Molecular Mechanisms Of Cisplatin Resistance Research Articles

MicroRNA-34a negatively regulates Netrin1 and mediates MEK/ERK pathway to regulate chemosensitivity of gastric cancer cells.

To explore the mechanism of action of MicroRNAs-34a (miR-34a) and Eurite growth guiding factor 1 (Netrin1) in cisplatin resistance in gastric cancer (GC), providing new clues for overcoming tumor resistance and optimizing anti-tumor therapy for GC. The Cancer Genome Atlas (TCGA), Differentially Expressed MicroRNAs (miRNAs) in human cancers (dbDEMC), and Starbase online databases were used to analyze the correlation between miR-34a and Netrin-1 and prognosis in GC, and to predict and verify the targeted binding of miR-34a to Netrin-1. The experimental methods including Cell transfection, real-time polymerase chain reaction (RT-PCR), Cell-Counting-Kit-8 (CCK8) assay, flow cytometry, wound scratch assay, transwell assay, and western blotting were used to investigate the effects of miR-34a and Netrin1 on chemotherapy resistance and biological characteristics in cisplatin-resistant GC cells (HGC27/DDP), and to analyze the molecular mechanism of cisplatin resistance. miR-34a expression was downregulated in gastric cancer clinical samples and cisplatin-resistant cells, while Netrin1 was upregulated, and was related to overall survival (OS). Upregulation of miR-34a can significantly reduce the IC50 value of cisplatin(0.65 vs 1.6 ng/mL) and Multidrug Resistance 1 (MDR-1) protein level, inhibit the proliferation activity, reduce the expression levels of proliferating cell nuclear antigen (PCNA) and ki-67 protein, and induce the increase of apoptosis rate and the enhancement of cycle arrest. Upregulation of miR-34a can also significantly reduce the expression level of Matrix metalloproteinase 9 (MMP9) protein, promote the expression of E-cadherin protein, reduce the wound healing rate and invasion number to inhibit migration and invasion ability in drug-resistant gastric cancer cells. Moreover, overexpression of Netrin1 on the basis of upregulation of miR-34a can weaken the above changes caused by upregulation of miR-34a. In addition, upregulation of miR-34a can significantly inhibit the Mitogen-activated protein kinase kinase (MEK) / Extracellular regulated protein kinases (ERK) pathway, while overexpression of Netrin1 can activate the MEK/ERK pathway, and inhibition of MEK/ERK pathway can effectively counteract the protein expression of Netrin1, and reverse changes in the expression of cisplatin IC50 and MDR-1 proteins caused by co-upregulation of miR-34a/Netrin1 in HGC27/DDP, as well as changes in proliferation, apoptosis, migration and invasion. In addition, upregulation of miR-34a can significantly inhibit the MEK/ERK pathway, while overexpression of Netrin1 can activate the MEK/ERK pathway. If the MEK/ERK pathway was inhibited, it can effectively counteract the protein overexpression of Netrin1, and reverse the changes in the expression of cisplatin IC50 and MDR-1 proteins in HGC27/DDP induced by co-upregulation of miR-34a / Netrin1, as well as changes in proliferation, apoptosis, migration and invasion. miR-34a targets and negatively regulates Netrin1 to mediate the proliferation, apoptosis, apoptosis, migration, and invasion of drug-resistant gastric cancer cells via the MEK/ERK pathway, and change the chemosensitivity in GC cells. miR-34a/Netrin1/MEK/ERK axis may serve as a novel therapeutic target for chemoresistance in GC, it is of great significance for overcoming drug resistance and developing new therapeutic strategies for GC.

Resistance to the platinum‑based chemotherapeutic drugs in oral cancer: Focus on the role of p22phox (Review).

