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Review

The Managed Acquisition of Chemoresistance as an Informative Tool for Tumor Research

by
Tatyana A. Grigoreva
*,
Daria N. Kindt
,
Aleksandra V. Sagaidak
,
Angelina A. Romanova
and
Vyacheslav G. Tribulovich
*
Laboratory of Molecular Pharmacology, St. Petersburg State Institute of Technology, St. Petersburg 190013, Russia
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(21), 10400; https://doi.org/10.3390/ijms262110400 (registering DOI)
Submission received: 28 August 2025 / Revised: 24 October 2025 / Accepted: 24 October 2025 / Published: 26 October 2025
(This article belongs to the Special Issue Multidrug Resistance in Cancer: Molecular Mechanisms and Therapeutic Challenges)
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Abstract

The problem of acquiring chemoresistance by tumor cells is a growing concern for researchers as the effectiveness of diagnosis and treatment of primary tumors increases. To study the mechanisms of resistance, as well as to evaluate the effectiveness of new drugs, it is necessary to use adequate cell models. The review presents modern methods for obtaining chemoresistant cell lines used by researchers in such studies. It examines the most common cytostatics and targeted drugs, such as cisplatin, oxaliplatin, paclitaxel, doxorubicin, 5-fluorouracil, gemcitabine, gefitinib, bortezomib, erlotinib, and the monoclonal antibody cetuximab. Particular attention is paid to cell mechanisms activated due to drug resistance development and to methods of cell cultivation in the presence of drugs. The presented information provides an opportunity to discuss trends in the creation of chemoresistant cell lines for further research on resistance mechanisms and the development of new therapeutic strategies.

1. Introduction

Cancer is one of the main problems of modern medicine and is the cause of death of almost every sixth person in the world (16.8% of the total number of deaths) [1]. Such a high mortality rate in 90% of cases is due to the formation of tumor drug resistance [2]. In addition, the development of drug resistance to a single drug is often accompanied by resistance to drugs with different structures and mechanisms of action, called multidrug resistance [3].
One of the key causes of multidrug resistance in tumors is the malfunction of ATP-binding transport proteins, which belong to the ATP-binding cassette (ABC) family, also known as ABC transporters [4,5]. Proteins of this family are responsible for the absorption, distribution and excretion of various substrates from the cell—metabolic products, toxins, endogenous lipids, peptides, nucleotides, and sterols, as well as drugs [6,7]. However, a number of other mechanisms are known, such as improved DNA damage repair, suppression of apoptosis, alteration of the drug target, target gene amplification, and others, that often occur simultaneously [2,8].
As the effectiveness of diagnostics and therapy for primary tumors increases, the role of the chemoresistant phenotype that develops in response to various types of therapy becomes increasingly significant. Accordingly, the use of cell models that are able to recreate the features of tumors with drug resistance to various therapeutic agents is becoming an important element in the identification of effective drugs. Two-dimensional cell lines resistant to one or more drugs and 3D cultures based on them—organoids and spheroids—as well as microfluidic systems are used in such in vitro models [9,10,11,12,13]. Classic 2D cultures are the most widely used among them, which is explained by their availability, low cost of reagents and laboratory plastic, and ease of maintenance [14,15].
Regardless of the purpose of studying chemoresistant cells, they must first be isolated from a specific cell line resistant to a particular drug.
Establishment of drug–resistant cell lines is a complex, time-consuming process that requires careful selection of conditions. In this review, we systematize the data presented in the literature on methods for obtaining chemoresistant cell lines.

2. Application of Chemoresistant Cell Lines in Cancer Research

The development of chemoresistant cell lines still has specific scientific and applied significance, although it may also be an independent experimental task.
In general, cell lines obtained by cultivation in the presence of drugs can be used to study the mechanisms of chemoresistance and biomarkers that influence therapeutic efficacy or to assess the ability of any biologically active substances to overcome it [16]. In the first case, the focus may be on the drug specificity that provokes resistance (for example, to the effects of using paclitaxel in different cell lines) [5,17,18,19,20] or to cell-specific mechanisms (for example, MCF7 breast cancer cells) [21,22,23,24]. In the second case, cells serve as a tool for predicting the effectiveness of a therapy [20,25,26,27,28]. Accordingly, the tasks facing the researchers determine the specifics of the methods used to obtain chemoresistant cell lines.

