Drug resistance evaluation in novel 3D in vitro model

Nowacka, Marta; Sterzyńska, Karolina; Andrzejewska, Małgorzata; Nowicki, Michał; Januchowski, Radosław

doi:10.1016/j.biopha.2021.111536

Cited by 46 publications

(34 citation statements)

References 83 publications

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“…In contrast to W1 cell line, W1PR1 and W1PR1-C7 cell lines were resistant to lower PAC-concentration, and only high drug concentration was able to reduce spheroids’ viability. A similar observation was previously made by our team for spheroids derived from A2780 PAC-resistant cell lines [ 41 ]. The possible explanation is a dense cellular structure and the presence of ECM molecules in W1 that can limit drug diffusion into the central part of the spheroid [ 63 ].…”

Section: Discussionsupporting

confidence: 82%

“…Because previously we had observed different morphology of drug-sensitive and resistant cell lines and various shapes of spheroids [ 41 ], we were interested in whether a knockout of ALDH1A1 affects these parameters. In 2D conditions, W1, W1PR1, W1PR1-C7, W1TR, W1TR-1p17, W1 TR-2p17 cells grow as a monolayer in tissue culture flasks ( Figure 6 A).…”

Section: Resultsmentioning

confidence: 99%

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Effect of ALDH1A1 Gene Knockout on Drug Resistance in Paclitaxel and Topotecan Resistant Human Ovarian Cancer Cell Lines in 2D and 3D Model

Nowacka

Ginter-Matuszewska

Świerczewska

et al. 2022

IJMS

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Ovarian cancer is the most common cause of gynecological cancer death. Cancer Stem Cells (CSCs) characterized by drug transporters and extracellular matrix (ECM) molecules expression are responsible for drug resistance development. The goal of our study was to examine the role of aldehyde dehydrogenase 1A1 (ALDH1A1) expression in paclitaxel (PAC) and topotecan (TOP) resistant ovarian cancer cell lines. In both cell lines, we knocked out the ALDH1A1 gene using the CRISPR/Cas9 technique. Additionally, we derived an ALDH1A1 positive TOP-resistant cell line with ALDH1A1 expression in all cells via clonal selection. The effect of ALDH1A1 gene knockout or clonal selection on the expression of ALDH1A1, drug transporters (P-gp and BCRP), and ECM (COL3A1) was determined by Q-PCR, Western blot and immunofluorescence. Using MTT assay, we compared drug resistance in two-dimensional (2D) and three-dimensional (3D) cell culture conditions. We did not observe any effect of ALDH1A1 gene knockout on MDR1/P-gp expression and drug resistance in the PAC-resistant cell line. The knockout of ALDH1A1 in the TOP-resistant cell line resulted in a moderate decrease of BCRP and COL3A1 expression and weakened TOP resistance. The clonal selection of ALDH1A1 cells resulted in very strong downregulation of BCPR and COL3A1 expression and overexpression of MDR1/P-gp. This finally resulted in decreased resistance to TOP but increased resistance to PAC. All spheroids were more resistant than cells growing as monolayers, but the resistance mechanism differs. The spheroids’ resistance may result from the presence of cell zones with different proliferation paces, the density of the spheroid, ECM expression, and drug capacity to diffuse into the spheroid.

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Section: Discussionsupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Effect of ALDH1A1 Gene Knockout on Drug Resistance in Paclitaxel and Topotecan Resistant Human Ovarian Cancer Cell Lines in 2D and 3D Model

Nowacka

Ginter-Matuszewska

Świerczewska

et al. 2022

IJMS

Self Cite

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“…In addition, the same study proved that MGP might contribute to increased cancer resistance to chemotherapeutic drugs by augmenting the interaction of stromal cancerous cells with the extracellular matrix components [ 40 ]. It has also been shown that an increased expression of MGP is linked to the respective chemotherapeutic drugs [ 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

The First Evaluation of Serum Levels of MGP, Gas6 and EGFR after First Dose of Chemotherapy in Lung Cancer