Oral cancer, commonly known as oral squamous cell carcinoma (OSCC), is an aggressive malignancy in the oral cavity with a poor prognosis and survival rate, particularly at the advanced stages. Oral cancer represents one of the most widespread cancers worldwide, in which the prevalence is particularly high in South and Southeast Asia. While the incidence and mortality rates continue to increase over the past decades, oral cancer treatment can be challenging and at times ineffective, largely due to drug resistance. To date, platinum-based drugs, such as cisplatin, remain the mainstay of chemotherapy for patients with oral cancer. However, long-term exposure to cisplatin inevitably leads to the development of resistance to the drug, which is still a major issue to overcome in oral cancer treatment. The molecular mechanisms of cisplatin resistance in oral cancer have been extensively studied in recent years and the present review places specific emphasis on a novel mechanism of resistance to the platinum drugs mediated by p22phox, an endoplasmic reticulum membrane protein. In addition to delineating the unique p22phox-dependent cisplatin resistance, the present review compares and contrasts the resistance mechanism to its current counterparts. Finally, with the goal of tackling the problem of chemotherapy resistance in oral cancer, various strategies are presented that may counteract p22phox-dependent cisplatin resistance, which may potentially improve the efficacy of the platinum-based drugs and warrant future clinical validation.

MiR-375 promotes cisplatin sensitivity of lung adenocarcinoma

BackgroundCisplatin-based chemotherapy has been widely used in the treatment of lung adenocarcinoma (LUAD). However, the development of cisplatin resistance becomes a major obstacle impeding the curative effect. It remains necessary to uncover the molecular mechanism of cisplatin resistance. MethodsBased on the CCLE database, lung cancer cell lines were divided into cisplatin-resistant and cisplatin-sensitive groups. The differentially expressed miRNAs were filtered and further identified by survival prognosis analysis. After transfection with miR-375 inhibitor or mimic, cell cytotoxicity assay, flow cytometry and western blot were conducted to validate the role of miR-375. The transcription factor (TF)-miRNA network was constructed based on TransmiR. The target genes of miR-375 were predicted by Starbase and further verified by RT-qPCR and immunohistochemistry results in the Human Protein Atlas. Functional enrichment analysis was performed with GO terms and KEGG. ResultsIn this study, miR-375 showed the ability to promote cisplatin sensitivity and apoptosis of LUAD. Genes correlated with miR-375 in LUAD were analyzed and ABCC8 showed the strongest positive correlation. Moreover, transcription factors that regulate miR-375 expression were predicted. MBNL1, PTPN3, PRKD1 and RPN1 were identified as the target genes of miR-375. Enrichment analysis demonstrated that miR-375-related genes associated with promoting cell proliferation and anti-apoptosis were involved in the MAPK signaling pathway. ConclusionOverall, this study provides new insights into the role of miR-375 in the cisplatin sensitivity of LUAD. Our present findings may serve as a theoretical basis for new therapeutic strategies and predictive models of cisplatin resistance in LUAD.

A biscarbene gold(I)-NHC-complex overcomes cisplatin-resistance in A2780 and W1 ovarian cancer cells highlighting pERK as regulator of apoptosis