2.1. The Study of Chemoresistance Mechanisms

For successful tumor therapy in clinical practice, it is necessary to take into account the cellular complexity of the disease and its dynamic and evolutionary features, which can both create obstacles and provide opportunities for successful treatment [29]. Anticancer therapy simultaneously creates conditions favorable for the selective growth of chemoresistant clones by destroying sensitive cells and disrupting their interaction. Currently, there are several theories describing tumor development, but the exact molecular mechanism underlying the development of drug resistance is still unknown [15].
Obtaining chemoresistant lines by using certain drugs makes it possible to identify specific mechanisms that are triggered in response to treatment. A comparative analysis of sensitive and resistant cell lines pairs makes it possible to study the molecular basis of resistance in detail. Among the most common mechanisms are:
-
Overexpression of ABC transporters, such as P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), which reduce intracellular drug concentration to ineffective level due to efflux [4,5];
-
Activation of anti-apoptotic signaling pathways, including proteins of the Bcl-2 family, which prevents the initiation of cell death in response to the drug [30];
-
Induction of epithelial–mesenchymal transition, promoting metastasis and tumor progression, as well as the development of therapeutic resistance [31,32] and accompanied by the loss of epithelial markers, for example, E-cadherin;
-
Structural changes in drug targets, for example, the predominance of tubulin isoforms that are less sensitive to taxanes [33].
Often acting synergistically, these mechanisms form a complex and multicomponent basis of chemoresistance, which emphasizes the need for an integrated approach to its study [34].
Furthermore, studies of differences in chemoresistant cells using omics methodologies make it possible to identify specific biomarkers that predict the effectiveness of therapy. In particular, various sets of miRNAs, including miRNAs of genes associated with apoptosis, DNA repair, or drug transport, correlate with resistance to 5-FU or oxaliplatin [35].

2.2. Search for Effective Anticancer Agents

Artificially developed chemoresistant cell lines play an important role in modern preclinical development strategies for anticancer agents. In vitro chemoresistance models enable researchers to identify compounds that overcome resistance in the nascent stages of drug development. This strategy is increasingly important with the development of personalized therapy and the rise of chemoresistant tumors.
Such models are used to test both new drug candidates and combination therapy regimens for previously known drugs. Such drugs can be based on components of natural origin or synthetic [36,37,38]. To overcome resistance to a particular drug, the use of sensitizing additives to the original drug is primarily considered, but a transition to fundamentally different treatment regimens is also possible [39].
Considerable attention of researchers is paid to the search for schemes to overcome P-gp-mediated multidrug resistance through the use of its inhibitors [40,41,42,43], as well as the search for alternative schemes based on targeted effects on pathways specific to a particular chemoresistant tumor. Thus, the use of the orally bioavailable targeted inhibitor ABT-263 reversed the resistance in the case of osimertinib-resistant subline HCC827/OR, where a significant increase in expression levels of Bcl-2 and Bcl-xL was noted [44].

2.3. 3D Cell Culturing

A separate area of chemoresistance research focuses on 3D structures. In such complexes, cancer cells resist therapy more effectively and exhibit their stem-like properties, as they reproduce the specificity of real tumors [45,46].
Although researchers often use two-dimensional (2D) cell cultures to study chemoresistance [9,47,48,49], they have a number of limitations related to the growth method and conditions that are atypical for a living organism. The inability to grow in three dimensions and the absence of a natural tumor microenvironment lead to changes in cell morphology [10,50]. Cell cultures cultivated on flat surfaces differ from in vivo tumors in their architecture, proliferation, and response to external stimuli [51,52,53]. In particular, they are more sensitive to the effects of drugs [54,55].
In order to make in vitro cell cultures more physiologically relevant, technologies for producing 3D cultures such as spheroids and organoids have been developed [15,56]. Spheroids are small spherical cellular formations spontaneously formed by self-assembly when creating specific non-adhesive growth conditions [9,57,58]. Spheroid cells more effectively form intercellular contacts, produce extracellular matrix, and exchange signals [59,60,61]. In turn, organoids are complex self-organizing cellular aggregates obtained from normal and cancer stem cells using special scaffolds and a particular nutrient medium [62,63,64,65].
Due to the more complex structural organization and reconstruction of the microenvironment, 3D models are closer to in vivo tumors than 2D models in terms of proliferation, tissue differentiation, and response to external stimuli [53,66,67]. Such systems are actively used for research purposes but have not yet found wide application in applied works in the search for anticancer agents. This is primarily due to the complexity and high cost of conducting such experiments, which are the main reason for excluding multiple drug candidate screenings.

