Flavonoids Restore Platinum Drug Sensitivity to Ovarian Carcinoma Cells in a Phospho-ERK1/2-Dependent Fashion

Ovarian cancer (OC) is the second most common type of gynecological malignancy; it has poor survival rates and is frequently (>75%) diagnosed at an advanced stage. Platinum-based chemotherapy, with, e.g., carboplatin, is the standard of care for OC, but toxicity and acquired resistance to therapy have proven challenging. Despite advances in OC diagnosis and treatment, approximately 85% of patients will experience relapse, mainly due to chemoresistance. The latter is attributed to alterations in the cancer cells and is also mediated by tumor microenvironment (TME). Recently, we reported the synthesis of a platinum (IV) prodrug that exhibits equal potency toward platinum-sensitive and resistant OC cell lines. Here, we investigated the effect of TME on platinum sensitivity. Co-culture of OC cells with murine or human mesenchymal stem cells (MS-5 and HS-5, respectively) rendered them resistant to chemotherapeutic agents, including platinum, paclitaxel and colchicine. Platinum resistance was also conferred by co-culture with differentiated murine adipocyte progenitor cells. Exposure of OC cells to chemotherapeutic agents resulted in activation of phospho-ERK1/2. Co-culture with MS-5, which conferred drug resistance, was accompanied by blockage of phospho-ERK1/2 activation. The flavonoids fisetin and quercetin were active in restoring ERK phosphorylation, as well as sensitivity to platinum compounds. Exposure of OC cells to cobimetinib—a MEK1 inhibitor that also inhibits extracellular signal-regulated kinase (ERK) phosphorylation—which resulted in reduced sensitivity to the platinum compound. This suggests that ERK activity is involved in mediating the function of flavonoids in restoring platinum sensitivity to OC co-cultured with cellular components of the TME. Our data show the potential of combining flavonoids with standard therapy to restore drug sensitivity to OC cells and overcome TME-mediated platinum drug resistance.

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SENP1-mediated deSUMOylation of JAK2 regulates its kinase activity and platinum drug resistance

Cell Death and Disease ◽

10.1038/s41419-021-03635-6 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Jing Li ◽

Ruiqin Wu ◽

Mingo M. H. Yung ◽

Jing Sun ◽

Zhuqing Li ◽

...

Keyword(s):

Ovarian Cancer ◽

Drug Resistance ◽

Kinase Activity ◽

Regulatory Mechanism ◽

Platinum Resistance ◽

Platinum Drug ◽

Clinical Prognosis ◽

Platinum Resistant ◽

Poor Clinical Prognosis ◽

Stat Pathway

AbstractThe JAK2/STAT pathway is hyperactivated in many cancers, and such hyperactivation is associated with a poor clinical prognosis and drug resistance. The mechanism regulating JAK2 activity is complex. Although translocation of JAK2 between nucleus and cytoplasm is an important regulatory mechanism, how JAK2 translocation is regulated and what is the physiological function of this translocation remain largely unknown. Here, we found that protease SENP1 directly interacts with and deSUMOylates JAK2, and the deSUMOylation of JAK2 leads to its accumulation at cytoplasm, where JAK2 is activated. Significantly, this novel SENP1/JAK2 axis is activated in platinum-resistant ovarian cancer in a manner dependent on a transcription factor RUNX2 and activated RUNX2/SENP1/JAK2 is critical for platinum-resistance in ovarian cancer. To explore the application of anti-SENP1/JAK2 for treatment of platinum-resistant ovarian cancer, we found SENP1 deficiency or treatment by SENP1 inhibitor Momordin Ic significantly overcomes platinum-resistance of ovarian cancer. Thus, this study not only identifies a novel mechanism regulating JAK2 activity, but also provides with a potential approach to treat platinum-resistant ovarian cancer by targeting SENP1/JAK2 pathway.

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CAMSAP1 Mutation Correlates With Improved Prognosis in Small Cell Lung Cancer Patients Treated With Platinum-Based Chemotherapy

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.770811 ◽

2022 ◽

Vol 9 ◽

Author(s):

Yonglin Yi ◽

Zhengang Qiu ◽

Zifu Yao ◽

Anqi Lin ◽

Yimin Qin ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Drug Sensitivity ◽

Gene Mutations ◽

Small Cell ◽

Small Cell Lung ◽

Platinum Drug ◽

Platinum Based Chemotherapy ◽

Patient Prognosis

Platinum-based chemotherapy is the first-line treatment for small cell lung cancer (SCLC). However, due to patients developing a resistance to the drug, most experience relapse and their cancer can become untreatable. A large number of recent studies have found that platinum drug sensitivity of various cancers is affected by specific gene mutations, and so with this study, we attempted to find an effective genetic biomarker in SCLC patients that indicates their sensitivity to platinum-based drugs. To do this, we first analyzed whole exome sequencing (WES) and clinical data from two cohorts to find gene mutations related to the prognosis and to the platinum drug sensitivity of SCLC patients. The cohorts used were the Zhujiang cohort (N = 138) and the cohort reported by George et al. (N = 101). We then carried out gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) to investigate possible molecular mechanisms through which these gene mutations affect patient prognosis and platinum drug sensitivity. We found that for SCLC patients, CAMSAP1 mutation can activate anti-tumor immunity, mediate tumor cell apoptosis, inhibit epithelial-mesenchymal transition (EMT), improve prognosis, and improve platinum drug sensitivity, suggesting that CAMSAP1 mutation may be a potential biomarker indicating platinum drug sensitivity and patient prognosis in SCLC.