PurposeCisplatin resistance is the major obstacle in the clinical treatment of ovarian cancer patients. Molecular mechanisms of cisplatin resistance are multifaceted. Gold(I)-compounds, i.e. N-heterocyclic carbene-gold(I)-complexes (NHC-Au(I)) has been regarded as promising cytotoxic drug candidates. However, their potential to overcome cisplatin resistance has hardly been addressed yet. Here we investigated the activity of the gold(I) drug auranofin and the NHC-Au(I)-compound MC3 in W1CR and A2780cis cisplatin-resistant ovarian cancer cells.MethodsCytotoxicity of auranofin and MC3 was detected by MTT assay, correlated with intracellular gold(I) content, analyzed by AAS, and with flow cytometric detection of the cell cycle. Insight into cellular redox balance was provided by fluorimetric ROS-formation assay and western blotting thioredoxin (Trx) and Nrf2. The role of ERK was elucidated by using the inhibitor SCH772984 and its impact on cytotoxicity upon co-treatment with cisplatin and Au(I)-compounds, respectively.ResultsMC3 overcomes cisplatin resistance in A2780cis and W1CR, and auranofin in W1CR cells completely, which is neither reflected by intracellular gold levels nor cell cycle changes. Upregulated redox balance appears as a basis for resistance. W1CR cells possess higher Trx levels, whereas A2780cis cells display strong Nrf2 expression as anti-oxidative protection. Nevertheless, overcoming redox balance appears not primary mode of activity comparing cisplatin and gold(I)-compounds. pERK emerges as a critical component and thus a promising target for overcoming resistance, regulating apoptosis differently in response to either gold(I) or cisplatin in A2780 cells.ConclusionThese data reflect the complexity of cisplatin resistance in cell models and emphasize NHC-Au(I)-complexes as prospective cytotoxic agents for further investigations in that respect.

Circular RNA ARHGAP5 inhibits cisplatin resistance in cervical squamous cell carcinoma by interacting with AUF1.

Cervical squamous cell carcinoma (CSCC) is one of the leading causes of cancer death in women worldwide. Patients with advanced cervical carcinoma always have a poor prognosis once resistant to cisplatin due to the lack of effective treatment. It is urgent to investigate the molecular mechanisms of cisplatin resistance. Circular RNAs (circRNAs) are known to exert their regulatory functions in a series of malignancies. However, their effects on CSCC remain to be elucidated. Here, we found that cytoplasmic circARHGAP5, derived from second and third exons of the ARHGAP5 gene, was downregulated in cisplatin-resistant tissues compared with normal cervix tissues and untreated cervical cancer tissues. In addition, experiments from overexpression/knockdown cell lines revealed that circARHGAP5 could inhibit cisplatin-mediated cell apoptosis in CSCC cells both in vitro and in vivo. Mechanistically, circARHGAP5 interacted with AU-rich element RNA-binding protein (AUF1) directly. Overexpression of AUF1 could also inhibit cell apoptosis mediated by cisplatin. Furthermore, we detected the potential targets of AUF1 related to the apoptotic pathway and found that bcl-2-like protein 11 (BIM) was not only negatively regulated by AUF1 but positively regulated by circARHGAP5, which indicated that BIM mRNA might be degraded by AUF1 and thereby inhibited tumor cell apoptosis. Collectively, our data indicated that circARHGAP5 directly bound to AUF1 and prevented AUF1 from interacting with BIM mRNA, thereby playing a pivotal role in cisplatin resistance in CSCC. Our study provides insights into overcoming cancer resistance to cisplatin treatment.

Focus on the molecular mechanisms of cisplatin resistance based on multi-omics approaches.

Cisplatin is commonly used in combination with other cytotoxic agents as a standard treatment regimen for a variety of solid tumors, such as lung, ovarian, testicular, and head and neck cancers. However, the effectiveness of cisplatin is accompanied by toxic side effects, for instance, nephrotoxicity and neurotoxicity. The response of tumors to cisplatin treatment involves multiple physiological processes, and the efficacy of chemotherapy is limited by the intrinsic and acquired resistance of tumor cells. Although enormous efforts have been made toward molecular mechanisms of cisplatin resistance, the development of omics provides new insights into the understanding of cisplatin resistance at genome, transcriptome, proteome, metabolome and epigenome levels. Mechanism studies using different omics approaches revealed the necessity of multi-omics applications, which provide information at different cellular function levels and expand our recognition of the peculiar genetic and phenotypic heterogeneity of cancer. The present work systematically describes the underlying mechanisms of cisplatin resistance in different tumor types using multi-omics approaches. In addition to the classical mechanisms such as enhanced drug efflux, increased DNA damage repair and changes in the cell cycle and apoptotic pathways, other changes like increased protein damage clearance, increased protein glycosylation, enhanced glycolytic process, dysregulation of the oxidative phosphorylation pathway, ferroptosis suppression and mRNA m6A methylation modification can also induce cisplatin resistance. Therefore, utilizing the integrated omics to identify key signaling pathways, target genes and biomarkers that regulate chemoresistance are essential for the development of new drugs or strategies to restore tumor sensitivity to cisplatin.