3. The Main Drugs Associated with Research of Chemoresistant Cells

Currently, there are a number of proven approaches to anti-cancer therapy, including surgical removal of the tumor, chemotherapy, radiotherapy, hormone therapy, immunotherapy, targeted therapy, etc. (Figure 1) [68,69]. To achieve the best clinical effect, different types of therapy are combined with each other; for example, surgical removal of a solid tumor is often combined with chemotherapy [70,71,72].
Despite the wide variety of treatments for malignant neoplasms, chemotherapy is the main and, in some cases, the only possible way of anti-cancer therapy [73,74,75,76]. Chemotherapeutic or cytostatic drugs disrupt the processes of growth, development, and division of cancer cells. Although this group includes agents that differ highly in their mechanism of action, the main classes of cytostatic drugs can be distinguished, such as alkylating agents, antimetabolites, topoisomerase inhibitors, and mitosis inhibitors [73,77,78,79,80].
The most dangerous side effects of cytostatic drugs are their toxicity to healthy cells and the development of tumor drug resistance [29]. To increase the effectiveness of chemotherapy and reduce side effects, targeted drugs are being actively developed and used. They act on specific molecular targets in cancer cells, stopping their growth and invasion [81]. Targeted drugs are small molecular compounds acting by various mechanisms. Their common feature is a direct interaction with a specific protein, leading to inhibition of signaling in cancer cells, which plays an important role in carcinogenesis [81,82]. They are highly selective and are successfully used in combinations with other methods, including chemotherapy [83,84]. An example of a targeted drug is the EGFR inhibitor gefitinib [85,86,87,88]. Nevertheless, targeted drugs are also involved in the development of tumor drug resistance [85,86,89].
Cytostatics occupy the main place among the drugs that attract the greatest interest from researchers in the context of the development of chemoresistance [90]. Cytostatics are widely used in chemotherapy and are believed to be a major contributor to the development of resistant tumors in patients. Such agents include cisplatin [91,92,93,94], oxaliplatin [39,95,96,97], paclitaxel (taxol) [17,89,98,99], doxorubicin (adriamycin) [100,101,102,103,104,105,106,107] and fluorouracil (5-FU) [39,108,109]. Nevertheless, in some cases, targeted drugs are also being investigated. Among them the greatest attention is paid to gemcitabine [39,110,111,112], bortezomib [113,114,115], erlotinib [86,116,117] and monoclonal antibody cetuximab [86,118]. These drugs are discussed in detail in Section 5.

4. Establishment of Cell Lines Resistant to Anticancer Drugs

Currently, more than 100 different cell lines resistant to cytotoxic and targeted drugs have been mentioned in literature. Resistant lines of various types of lung cancer and leukemia are most often obtained [90]. However, despite such a large amount of literature data and accumulated experience, there is still no single scheme for obtaining chemoresistant cell lines. In general, the basis for obtaining cell lines resistant to anticancer drugs is the routine treatment of cells with appropriate drugs for a certain period of time. Main parameters that must be determined prior to treatment include the drug concentration during initial cell treatment, the treatment cycle, and the treatment duration.

4.1. Determination of Anticancer Drug Concentration for Initial Cell Treatment

The concentration of anticancer drugs during initial cell treatment is an important parameter that directly affects the success of obtaining chemoresistant cell lines. It is obvious that using too high concentrations will lead to total cell death. At the same time, the concentration of the drug should be sufficient to activate the protective mechanisms of cell resistance. Accordingly, a necessary preliminary step is to establish the dependence of the survival and proliferation of a particular cell line on the concentration of a particular drug under conditions similar to selection. The most common is the use of colorimetric analysis methods, primarily MTT (for example, [119]), less often XTT [120] or SRB assay [121].
In most cases, half maximum inhibitory concentration (IC50) of the drug compound is used for the primary treatment of cells with anticancer drugs [86,106,110,122,123]. However, this is not a mandatory requirement; the initial concentrations of drugs can also be significantly higher or lower than IC50 [105,124,125]. IC50 values are also conveniently used to compare the sensitivities of parental and resistant lines, determining resistance index RI = (IC50 for resistant cell line/IC50 for parental cell line) [126,127]. Depending on the duration and cultivation scheme in the presence of drug compounds, the resulting cell lines may be resistant to final concentrations of the drugs used, exceeding the IC50 value of the parental lines from several to one hundred and a half times [5,99,122,124,128]. RI in the range 2–10 indicates moderate resistance, while RI above 10 indicates strong drug resistance [126]. However, it should be borne in mind that comparison of RI values is only valid for the same drug or for the same line and using identical viability assessment conditions.