Crintea

Duţu

Constantin

et al. 2022

Biology

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Background: Vitamin K-dependent proteins (VKDPs) and the epidermal growth factor receptor (EGFR) are involved in lung cancer progression. Therefore, we aimed to study the serum concentration of Matrix Gla protein (MGP), Growth Arrest-specific 6 (Gas6), and EGFR before and after the first cycle of chemotherapy and to investigate how MGP, Gas6, and EGFR are modified after one cycle of chemotherapy. Methods: We performed an observational study on twenty patients diagnosed with lung cancer, by assessing the serum concentration of vitaminK1 (VitK1), MGP, Gas6, and EGFR using the ELISA technique before and after three weeks of the first cycle of chemotherapy. Patients were evaluated using RECIST 1.1 criteria. Results: Serum levels of MGP, Gas6, EGFR, and VK1 before and after treatment were not changed significantly. Regarding the pre-treatment correlation of the MGP values, we found a strong positive relationship between MGP and VK1 pre-treatment values (r = 0.821, 95%CI 0.523; 0.954, p < 0.001). Furthermore, there was a moderately negative correlation between VK1 and EGFR pre-treatment values, with the relationship between them being marginally significant (r = −0.430, 95%CI −0.772; 0.001, p = 0.058). Post-treatment, we found a strong positive relationship between MGP and VK1 post-treatment values (r = 0.758, 95%CI 0.436; 0.900, p < 0.001). We also found a moderate positive relationship between Gas6 and EGFR post-treatment values, but the correlation was only marginally significant (r = 0.442, p = 0.051).

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“…Their spatial architecture promotes the establishment of diffusion gradients that could modify what it is seen in monolayer, where all cells are equally exposed to drugs ( 25 ). Our group has already published a work that supports the theory that OC cells tend to be more resistant to CDDP treatment when growing on 3D ( 17 ), and similar results have also been recently described for different drugs in 3D models of colorectal cancer ( 26 ), hepatocarcinoma ( 27 ), glioblastoma ( 28 ), breast cancer ( 29 ), melanoma ( 30 ), and also in OC ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

Antitumoral Effect of Plocabulin in High Grade Serous Ovarian Carcinoma Cell Line Models

et al. 2022

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Ovarian cancer (OC) is a life-threatening tumor and the deadliest among gynecological cancers in developed countries. First line treatment with a carboplatin/paclitaxel regime is initially effective in the majority of patients, but most advanced OC will recur and develop drug resistance. Therefore, the identification of alternative therapies is needed. In this study, we employed a panel of high-grade serous ovarian cancer (HGSOC) cell lines, in monolayer and three-dimensional cell cultures. We evaluated the effects of a novel tubulin-binding agent, plocabulin, on proliferation, cell cycle, migration and invasion. We have also tested combinations of plocabulin with several drugs currently used in OC in clinical practice. Our results show a potent antitumor activity of plocabulin, inhibiting proliferation, disrupting microtubule network, and decreasing their migration and invasion capabilities. We did not observe any synergistic combination of plocabulin with cisplatin, doxorubicin, gemcitabine or trabectedin. In conclusion, plocabulin has a potent antitumoral effect in HGSOC cell lines that warrants further clinical investigation.

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Drug resistance evaluation in novel 3D in vitro model

Cited by 46 publications

References 83 publications

Effect of ALDH1A1 Gene Knockout on Drug Resistance in Paclitaxel and Topotecan Resistant Human Ovarian Cancer Cell Lines in 2D and 3D Model

Effect of ALDH1A1 Gene Knockout on Drug Resistance in Paclitaxel and Topotecan Resistant Human Ovarian Cancer Cell Lines in 2D and 3D Model

The First Evaluation of Serum Levels of MGP, Gas6 and EGFR after First Dose of Chemotherapy in Lung Cancer

Antitumoral Effect of Plocabulin in High Grade Serous Ovarian Carcinoma Cell Line Models

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