Identifying Biomarkers of Cisplatin Sensitivity in Non-Small Cell Lung Cancer via Comprehensive Integrative Analysis

Background: Only 30-40% of non-small cell lung cancer (NSCLC) patients are clinically sensitive to cisplatin-based chemotherapy. Thus, it is necessary to identify biomarkers for personalized cisplatin chemotherapy in NSCLC. However, data heterogeneity and low-value density make it challenging to detect reliable cisplatin efficacy biomarkers using traditional analysis methods. Objective: This paper aims to find reliable cisplatin efficacy biomarkers for NSCLC patients using comprehensive integrative analysis. Method: We searched online resources and collected six NSCLC transcriptomics data sets with responses to cisplatin. The six data sets are divided into two groups: the learning group for biomarker identification and the test group for independent validation. We performed comprehensive integrative analysis under two kinds of frameworks, i.e., one-level and two-level, with three integrative models. Pathway analysis was performed to estimate the biological significance of the resulting biomarkers. For independent validation, logrank statistic was employed to test how significant the difference of Kaplan- Meier (KM) curves between two patient groups is, and the Cox proportional-hazards model was used to test how the expression of a gene is associated with patients’ survival time. Especially, a permutation test was performed to verify the predictive power of a biomarker panel on cisplatin efficacy. For comparison, we also analyzed each learning data set individually, in which three popular differential expression models, Limma, SAM, and RankSum, were used. Results: A total of 318 genes were identified as a core panel of cisplatin efficacy markers for NSCLC patients, exhibiting consistent differential expression between cisplatin-sensitive and –resistant groups across studies. A total of 129 of 344 KEGG pathways were found to be enriched in the core panel, reflecting a picture of the molecular mechanism of cisplatin resistance in NSCLC. By mapping onto the KEGG pathway tree, we found that a KEGG pathway-level I module, genetic information processing, is most active in the core panel with the highest activity ratio in response to cisplatin in NSCLC as expected. Related pathways include mismatch repair, nucleotide excision repair, aminoacyl-tRNA biosynthesis, and basal transcription factors, most of which respond to DNA double-strand damage in patients. Evaluation on two independent data sets demonstrated the predictive power of the core marker panel for cisplatin sensitivity in NSCLC. Also, some single markers, e.g., MST1R, were observed to be remarkably predictive of cisplatin resistance in NSCLC. Conclusion: Integrative analysis is more powerful in detecting biomarkers for cisplatin efficacy by overcoming data heterogeneity and low-value density in data sets, and the identified core panel (318 genes) can help develop personalized medicine of cisplatin chemotherapy for NSCLC patients.

Literature Review: Mekanisme Resistensi Kemoterapi Berbasis Platinum

Cisplatin is a type of platinum-based chemotherapy that is often used in the spectrum of solid neoplasms, including the ovaries, testicles, urinary vesicles, colorectal, lungs, and head-neck. The clinical success of platinum-based chemotherapy, however, is limited to side effects and the incidence of treatment resistance. Resistance has limited the efficacy of these agents in most diseases, so further knowledge is needed on how the resistance mechanism can occur so that further development can be carried out. Molecular mechanism of cisplatin resistance. Malignant cells can lose their sensitivity to the cytostatic/cytotoxic activity of cisplatin as a result of genetic or epigenetic damage. These changes can affect processes that precede the actual binding of cisplatin to its targets (pre-target resistance), potentiating the cell's ability to repair molecular damage caused by cisplatin (resistance at the target level) and damaging the signal transmission that usually imparts damage caused by cisplatin in apoptosis (post-target resistance) or stimulates pro-survival signaling that counteracts the cytotoxicity of cisplatin even though it usually does not occur by this drug (target resistance).