4.2. Total Duration of Cell Culture with Anticancer Drugs

The duration of cells in the presence of anticancer drugs is an important parameter of the process of obtaining chemoresistant cell lines. Depending on the tasks, it may take months for a researcher to obtain a line with the desired properties. The degree of cellular adaptation to the drug and, accordingly, the degree of chemoresistance developed directly depends on this parameter [129]. Cell culture in the presence of an anticancer drug can be both short-term and long-term.
Short-term treatment may be appropriate in the context of reproducing a specific therapeutic regimen or as an illustration of the drug’s potential to develop resistance. In this case, short-term cell culture in the presence of an anticancer drug is carried out until their proliferative ability is restored. On average, this process can take 2–3 weeks from the first treatment [122,124]. However, it should be borne in mind that short-term treatment can lead to incomplete adaptation of cells to the drug and weak activation of cellular defense mechanisms, which does not allow obtaining an adequate cellular model. With such “insufficient” treatment, a subsequent increase in the concentration of the anticancer drug can lead to cell death instead of adaptation [129].
Long-term cell culturing in the presence of an anticancer drug is carried out until they achieve stable proliferation. Depending on the cell type, the mechanism of drug action, and its concentration, this process can take from one month to one and a half years, during which the concentration of the drug is gradually increased as the cells adapt [89,130]. This approach allows achieving maximum activation of the cellular defense mechanisms against the anticancer drug [129].

4.3. The Schedules of Anticancer Drugs

The scheme of cell culturing in the presence of an anticancer drug directly affects the formation of cellular mechanisms of chemoresistance. Two opposing schemes can be distinguished: episodic and continuous treatment (Figure 2). The differences between these schemes are due to the cell culture conditions that are maintained until cell growth and proliferation rates are restored [130].
With continuous treatment, cells are constantly exposed to the anticancer drug until they restore vitality and normal proliferation; after that, the concentration of the substance is increased [94,101,104,109,110]. This cultivation scheme promotes the survival of cells that can quickly activate defense mechanisms and, conversely, the death of cells that cannot adapt to adverse conditions.
During episodic treatment, cells are exposed to an anticancer drug for a short time, from several hours to several days, after which the drug is completely removed from the culture medium. Re-treatment with the drug is carried out only after the cells restore their viability and normal proliferation [17,87,91,108]. Removing the drug from the medium allows cells of various subpopulations, including the most sensitive ones, to develop resistance mechanisms before the next treatment. The cycle of treatment with the drug and its removal from the culture medium is repeated until the cells restore viability and normal proliferation in the presence of the drug used [93,98,100,108].
Episodic treatment (short-term drug pulses) mimics clinical bolus therapy, while continuous treatment essentially corresponds to continuous infusion of the drug [95,115].

5. Trends in the Development of Chemoresistant Cell Lines

In this review, we examined published data describing the establishment of cell lines resistant to the most commonly used anticancer drugs [90]. Methods for obtaining resistant cell lines depending on the specific drug are shown in Table 1.
While the choice of drug is generally determined by its applicability of a treatment to specific tumor types (for example, gefitinib against lung cancer or platinum-based drugs for ovarian cancer), the rationale for selecting a specific scheme is not always explicitly stated in the literature. Nevertheless, general trends can be noted. Thus, continuous treatment appears to be more commonly used in case of chemotherapy drugs (gemcitabine) and targeted drugs (cetuximab and lenvatinib). For 5-FU, doxorubicin, and gefitinib, episodic treatment is rather a rare exception. However, at the same time, an episodic type of drug treatment is mainly used to obtain cisplatin-resistant cell lines [91,92,93,123,131,132,133]. Thus, the researcher can choose a scheme for obtaining a chemoresistant cell line based on both the general trends shown in the table and their own preferences, depending on the tasks to be solved and the time frame.
The oxaliplatin example is illustrative, in which an episodic treatment was used in comparison with a continuous one [95]. The approach presented in this article allows a realistic assessment of the differences in treatment effectiveness. The authors showed that 7 months of continuous treatment can achieve significantly better results compared to 4-h pulses every passage. Notably, this resulted in a two-fold difference in RI for oxaliplatin in ovarian carcinoma cells.
In general, continuous treatment seems preferable, as it allows for the effective selection of cells with greater drug resistance compared to episodic treatment. At the same time there are no significant differences in the activated mechanisms between these treatment schemes. In addition, continuous treatment is more universal, since it does not involve variability in the frequency or duration of individual pulses.
Studies of different drugs on a single cell line identified mechanisms inherent to the line [39]. In particular, in a gastric adenocarcinoma cell line, any drug provoked the activation of the efflux pump (MRP↑), although 5-FU also activated P-gp, and oxaliplatin and paclitaxel suppressed the tumor suppressor DAPK2. Similarly, MCF7 adapts to taxol and doxorubicin by overexpressing specific transporters [98,99,105].

