Transcriptome Remodeling in Gradual Development of Inverse Resistance between Paclitaxel and Cisplatin in Ovarian Cancer Cells

Szenajch, Jolanta; Szabelska‐Berȩsewicz, Alicja; Świercz, Aleksandra; Zyprych-Walczak, Joanna; Siatkowski, Idzi; Goralski, Michal; Synowiec, Agnieszka; Handschuh, Luiza

doi:10.3390/ijms21239218

Cited by 11 publications

(11 citation statements)

References 104 publications

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“…One of the limiting factors to achieve cures for cancer and other diseases is drug resistance. This phenomenon is well known, universal, and its development is almost inevitable [1,2]. Some of the tumors are characterized by primary drug resistance, while others become unresponsive to treatment during chemotherapy [3].…”

Section: Introductionmentioning

confidence: 99%

Spheroid Culture Differentially Affects Cancer Cell Sensitivity to Drugs in Melanoma and RCC Models

Filipiak-Duliban

Brodaczewska

Kajdasz

et al. 2022

IJMS

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2D culture as a model for drug testing often turns to be clinically futile. Therefore, 3D cultures (3Ds) show potential to better model responses to drugs observed in vivo. In preliminary studies, using melanoma (B16F10) and renal (RenCa) cancer, we confirmed that 3Ds better mimics the tumor microenvironment. Here, we evaluated how the proposed 3D mode of culture affects tumor cell susceptibility to anti-cancer drugs, which have distinct mechanisms of action (everolimus, doxorubicin, cisplatin). Melanoma spheroids showed higher resistance to all used drugs, as compared to 2D. In an RCC model, such modulation was only observed for doxorubicin treatment. As drug distribution was not affected by the 3D shape, we assessed the expression of MDR1 and mTor. Upregulation of MDR1 in RCC spheroids was observed, in contrast to melanoma. In both models, mTor expression was not affected by the 3D cultures. By NGS, 10 genes related with metabolism of xenobiotics by cytochrome p450 were deregulated in renal cancer spheroids; 9 of them were later confirmed in the melanoma model. The differences between 3D models and classical 2D cultures point to the potential to uncover new non-canonical mechanisms to explain drug resistance set by the tumor in its microenvironment.

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Section: Introductionmentioning

confidence: 99%

Spheroid Culture Differentially Affects Cancer Cell Sensitivity to Drugs in Melanoma and RCC Models

Filipiak-Duliban

Brodaczewska

Kajdasz

et al. 2022

IJMS

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“…In the ovarian cancer (OC) context, the majority of established chemoresistant cell lines are patient derived and have intrinsic resistance (30,31). Also, A2780 and IGROV1 PTX-induced variants are available, but these cell lines correspond to endometrioid OC subtype (32)(33)(34)(35)(36).…”

Section: Introductionmentioning

confidence: 99%

Generation of Two Paclitaxel-Resistant High-Grade Serous Carcinoma Cell Lines With Increased Expression of P-Glycoprotein

et al. 2021

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Debulking surgery followed by chemotherapy are the standard of care for high-grade serous carcinoma. After an initial good response to treatment, the majority of patients relapse with a chemoresistant profile, leading to a poor overall survival. Chemotherapy regimens used in high-grade serous carcinomas are based in a combination of classical chemotherapeutic drugs, namely, Carboplatin and Paclitaxel. The mechanisms underlying drug resistance and new drug discovery are crucial to improve patients’ survival. To uncover the molecular mechanisms of chemoresistance and test drugs capable of overcoming this resistant profile, it is fundamental to use good cellular models capable of mimicking the chemoresistant disease. Herein, we established two high-grade serous carcinoma cell lines with intrinsic resistance to Carboplatin and induced Paclitaxel resistance (OVCAR8 PTX R C and OVCAR8 PTX R P) derived from the OVCAR8 cell line. These two chemoresistant cell line variants acquired an enhanced resistance to Paclitaxel-induced cell death by increasing the drug efflux capacity, and this resistance was stable in long-term culture and following freeze/thaw cycles. The mechanism underlying Paclitaxel resistance resides in a significant increase in P-glycoprotein expression and, when this drug efflux pump was blocked with Verapamil, cells re-acquired Paclitaxel sensitivity. We generated two high-grade serous carcinoma cell lines, with a double-chemoresistant (Carboplatin and Paclitaxel) phenotype that mimics the majority of tumor recurrences in ovarian cancer context. This robust tool is suitable for preliminary drug testing towards the development of therapeutic strategies to overcome chemoresistance.

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“…Reportedly, PLK2 expression was positively correlated to paclitaxel resistance resulting from its anti-proliferative effects during mitosis in ovarian cancer cell line A2780 and promoting tumor cell viability (122). Different from Syed et al (104), the difference in chemotherapeutic drug resistance pattern may be responsible for the difference in the influence of PLK2.…”

Section: Solid Organ Tumormentioning

confidence: 84%

Section: Role Of Plk2 In Diseasesmentioning

confidence: 99%

Polo-Like Kinase 2: From Principle to Practice

Zhang

2022

Front. Oncol.

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Polo-like kinase (PLK) 2 is an evolutionarily conserved serine/threonine kinase that shares the n-terminal kinase catalytic domain and the C-terminal Polo Box Domain (PBD) with other members of the PLKs family. In the last two decades, mounting studies have focused on this and tried to clarify its role in many aspects. PLK2 is essential for mitotic centriole replication and meiotic chromatin pairing, synapsis, and crossing-over in the cell cycle; Loss of PLK2 function results in cell cycle disorders and developmental retardation. PLK2 is also involved in regulating cell differentiation and maintaining neural homeostasis. In the process of various stimuli-induced stress, including oxidative and endoplasmic reticulum, PLK2 may promote survival or apoptosis depending on the intensity of stimulation and the degree of cell damage. However, the role of PLK2 in immunity to viral infection has been studied far less than that of other family members. Because PLK2 is extensively and deeply involved in normal physiological functions and pathophysiological mechanisms of cells, its role in diseases is increasingly being paid attention to. The effect of PLK2 in inhibiting hematological tumors and fibrotic diseases, as well as participating in neurodegenerative diseases, has been gradually recognized. However, the research results in solid organ tumors show contradictory results. In addition, preliminary studies using PLK2 as a disease predictor and therapeutic target have yielded some exciting and promising results. More research will help people better understand PLK2 from principle to practice.

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Transcriptome Remodeling in Gradual Development of Inverse Resistance between Paclitaxel and Cisplatin in Ovarian Cancer Cells

Cited by 11 publications

References 104 publications

Spheroid Culture Differentially Affects Cancer Cell Sensitivity to Drugs in Melanoma and RCC Models

Spheroid Culture Differentially Affects Cancer Cell Sensitivity to Drugs in Melanoma and RCC Models

Generation of Two Paclitaxel-Resistant High-Grade Serous Carcinoma Cell Lines With Increased Expression of P-Glycoprotein

Polo-Like Kinase 2: From Principle to Practice

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