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Sensitivity Assessment of Chemotherapeutic Agents for Ovarian Tumors Based on Test in Vitro Culture: A Blind Study

10.21203/rs.3.rs-850505/v1 ◽

2021 ◽

Author(s):

Qunxian RAO ◽

Yuan WEI ◽

Qing CHEN ◽

Meimei GUAN ◽

Hui ZHOU ◽

...

Keyword(s):

Drug Resistance ◽

Drug Sensitivity ◽

Chemotherapeutic Agents ◽

Ovarian Tumors ◽

Individualized Treatment ◽

Blind Study ◽

Combination Regimen ◽

Chemotherapy Drugs ◽

Sensitivity Assessment ◽

Response To Chemotherapy

Abstract Background: Ovarian cancer is common malignant tumors but the survival rate has not been improved well for a long time. One of the important reasons is that the current clinical guidelines for treatment still do not solve the problem of patient heterogeneity and drug resistance, which are exactly the key factors affecting the efficacy of chemotherapy. In addition, there are limited research data that can help accurately identify patients' preferred drugs and combination regimen, which fails to meet the needs of individualized treatment. Methods：The objective was used the Hydrogel Embedded Histoculture Drug Sensitivity Test (HDST), to verified its accuracy in predicting the response to chemotherapy in ovarian tumors and evaluate the sensitivity of chemotherapy drugs. Tissue samples of 82 ovarian tumor patients were tested for HDST drug sensitivity and follow-up who were included in randomized study. The consistency of drug sensitivity results and clinical outcomes were analyzed through preliminary study to determine the feasibility of this technology, and then a comprehensive blind study was conducted to evaluate Drug sensitivity.Result: HDST in determining the efficacy of chemotherapy drugs were consistent with the actual clinical efficacy of patients (Kappa=0.535), and the sensitivity, specificity, AUC were 82.14%, 100.00%, 0.911. Single-drug resistance rates of TXL, DOC, CDDP, CBP, Lobaplatin, and VP-16 were 21.95%, 74.39%, 62.20% , 52.44%, 39.02%, 60.98%, respectively. Highest Secondary drug resistance rate of CBP was 44.44%, followed by CDDP and VP-16 (22.22%). TXL’s IR was significantly higher than DOC wherever the location, and Loplatin’s was higher than CDDP (P<0.05). TXL’s IR was higher than VP-16 in primary foci, but VP-16’s was not only higher than DOC, but also CDDP, and similar to the CBP and Lobaplatin in abdominal metastases(P<0.05).Conclusion: HDST can effectively predict the response to existing chemotherapy regimens as new tool to screen individualized treatment for patients. Paclitaxel combined with Lobaplatin regimen may have more advantages in chemotherapy and Etoposide should not be ignored in ovarian tumors.

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Hybrid Compounds & Oxidative Stress Induced Apoptosis in Cancer Therapy

Current Medicinal Chemistry ◽

10.2174/0929867325666180719145819 ◽

2020 ◽

Vol 27 (13) ◽

pp. 2118-2132 ◽

Cited By ~ 5

Author(s):

Aysegul Hanikoglu ◽

Hakan Ozben ◽

Ferhat Hanikoglu ◽

Tomris Ozben

Keyword(s):

Oxidative Stress ◽

Drug Resistance ◽

Side Effects ◽

Cancer Therapy ◽

Tumor Cells ◽

Anticancer Drugs ◽

Chemotherapeutic Agents ◽

Oxidation Reactions ◽

Hybrid Compounds ◽

Induced Apoptosis

: Elevated Reactive Oxygen Species (ROS) generated by the conventional cancer therapies and the endogenous production of ROS have been observed in various types of cancers. In contrast to the harmful effects of oxidative stress in different pathologies other than cancer, ROS can speed anti-tumorigenic signaling and cause apoptosis of tumor cells via oxidative stress as demonstrated in several studies. The primary actions of antioxidants in cells are to provide a redox balance between reduction-oxidation reactions. Antioxidants in tumor cells can scavenge excess ROS, causing resistance to ROS induced apoptosis. Various chemotherapeutic drugs, in their clinical use, have evoked drug resistance and serious side effects. Consequently, drugs having single-targets are not able to provide an effective cancer therapy. Recently, developed hybrid anticancer drugs promise great therapeutic advantages due to their capacity to overcome the limitations encountered with conventional chemotherapeutic agents. Hybrid compounds have advantages in comparison to the single cancer drugs which have usually low solubility, adverse side effects, and drug resistance. This review addresses two important treatments strategies in cancer therapy: oxidative stress induced apoptosis and hybrid anticancer drugs.