5.1. Cytostatics

It is evident that a mechanism of drug action should largely determine the cellular response, including the mechanisms of successful tumor cell defense. Thus, ovarian and colorectal cells reacted to oxaliplatin in a similar way, demonstrating a decreased uptake by one of the OCTs or CTR1, while the ATPases contributed to the efflux of platinum derivatives [95].
The cytotoxic drugs cisplatin and oxaliplatin belong to the class of alkylating agents. These drugs transfer alkyl groups to guanine residues of DNA, forming DNA adducts, DNA cross-links, and DNA strand breaks [77]. In addition, platinum-based drugs, including cisplatin and oxaliplatin, cause the formation of reactive oxygen species and cell death as a result of oxidative stress [145]. Accordingly, in the case of cell survival, they are expected to show changes in both the amount of DNA and its sequence, which contributes to the cell cycle arrest at different phases [39,91,93,94,123,132], and DNA repair activated by ERCC1 [92,95].
Paclitaxel belongs to the class of mitosis inhibitors. It binds to the tubulin, prevents the movement and functioning of microtubules, disrupts the formation of the mitotic spindle, and, as a result, suppresses the mitosis of tumor cells [78]. Overcoming such an effect in resistant cells, regardless of the drug treatment scheme, is facilitated by cell cycle arrest in the G0/G1 or G2/M phases [39,98], as well as the activation of drug efflux via P-glycoprotein or related MRP/LRP proteins, which in the case of paclitaxel was noted for all cell types [17,39,89,98,99,135].
Doxorubicin is an inhibitor of topoisomerase, an enzyme involved in DNA replication. Binding to topoisomerase eventually leads to DNA double-strand breaks [79]. Doxorubicin also causes the generation of reactive oxygen species and cell death from oxidative stress [146]. This drug has several cytotoxic mechanisms of action, which also allow it to be classified as an alkylating agent and an inhibitor of mitosis [73]. Nevertheless, all its potential effects are effectively overcome by P-gp-mediated efflux [100,102,103,105,106,107,136,137].
5-Fluorouracil (5FU) and gemcitabine are antimetabolites. Due to structural similarity to purines and pyrimidines, drugs of this class integrate into DNA, suppress its synthesis, and cause DNA strand breaks [80].
Accordingly, cells manage to adapt to 5-FU independently of the drug treatment scheme by activating the Twist transcription factor [108,139], which is associated with tumor stage, grade, and poor prognosis in multiple cancers [147]. Gemcitabine also inhibits the DNA polymerase and ribonucleotide reductase enzymes [148]. Thus, the activation of ribonucleotide reductase RRM1/2 [112,140] protects cells by providing DNA repair. Cell cycle arrest, as well as efflux activation, is also effective in cases of antimetabolites resistance [39,109,110].
In general, ABC family transporters, particularly P-gp, are a universal mechanism that is activated in cells in response to cytostatics, which has been noted in the vast majority of studies.

5.2. Targeted Drugs

It is known that the main mechanism of cellular defense against cytotoxic drugs is to prevent the accumulation of dangerous drug concentrations. In the case of targeted drugs, a change in the affected mechanism has a greater effect, which has been shown not only for modulators of the epidermal growth factor receptor (EGFR) but also for other agents [89].
EGFR is a central regulator of proliferation and progression in human cancers, as its ligand EGF regulates epithelial cells, which are known as the carcinoma precursor cells. EGF binding activates the EGFR tyrosine kinase, leading to autophosphorylation of tyrosine residues and activation of several signaling cascades, including MAPK, AKT, and STAT [149]. Cetuximab is a monoclonal antibody that blocks EGFR from outside the cell, while erlotinib and gefitinib are small molecular tyrosine kinase inhibitors that block EGFR signals inside the cell. It is quite predictable that the target drug loses its effectiveness due to any changes both in the structure of the target protein or in the mechanisms associated with it [85,86,144]. In the case of EGFR, signaling changes that promote tumor cell survival are associated with epithelial-to-mesenchymal transition, which is mediated by decreased E-cadherin levels [150]. Cell cycle arrest protects cells against apoptosis [87].
Both tumor and non-tumor cells become insensitive to the proteasome inhibitor bortezomib in the presence of mutations in the β5 subunit of the proteasome, to which the inhibitor is intended to bind [151,152,153]. Upon successful binding, bortezomib-mediated inhibition of proteasomes leads to the accumulation of a wide variety of proteins in cells. In turn, changes in mitochondrial metabolism (Bcl/Mcl) help cells adapt to proteotoxic stress [115,154], while increased expression of p-ERK and p-p65, which are involved in the NF-κB pathway [114,155], may exert an anti-apoptotic effect.