Epigenetic activation of FOXF1 confers cancer stem cell properties to cisplatin‑resistant non‑small cell lung cancer.

The underlying molecular mechanisms of cisplatin resistance in non-small cell lung cancer (NSCLC) are unclear. In this study, a novel differential methylation region located in the upstream regulatory region of the forkhead box F1 (FOXF1) gene was identified. The abnormal hypomethylation of FOXF1 increased the expression of FOXF1, and the high expression of FOXF1 promoted cell proliferation and inhibited cell apoptosis induced by cisplatin, which resulted in cisplatin resistance in NSCLC cells. In addition, FOXF1 promoted the expression of stem cell markers and self-renewal capability, indicating that FOXF1 regulated cisplatin resistance by promoting cancer stem cell properties in NSCLC cells. Moreover, a strong association was observed between FOXF1 upregulation and the presence of platinum-based chemotherapy resistance in patients with NSCLC. On the whole, the findings of this study indicate the regulatory mechanisms of cisplatin resistance by FOXF1 in NSCLC, and suggest that FOXF1 may be used as a prognostic biomarker of platinum-based chemotherapy resistance in NSCLC.

The Pentose Phosphate Pathway and Its Involvement in Cisplatin Resistance.

Cisplatin is the first-line treatment for different types of solid tumors, such as ovarian, testicular, bladder, cervical, head and neck, lung, and esophageal cancers. The main problem related to its clinical use is the onset of drug resistance. In the last decades, among the studied molecular mechanisms of cisplatin resistance, metabolic reprogramming has emerged as a possible one. This review focuses on the pentose phosphate pathway (PPP) playing a pivotal role in maintaining the high cell proliferation rate and representing an advantage for cancer cells. In particular, the oxidative branch of PPP plays a role in oxidative stress and seems to be involved in cisplatin resistance. In light of these considerations, it has been demonstrated that overexpression and higher enzymatic activity of different enzymes of both oxidative and non-oxidative branches (such as glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and transketolase) increase cisplatin resistance, and their silencing or combined treatment with cisplatin could restore cisplatin sensitivity. Moreover, drug delivery systems loaded with both PPP inhibitors and cisplatin give the possibility of reaching cancer cells selectively. In conclusion, targeting PPP is becoming a strategy to overcome cisplatin resistance; however, further studies are required to better understand the mechanisms.

Molecular mechanisms of cisplatin resistance in cervical cancer.

Patients with advanced or recurrent cervical cancer have poor prognosis, and their 1-year survival is only 10%–20%. Chemotherapy is considered as the standard treatment for patients with advanced or recurrent cervical cancer, and cisplatin appears to treat the disease effectively. However, resistance to cisplatin may develop, thus substantially compromising the efficacy of cisplatin to treat advanced or recurrent cervical cancer. In this article, we systematically review the recent literature and summarize the recent advances in our understanding of the molecular mechanisms underlying cisplatin resistance in cervical cancer.

Pharmacological focal adhesion kinase (FAK) inhibition suppresses cisplatin-resistant human ovarian carcinoma growth

