org/10.3390/cells10020458 - 21 Feb 2021

Cited by 33 | Viewed by 5234

Abstract

Multidrug resistance (MDR) is one of the major clinical challenges in cancer treatment and compromises the effectiveness of conventional anticancer chemotherapeutics. Among known mechanisms of drug resistance, drug efflux via ATP binding cassette (ABC) transporters, namely P-glycoprotein (P-gp) has been characterized as a [...] Read more.

Multidrug resistance (MDR) is one of the major clinical challenges in cancer treatment and compromises the effectiveness of conventional anticancer chemotherapeutics. Among known mechanisms of drug resistance, drug efflux via ATP binding cassette (ABC) transporters, namely P-glycoprotein (P-gp) has been characterized as a major mechanism of MDR. The primary function of ABC transporters is to regulate the transport of endogenous and exogenous small molecules across the membrane barrier in various tissues. P-gp and similar efflux pumps are associated with MDR because of their overexpression in many cancer types. One of the intensively studied approaches to overcome this mode of MDR involves development of small molecules to modulate P-gp activity. This strategy improves the sensitivity of cancer cells to anticancer drugs that are otherwise ineffective. Although multiple generations of P-gp inhibitors have been identified to date, reported compounds have demonstrated low clinical efficacy and adverse effects. More recently, natural polyphenols have emerged as a promising class of compounds to address P-gp linked MDR. This review highlights the chemical structure and anticancer activities of selected members of a structurally unique class of ‘biaryl’ polyphenols. The discussion focuses on the anticancer properties of ellagic acid, ellagic acid derivatives, and schisandrins. Research reports regarding their inherent anticancer activities and their ability to sensitize MDR cell lines towards conventional anticancer drugs are highlighted here. Additionally, a brief discussion about the axial chirality (i.e., atropisomerism) that may be introduced into these natural products for medicinal chemistry studies is also provided. Full article

(This article belongs to the Special Issue Studying Drug Resistance Using Cancer Cell Lines)

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14 pages, 1325 KiB

Open AccessReview

Cell Line Models for Acquired Resistance to First-Line Osimertinib in Lung Cancers—Applications and Limitations

by Shuta Ohara, Kenichi Suda and Tetsuya Mitsudomi

Cells 2021, 10(2), 354; https://doi.org/10.3390/cells10020354 - 9 Feb 2021

Cited by 11 | Viewed by 5289

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are first-line drugs for lung cancers with activating EGFR mutations. Although first- and second-generation EGFR-TKIs were standard first-line treatments, acquired resistance (AR) to these drugs is almost inevitable. Cell line models have been widely [...] Read more.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are first-line drugs for lung cancers with activating EGFR mutations. Although first- and second-generation EGFR-TKIs were standard first-line treatments, acquired resistance (AR) to these drugs is almost inevitable. Cell line models have been widely used to explore the molecular mechanisms of AR to first- and second-generation EGFR-TKIs. Many research groups, including ours, have established AR cell lines that harbor the EGFR T790M secondary mutation, MET gene amplification, or epithelial–mesenchymal transition (EMT) features, which are all found in clinical specimens obtained from TKI-refractory lesions. Currently, many oncologists prescribe osimertinib, a third-generation EGFR-TKI that can overcome T790M-mediated resistance, as a first-line TKI. Although few clinical data are available about AR mechanisms that arise when osimertinib is used as a first-line therapy, many research groups have established cell lines with AR to osimertinib and have reported on their AR mechanisms. In this review, we summarize the findings on AR mechanisms against first-line osimertinib obtained from analyses of cell line models. Full article

(This article belongs to the Special Issue Studying Drug Resistance Using Cancer Cell Lines)

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27 pages, 1235 KiB

Open AccessReview

Functional Genomics Approaches to Elucidate Vulnerabilities of Intrinsic and Acquired Chemotherapy Resistance

by Ronay Cetin, Eva Quandt and Manuel Kaulich

Cells 2021, 10(2), 260; https://doi.org/10.3390/cells10020260 - 28 Jan 2021

Cited by 5 | Viewed by 4591

Abstract

Drug resistance is a commonly unavoidable consequence of cancer treatment that results in therapy failure and disease relapse. Intrinsic (pre-existing) or acquired resistance mechanisms can be drug-specific or be applicable to multiple drugs, resulting in multidrug resistance. The presence of drug resistance is, [...] Read more.

Drug resistance is a commonly unavoidable consequence of cancer treatment that results in therapy failure and disease relapse. Intrinsic (pre-existing) or acquired resistance mechanisms can be drug-specific or be applicable to multiple drugs, resulting in multidrug resistance. The presence of drug resistance is, however, tightly coupled to changes in cellular homeostasis, which can lead to resistance-coupled vulnerabilities. Unbiased gene perturbations through RNAi and CRISPR technologies are invaluable tools to establish genotype-to-phenotype relationships at the genome scale. Moreover, their application to cancer cell lines can uncover new vulnerabilities that are associated with resistance mechanisms. Here, we discuss targeted and unbiased RNAi and CRISPR efforts in the discovery of drug resistance mechanisms by focusing on first-in-line chemotherapy and their enforced vulnerabilities, and we present a view forward on which measures should be taken to accelerate their clinical translation. Full article

(This article belongs to the Special Issue Studying Drug Resistance Using Cancer Cell Lines)

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