6. Conclusions and Perspectives

The problems of effective treatment of chemoresistant tumors are associated with a high degree of complexity and diversity of mechanisms for the development of cell resistance to antitumor drugs. Overcoming these problems requires a deep understanding of the processes underlying the development of resistance, as well as the mechanisms of their regulation at the molecular and cellular levels. Accordingly, an important aspect is the use of adequate cellular models that allow modeling the dynamics of the development of resistant phenotypes and studying their biological properties. Such models provide an opportunity to carry out an early-stage assessment of the potential of new drugs and also allow identifying the mechanisms that contribute to the emergence and progression of chemoresistance. In the context of modern pharmacology and oncology, the use of cellular systems that are as close as possible to clinical situations will facilitate a more accurate assessment of the effectiveness and risks of developing resistance to new drugs.
To date there are no generally accepted conditions for obtaining reproducible universal models in different laboratories, which would provide reproducible and comparable results. Treatment of the cells with anticancer drugs can be episodic or continuous, short-term or prolonged. The concentration of the drug and the cell culture conditions may also vary. Accordingly, a step towards obtaining more reproducible and relevant results would be the adoption of generalized protocols that could be used by researchers from different organizations and countries. As noted above, under current conditions, it is not possible to use even the resistance index (RI) for comparison, since all data are obtained under different conditions and, with rare exceptions (for example, [95,115,156]), the authors do not provide justification for the selected parameters.
To make the cell models clinically relevant, the use of 3D culture techniques can be considered. In the only study that investigated the development of resistance directly in gastric cancer organoids, 5-FU was used for 72 h, and the authors managed to achieve an almost 10-fold increase in IC50 [157]. 3D cultures are not suitable for prolonged studies due to their low stability [15]. However, these models are successfully used to study the mechanisms of resistance by reproducing the three-dimensional structure of in vivo tumors, which are characterized by diffusion gradients of substances and oxygen. [158]. Hypoxia and the uneven distribution of drugs within in vivo tumors contribute to the development of specific drug resistance mechanisms [158] that can only be replicated under appropriate conditions. Such models can be derived from 2D cultures with induced resistance, from the tissues of a patient’s drug-resistant tumor, or by treating three-dimensional systems with a drug.
Cell lines with induced drug resistance to various antitumor drugs remain a convenient, widely used model for studying the mechanisms of tumor cell resistance to drug compounds and preclinical evaluation of the effectiveness of new anticancer agents. Cell lines resistant to cytostatic drugs such as cisplatin or doxorubicin are most often obtained. Targeted drugs are less commonly considered. Nevertheless, given the increasing role of chemoresistance in the problems of successful cancer therapy, it seems advisable to expand the pool of similar trials to other drugs used in anticancer therapy, as well as ongoing preclinical and clinical trials.

Author Contributions

Conceptualization, T.A.G.; writing—original draft preparation, A.V.S., D.N.K. and A.A.R.; writing—review and editing, A.A.R., V.G.T. and T.A.G.; visualization, T.A.G.; supervision, T.A.G. and V.G.T. All authors have read and agreed to the published version of the manuscript.