Objectives: FAK is a cytoplasmic protein tyrosine kinase promoting ovarian cancer tumor growth and metastasis. Phase I and II clinical trials are testing small molecule inhibitors to FAK in different cancers. Determination of cancer cell susceptibility to FAK inhibition is an important yet undefined parameter. We test the hypothesis that elevated FAK activity contributes to the growth of aggressive cisplatin (CP)–resistant ovarian cancer. Methods: Growth of paired CP-sensitive (A2780 and OVCAR10) and CP-resistant (A2780-CP and OVCAR10-CP) human ovarian cells was evaluated in adherent, nonadherent, and methylcellulose spheroid culture in the presence or absence of 100 nM concentration of FAK inhibitor (FAKi). Quantification of cancer stemlike cells (CSCs) and cell cycle analyses was performed using flow cytometry for aldehyde dehydrogenase (ALDH) activity and propidium iodide DNA staining, respectively. Cell apoptosis was evaluated with Annexin-V and (7-aminoactinomycin D) 7-AAD staining. Changes in cellular protein expression were determined with quantitative immunoblotting. Intraperitoneal tumor growth in mice was evaluated for combined inhibitory effects of CP and FAKi administration. Results: FAK tyrosine phosphorylation and CSC protein markers were elevated in CP-resistant cells, which was reversed by FAKi addition. On immunoblotting, the levels of the transcription factor OCT4, ALDH, and the cell surface protein N-cadherin were increased in CP-resistant cells. FAKi addition selectively prevented CP-resistant cell growth as spheroids. The combination of FAKi with CP exhibited a combined effect on the CP-resistant cells, with significant decreases in spheroid and tumor growth compared with either agent alone. When comparing the percentage of CSCs with flow cytometry, FAKi addition dramatically reduced the ALDH-positive cell population in both parental and CP-resistant cells. This was associated with a G1 cell cycle growth phase arrest, decreased cyclin D protein expression, but not increased cell apoptosis. (See Fig. 1.) Conclusions: CSCs are implicated in the molecular mechanisms of cisplatin-resistance, and we find that FAK inhibition prevents CP-resistant CSC growth. Because FAKi therapy is well tolerated with limited adverse events, our results support further testing of FAKi in either primary or recurrent settings of CP-resistant ovarian cancer.

Cisplatin in the modern era: The backbone of first-line chemotherapy for non-small cell lung cancer.

The treatment of advanced non-small cell lung cancer (NSCLC) may be changing, but the cisplatin-based doublet remains the foundation of treatment for the majority of patients with advanced NSCLC. In this respect, changes in practice to various aspects of cisplatin use, such as administration schedules and the choice of methods and frequency of monitoring for toxicities, have contributed to an incremental improvement in patient management and experience. Chemoresistance, however, limits the clinical utility of this drug in patients with advanced NSCLC. Better understanding of the molecular mechanisms of cisplatin resistance, identification of predictive markers and the development of newer, more effective and less toxic platinum agents is required. In addition to maximising potential benefits from advances in molecular biology and associated therapeutics, modification of existing cisplatin-based treatments can still lead to improvements in patient outcomes and experiences.

Interference with the expression of β-catenin reverses cisplatin resistance in A2780/DDP cells and inhibits the progression of ovarian cancer in mouse model.

Cisplatin is a most active drug for the treatment of ovarian cancer; however, acquired cisplatin resistance is easily seen in patients with ovarian cancer. The aim of this study is to clarify the molecular mechanism of cisplatin resistance and try to reverse cisplatin resistance in ovarian cancer lines in vitro and in vivo. First, we used ovarian cancer cell line A2780, and its cisplatin-resistant subline, A2780/DDP as cell model. Cell viability was determined by MTT assay and the IC50 values were observed to increase in a dose- and time-dependent manner. Next, the expression of β-catenin was determined by western blotting analysis, and the results demonstrated that the expression level of β-catenin in A2780/DDP cells was significantly higher than that in A2780 cells (p<0.01). Moreover, we detected the distribution of cytoplasmic and nuclear β-catenin by western blot analysis, which showed that β-catenin was mainly located in nucleus. Compared with A2780 cells, there was no obvious change as the increasing dose of cisplatin in A2780/DDP cells reveal that cisplatin resistance was related to the exrpession of β-catenin. Furthermore, interference with the expression of β-catenin could effectively reverse cisplatin resistance as IC50 was significantly decreased from 123.7 to 42.43 μM in A2780/DDP cells. Additionally, transient interference of β-catenin by siRNA promoted the apoptosis of A2780/DDP cells, for increased apoptosis rates and cleaved caspase-3 levels were detected being treated with cisplatin. Finally, tumorigenicity experiments showed that tumor growth was significantly suppressed in β-catenin shRNA group. The body weight was not significantly changed during the experimental days. In conclusion, all the results showed that cisplatin resistance was partly induced by Wnt/β-catenin signaling pathway. Interfering the expression of β-catenin could reverse cisplatin resistance in vitro and in vivo. Thus, β-catenin could be a potential therapeutic target for the therapy of cisplatin-resistant ovarian cancer.

