Establishment of drug-resistant cell lines under the treatment with chemicals acting through different mechanisms

Grigoreva, Tatyana A.; Sagaidak, Aleksandra; Romanova, Angelina; Novikova, Daria; Garabadzhiu, Aleksander; Tribulovich, Viacheslav

doi:10.1016/j.cbi.2021.109510

Cited by 12 publications

(14 citation statements)

References 37 publications

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“…Increased drug export is an additional form of treatment resistance observed with MDM2 inhibitors. Grigoreva et al compared the expression levels of the ABC gene encoding P-glycoprotein export protein in colon cancer cell lines treated with Nutlin-3a compared with controls and demonstrated that resistant lines exhibited 3-19fold increased mRNA expression, which correlated with increased protein expression by Western blot (217). The authors utilized a fluorescent dye that binds to the intracellular H-site of P-glycoprotein and is actively released from cells.…”

Section: Mechanisms Of Resistance To Mdm2 Inhibitionmentioning

confidence: 99%

Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma

et al. 2022

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Dedifferentiated liposarcoma (DDLPS) is an aggressive adipogenic cancer with poor prognosis. DDLPS tumors are only modestly sensitive to chemotherapy and radiation, and there is a need for more effective therapies. Genetically, DDLPS is characterized by a low tumor mutational burden and frequent chromosomal structural abnormalities including amplification of the 12q13-15 chromosomal region and the MDM2 gene, which are defining features of DDLPS. The MDM2 protein is an E3 ubiquitin ligase that targets the tumor suppressor, p53, for proteasomal degradation. MDM2 amplification or overexpression in human malignancies is associated with cell-cycle progression and worse prognosis. The MDM2–p53 interaction has thus garnered interest as a therapeutic target for DDLPS and other malignancies. MDM2 binds p53 via a hydrophobic protein interaction that is easily accessible with synthetic analogues. Multiple agents have been developed, including Nutlins such as RG7112 and small molecular inhibitors including SAR405838 and HDM201. Preclinical in vitro and animal models have shown promising results with MDM2 inhibition, resulting in robust p53 reactivation and cancer cell death. However, multiple early-phase clinical trials have failed to show a benefit with MDM2 pathway inhibition for DDLPS. Mechanisms of resistance are being elucidated, and novel inhibitors and combination therapies are currently under investigation. This review provides an overview of these strategies for targeting MDM2 in DDLPS.

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Section: Mechanisms Of Resistance To Mdm2 Inhibitionmentioning

confidence: 99%

Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma

et al. 2022

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“…Unfortunately, acquired resistance represents a particular problem for MDM2 inhibitors, as even short treatment results in generation of resistant cell populations across divergent cell lines [ 229 – 231 ]. Resistance originating from activation of ABC transporters such as P-glycoprotein leading to efflux of chemotherapeutic agents [ 232 ] is instrumental in resistance to nutlin-3a in colorectal cancer cells [ 233 ].…”

Section: Acquired Resistance To Mdm2 Inhibitionmentioning

confidence: 99%

Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?

et al. 2021

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Since the discovery of the first MDM2 inhibitors, we have gained deeper insights into the cellular roles of MDM2 and p53. In this review, we focus on MDM2 inhibitors that bind to the p53-binding domain of MDM2 and aim to disrupt the binding of MDM2 to p53. We describe the basic mechanism of action of these MDM2 inhibitors, such as nutlin-3a, summarise the determinants of sensitivity to MDM2 inhibition from p53-dependent and p53-independent points of view and discuss the problems with innate and acquired resistance to MDM2 inhibition. Despite progress in MDM2 inhibitor design and ongoing clinical trials, their broad use in cancer treatment is not fulfilling expectations in heterogenous human cancers. We assess the MDM2 inhibitor types in clinical trials and provide an overview of possible sources of resistance to MDM2 inhibition, underlining the need for patient stratification based on these aspects to gain better clinical responses, including the use of combination therapies for personalised medicine.

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“…The most characteristic P-gp function is the protection of organs and individual cells due to the release of various xenobiotics through the membrane. This transporter possesses a low specificity; its substrates include various endogenous substrates, dyes, and drugs. − …”

Section: Introductionmentioning

confidence: 99%

Analysis of P-Glycoprotein Transport Cycle Reveals a New Way to Identify Efflux Inhibitors

et al. 2022

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P-glycoprotein (P-gp) is found to be of considerable interest for the design of drugs capable of treating chemoresistant tumors. This transporter is an interesting target for which an efficient approach has not yet been developed in terms of computer simulation. In this work, we use a combination of docking, molecular dynamics, and metadynamics to fully explore the states that occur during the capture of a ligand and subsequent efflux by P-gp. The proposed approach allowed us to substantiate a number of experimentally established facts, as well as to develop a new criterion for identifying potential P-gp inhibitors.

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Establishment of drug-resistant cell lines under the treatment with chemicals acting through different mechanisms

Cited by 12 publications

References 37 publications

Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma

Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma

Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?

Analysis of P-Glycoprotein Transport Cycle Reveals a New Way to Identify Efflux Inhibitors

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