Funding

The work was financially supported by the Russian Science Foundation (project no. 23-13-00344).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. The main types of anticancer therapy. The considered drugs are presented.
Figure 1. The main types of anticancer therapy. The considered drugs are presented.
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Figure 2. Basic cell treatment schemes to obtain chemoresistant cell lines. The arrows indicate the drug addiction. (A) Continuous treatment: the drug is constantly present in the medium; its concentration gradually increases as the cells adapt. (B) Episodic treatment: the drug is added for a certain time, then the cells are restored in a drug-free medium, and finally the drug is added again.
Figure 2. Basic cell treatment schemes to obtain chemoresistant cell lines. The arrows indicate the drug addiction. (A) Continuous treatment: the drug is constantly present in the medium; its concentration gradually increases as the cells adapt. (B) Episodic treatment: the drug is added for a certain time, then the cells are restored in a drug-free medium, and finally the drug is added again.
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Table 1. Methods for obtaining resistant cell lines depending on the specific antitumor drug.
Table 1. Methods for obtaining resistant cell lines depending on the specific antitumor drug.
DrugDrug Treatment SchemeTumor TypeParental Cell LineActivated Mechanisms of Drug Resistance *Reference
Platinum-based alkylating agentCisplatinContinuousGastric adenocarcinomaOCUM2MModal chromosome number ↓, DNA index ↑[94]
EpisodicColorectal carcinomaHCT116Migratory ability ↑[131]
Hepatocellular carcinomaSK-Hep1P-gp and MRP1 protein level ↑, G2/M cell cycle arrest[93]
NeuroblastomaTGWAlterations in the DNA sequence throughout the entire genome[132]
OsteosarcomaSOSP9607MRP1 and MRP2 mRNA ↑, G0/G1 cell cycle arrest[91]
Ovarian cancerNOY1p-Akt, p-Bcl-2 and GSTA1 ↑[133]
Squamous cell carcinomaEC109G0/G1 cell cycle arrest[123]
OxaliplatinContinuousColorectal cancerSW620E-cadherin ↓, Vimentin ↑[96]
HCT8 and HT29CDK1 protein and mRNA ↑[97]
THC8307DDB1 and RPA1 ↑, STK17A and BNIP3 ↓, RAP1B and RGS4 ↓[134]
Gastric adenocarcinomaOCUM2MDAPK2 ↑, G2/M cell cycle arrest[39]
Ovarian carcinomaA2780hCTR1, OCT1, ERCC1, ATP7B and ALDH1L2 ↓; ALDH1A2 ↑[95]
Colorectal cancerLoVo-92hCTR1, OCT1, OCT2, OCT3, ERCC1 and ALDH1L2 ↓; ATP7A, ATP7B and ALDH1A2 ↑[95]
LoVo-LihCTR1, OCT2, OCT3, ATP7A, ATP7B and ALDH1L2 ↓[95]
EpisodicOvarian carcinomaA2780hCTR1, OCT1, ATP7A, ATP7B and ALDH1L2 ↓; ERCC1 and ALDH1A2 ↑[95]
Colorectal cancerLoVo-92hCTR1, OCT1, OCT2, OCT3, ERCC1 and ALDH1L2 ↓; ATP7A, ATP7B and ALDH1A2 ↑[95]
Colorectal cancerLoVo-LihCTR1, OCT1, OCT2, OCT3, ERCC1, ATP7A, ATP7B and ALDH1L2 ↓; ALDH1A2 ↑[95]
Natural mitosis inhibitorPaclitaxel (taxol)ContinuousBreast cancerSK-BR3P-gp, BCRP, ABCC3, ABCC4 protein and mRNA ↑[99]
MCF7P-gp, BCRP, ABCC3, ABCC4 protein and mRNA ↑[99]
MCF7Hsp90, pre-dermcidin and actinin ↓[135]
Colorectal cancerHCT116P-gp ↑[89]
Gastric adenocarcinomaOCUM2MMRP ↑, DAPK2 ↓, G2/M cell cycle arrest[39]
EpisodicBreast cancerMCF7P-gp, LRP and GST-π ↑; G0/G1 cell cycle arrest[98]
Prostate cancerDU145 and PC3P-gp ↑[17]
VCaP, PC3 and DU145LARP1 and CCND1 ↑[124]
Topoisomerase inhibitorDoxorubicinContinuousBreast cancerMCF7 P-gp and BCRP ↑, procaspase-9 ↓ [105]
CholangiocarcinomaQBC939P-gp ↑, G2/M cell cycle arrest[136]
Colorectal cancerHCT15P-gp and MRP mRNA ↑[102]
LoVoP-gp and COX-2 ↑[137]
Kidney cancerRCC8701P-gp, GST-p, and topoisomerase II mRNA ↑; GSH and G-6-PDH ↑[101]