Advance in studies on molecular mechanisms of cisplatin resistance and intervention with traditional Chinese medicines

Cisplatin is a first-line anticancer drug widely used in clinic. However, its resistance reduces its efficacy. With a non-specific cell cycle, cisplatin's main targets are nucleophilic protein, DNA and RNA in cells. Among cisplatin's multi-factorial resistance mechanisms, abnormal expression of transport protein, intracellular detoxification enhancement, DNA repair capacity increase and apoptosis blocking are the main mechanisms. Because traditional Chinese medicines (TCMs) have unique advantages in cancer treatment, their combination with cisplatin can improve the efficacy. In this paper, the authors summarized the advance in studies on cisplatin's resistance and the combination of TCMs and cisplatin in recent years.

Brahma-related gene 1-associated expression of 9-27 and IFI-27 is involved in acquired cisplatin resistance of gastric cancer cells

In order to investigate the mechanism of cisplatin resistance, a cisplatin-resistant human gastric cancer cell line was established. Subsequent to the exposure of the YCC-3 gastric cancer cell line to equal concentrations of cis-diammine-dichloroplatinum (II) (cisplatin, CDDP) for 6 months, a cisplatin-resistant cell line was established (YCC-3/R). To determine the molecular mechanism of cisplatin resistance in YCC-3/R cells, differentially expressed genes (DEGs) were investigated between YCC-3 and YCC-3/R by annealing control primer-based reverse transcriptase-polymerase chain reaction (ACP RT-PCR) technology. Eleven DEGs were successfully identified and sequenced. Among them, interferon-induced transmembrane protein 1 (9-27) and interferon α-inducible protein 27 (IFI-27) were markedly increased in YCC-3/R cells. In addition, western blot analysis demonstrated that the Brahma-related gene 1 (BRG1), which was observed to selectively activate 9-27 and IFI-27 genes, was overexpressed in YCC-3/R cells. The results suggested that the BRG1‑associated expression of 9-27 and IFI-27 is involved in cisplatin resistance in gastric cancer cells.

Molecular mechanisms of cisplatin resistance in bladder cancer

Metastatic disease is the most common mechanism of death in patients with advanced bladder cancer. As for most solid tumors, chemotherapy remains the only realistic option for palliating or curing metastatic disease. However, bladder cancer is characterized by chemoresistance. Only modest response rates are obtained using multiagent regimens including cisplatin. These low response rates and the toxicity of these regimens limit their use to patients at highest risk. Here, we review the molecular mechanisms of cisplatin resistance. These include methods to reduce cisplatin bioavailability within a cell, and defects in the machinery that produces cell death following cisplatin-induced DNA damage. While overcoming these mechanisms is a potential therapeutic approach that can increase response rates, in the short term this knowledge could be used to predict response in individual tumors.

A texaphyrin–oxaliplatin conjugate that overcomes both pharmacologic and molecular mechanisms of cisplatin resistance in cancer cells

A texaphyrin-oxaliplatin conjugate, oxaliTEX, was designed to test the concept that a platinum analog can overcome defects in drug accumulation and p53-dependent DNA damage response in a tumor model expressing multifactorial mechanisms of cisplatin resistance. Cytotoxic studies resulted in a resistance factor of only 1.2, which essentially indicated complete reversal of resistance in 2780CP cells expressing a factor of 22 with cisplatin. Unlike cisplatin, oxaliTEX accumulated and formed DNA adducts, stabilized and activated p53 at similar levels in both sensitive and resistant cells, and induced apoptosis in both models. The ability and importance of a designer drug, such as oxaliTEX, to overcome cisplatin resistance by targeting two dominant resistance mechanisms is discussed.