LeukemiaBFTC905227 genes ↑, 213 genes ↓[104]
KK47P-gp ↑[106]
Lung cancerSBC3P-gp and GST ↑[103]
OsteosarcomaMNNG/HOSP-gp ↑, MRP ↓[107]
MG63P-gp ↑[107]
Prostate cancerDU145ABCG4 ↑[138]
EpisodicOsteosarcomaSAOS2P-gp and MRP mRNA ↑[100]
Antimetabolite5-Fluorouracil (5-FU)ContinuousBreast cancerMDA-MB231P-gp and BCRP ↑[109]
Gastric adenocarcinomaOCUM2MMDR1, MRP and DPD ↑, G2/M cell cycle arrest[39]
Hepatocellular carcinomaHLFCDH1 and TWIST1 ↑, MRP5 ↓[139]
EpisodicSquamous cell carcinomaHSC2 and HSC4N-cadherin and Twist ↑, E-cadherin ↓[108]
GemcitabineContinuousGastric adenocarcinoma OCUM2MMRP ↑, G2/M cell cycle arrest[39]
CholangiocarcinomaKKU-M139 and KKU-M214MRP1, Bcl-2, MMP-9 and uPA ↑; G2/M cell cycle arrest[110]
Lung cancerCL1-0p-PI3K/PI3K, p-AKT/AKT, and p-NF-κB/NF-κB ↑[111]
Pancreatic cancerPANC1NT5, RRM1 and RRM2 ↑[112]
PANC1 and Capan1SLC38A5 and RRM1 ↑[140]
BxPC3RUNX1 ↑[141]
Combination of docetaxel,
cisplatin and 5-FU		ContinuousHead and neck cancerHep2Survivin, CTR1, TS and ERCC1 ↑; G2/M cell cycle arrest[92]
CAL27CTR1, ERCC1 and TS ↑; G2/M cell cycle arrest[92]
EGFR inhibitorGefitinibContinuousHead and neck cancerSCC-1p-EGFR, MAPK, AKT and STAT3 ↑[86]
Lung cancerA549N/A[88]
A549 and PC9miR-342-3p ↑[142]
A549 and PC9Circ_MACF1 ↓[143]
EpisodicLung cancerPC9HER3 and AKT ↓, HER2 dimerization ↓, EGFR/HER2 and EGFR/HER3 heterodimer formation ↑, ratio of EGFR heterodimer to homodimer ↑[85]
H1975Vimentin ↑, E-cadherin ↓, G0/G1 cell cycle arrest[87]
ErlotinibContinuousHead and neckSCC-1p-EGFR, MAPK, AKT and STAT3 ↑[86]
Lung cancerHCC827E-cadherin ↓, laminA/C proteins ↓, N- cadherin ↑, vimentin ↑, SLUG ↑, ZEB1 ↑[116]
HCC827PHGDH ↑, ECAR (extracellular acidification rate) ↑[117]
CetuximabContinuousHead and neckLICR-HN2, LICR-HN5, and SC263Vimentin↑, fibronectin ↑, ABCG1 ↓, TP63 ↓, ALDH1A1 ↓, ALDH3A1 ↓, ABCA1 ↓, SOX21 ↓ [118]
SCC-1p-EGFR, MAPK, AKT and STAT3 ↑[86]
Multiple kinase inhibitorLenvatinibContinuousHepatocellular carcinomaHuH7 and PLC/PRF/5P-gp ↑, EGF ↑, RTK family proteins ↑[144]
Proteasome inhibitorBortezomibContinuousMultiple myelomaU266CD56 ↓, CD66a ↓[113]
U266pERK ↑, p-p65 ↑, CD138(-) ↑[114]
EpisodicKMS-12-BMBcl-2 ↓, Mcl-1 ↓[115]
* ↓ represent a decrease in the indicated gene, protein, or biological parameter; ↑ represent an increase in the indicated gene, protein, or biological parameter.
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Grigoreva, T.A.; Kindt, D.N.; Sagaidak, A.V.; Romanova, A.A.; Tribulovich, V.G. The Managed Acquisition of Chemoresistance as an Informative Tool for Tumor Research. Int. J. Mol. Sci. 2025, 26, 10400. https://doi.org/10.3390/ijms262110400

AMA Style

Grigoreva TA, Kindt DN, Sagaidak AV, Romanova AA, Tribulovich VG. The Managed Acquisition of Chemoresistance as an Informative Tool for Tumor Research. International Journal of Molecular Sciences. 2025; 26(21):10400. https://doi.org/10.3390/ijms262110400

Chicago/Turabian Style

Grigoreva, Tatyana A., Daria N. Kindt, Aleksandra V. Sagaidak, Angelina A. Romanova, and Vyacheslav G. Tribulovich. 2025. "The Managed Acquisition of Chemoresistance as an Informative Tool for Tumor Research" International Journal of Molecular Sciences 26, no. 21: 10400. https://doi.org/10.3390/ijms262110400

APA Style

Grigoreva, T. A., Kindt, D. N., Sagaidak, A. V., Romanova, A. A., & Tribulovich, V. G. (2025). The Managed Acquisition of Chemoresistance as an Informative Tool for Tumor Research. International Journal of Molecular Sciences, 26(21), 10400. https://doi.org/10.3390/ijms262110400

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