Establishment of Cisplatin-Resistant Ovarian Yolk Sac Tumor Cells and Investigation of the Mechanism of Cisplatin Resistance Using This Cell Line

Background: Cisplatin is used as a key drug for ovarian yolk sac tumor (YST), but relapse may occur. Details of the molecular mechanism responsible for cisplatin resistance remain unclear. Methods: We established cisplatin-resistant ovarian YST cells (NOY1-CR) from parent NOY1. To characterize these cells, we examined cross-resistance to other anticancer drugs. Then, cDNA microarray analysis was performed to quantify gene expression in NOY1 and NOY1-CR cells. The expression of several potential genes related to drug resistance was compared with parent cells by real-time PCR and Western blotting. Knockdown experiments using small interfering RNA (siRNA) were also performed to confirm the genetic association with drug resistance. Results: The IC₅₀ for cisplatin of NOY1-CR was 22.3-fold higher than that for parent cells. NOY1-CR cells showed cross-resistance to some drugs, but not to VP-16 and bleomycin. Microarray analysis identified 315 up-regulated and 412 down-regulated genes in NOY1-CR cells. Knockdown of GSTA1, which was up-regulated in resistant cells, by GSTA1 siRNA restored cisplatin sensitivity in NOY1-CR cells. Conclusions: Our data suggest the molecular mechanisms of cisplatin resistance and show the potential for GSTA1 to become a novel therapeutic target for cisplatin-resistant ovarian YST.

Intracellular ATP depletion leads to reduced platinum accumulation in ovarian cancer cells

Cisplatin is one of the most effective drugs in the treatment of ovarian cancer. However, its therapeutic potential is limited by intrinsic or acquired resistance. Several molecular mechanisms of cisplatin resistance have been described including increased repair of DNA adducts, increased tolerance to DNAdamage, elevated intracellular levels of glutathione or metallothioneines, increased efflux and decreased cellular uptake of platinum. The most frequently observed feature in cisplatin-resistant cell lines is reduced accumulation of the drug [1]. The exact mechanisms involved have not been completely identified yet. Although some findings suggest that passive diffusion across the membrane is a major mechanism of cisplatin uptake, other studies indicate that various energy-dependent cellular proteins, which utilize ATP hydrolysis as energy source, may be involved in intracellular trafficking of cisplatin [1]. Extracellular ATP is known to enhance cellular membrane permeability, which may lead to increased cellular accumulation of anticancer drugs due to enhanced passive diffusion. Therefore, extracellular ATP may be used to sensitize ovarian carcinoma cells [2]. However, the exposure to ATP does not increase the accumulation of cisplatin in A2780 and A2780cis cells [3]. One possible explanation is a simultaneous increase in cisplatin efflux by activating ATP-dependent efflux transporters (e.g., ATP7A, ATP7B and MRP2). Therefore, treatment of cancer cells with ATP may increase both cellular uptake and efflux of cisplatin at the same time resulting in unchanged net drug accumulation. To further assess the role of ATP in cisplatin uptake and efflux, we investigated the accumulation of cisplatin under ATP-depleting conditions. ATP depletion can be achieved by using inhibitors of oxidative phosphorylation or mitochondrial electron transport chain (ETC) complex I – IV inhibitors. The latter are known to induce the production of reactive oxygen species leading to apoptosis [4]. For that reason, we chose an inhibitor of the oxidative phosphorylation, oligomycin, which depletes intracellular ATP levels by specific inhibition of the F0F1 ATP synthase.