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Safety of Vinflunine in Patients with Advanced Urothelial Carcinoma Refractory to Platinum-based Chemotherapy: A Prospective Pilot Study

Current Drug Safety ◽

10.2174/1574886313666181001120752 ◽

2019 ◽

Vol 14 (1) ◽

pp. 31-36

Author(s):

Raafat Abdel-Malek ◽

Kyrillus S. Shohdy ◽

Noha Abbas ◽

Mohamed Ismail ◽

Emad Hamada ◽

...

Keyword(s):

Pilot Study ◽

Adverse Events ◽

Urothelial Carcinoma ◽

Transitional Cell ◽

Chemotherapeutic Agents ◽

Serious Adverse Events ◽

Platinum Based Chemotherapy ◽

Number Of Patients ◽

Advanced Urothelial Carcinoma ◽

Grade 3

Background: Several single chemotherapeutic agents have been evaluated as the second-line treatment of advanced urothelial carcinoma. Despite encouraging efficacy outcomes, toxicity has often led to dose modifications or discontinuation. We aimed to assess the safety of vinflunine in a particular population of advanced transitional cell carcinoma of urothelium (TCCU), that were exposed to the previous toxicity of chemotherapy. Methods: This is an open-label, prospective, single-center pilot study to evaluate the response rate and safety profile of vinflunine in patients with advanced TCCU. It was planned to enroll 25 evaluable patients. Eligible patients are those with progressive disease after first-line platinum-based regimen for advanced or metastatic disease. Results: The study was prematurely closed due to two sudden deaths that were judged by the review board as treatment-related. Only ten patients were evaluated and received at least one cycle of vinflunine. All but one were male and seven underwent radical surgery. Eight had a distant metastasis (mainly lung and/or liver). Disease control rate was 40%, four patients had a partial response with median duration of response of 3.5 months. The median overall survival was 3.2 months (95% CI:1.67- 4.73). There were three serious adverse events namely two sudden deaths and one grade 4 thrombocytopenia. Nine grade 3/4 adverse events occurred. The most common all-grade adverse events were fatigue (50%), constipation (40%) and vomiting (40%). Moreover, grade 3 fatigue occurred in 30% of patients. Only one patient, who achieved PR for 5 months, was fit to receive further cytotoxic chemotherapy. Conclusion: The activity of vinflunine in advanced urothelial carcinoma came at the expense of its safety. The use of vinflunine has to be limited to the selected group of patients. However, this is a single institute experience in a limited number of patients.

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Emodin Enhances the Chemosensitivity of Endometrial Cancer by Inhibiting ROS-Mediated Cisplatin-resistance

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666171219113036 ◽

2018 ◽

Vol 18 (7) ◽

pp. 1054-1063 ◽

Cited By ~ 4

Author(s):

Ning Ding ◽

Hong Zhang ◽

Shan Su ◽

Yumei Ding ◽

Xiaohui Yu ◽

...

Keyword(s):

Drug Resistance ◽

Endometrial Cancer ◽

Cancer Cells ◽

Chemotherapeutic Agent ◽

Annexin V ◽

Chemotherapeutic Agents ◽

Endometrial Cancer Cell ◽

Animal Survival ◽

Apoptosis Level

Background: Endometrial cancer is a common cause of death in gynecological malignancies. Cisplatin is a clinically chemotherapeutic agent. However, drug-resistance is the primary cause of treatment failure. Objective: Emodin is commonly used clinically to increase the sensitivity of chemotherapeutic agents, yet whether Emodin promotes the role of Cisplatin in the treatment of endometrial cancer has not been studied. Method: CCK-8 kit was utilized to determine the growth of two endometrial cancer cell lines, Ishikawa and HEC-IB. The apoptosis level of Ishikawa and HEC-IB cells was detected by Annexin V / propidium iodide double-staining assay. ROS level was detected by DCFH-DA and NADPH oxidase expression. Expressions of drug-resistant genes were examined by real-time PCR and Western blotting. Results: Emodin combined with Cisplatin reduced cell growth and increased the apoptosis of endometrial cancer cells. Co-treatment of Emodin and Cisplatin increased chemosensitivity by inhibiting the expression of drugresistant genes through reducing the ROS levels in endometrial cancer cells. In an endometrial cancer xenograft murine model, the tumor size was reduced and animal survival time was increased by co-treatment of Emodin and Cisplatin. Conclusion: This study demonstrates that Emodin enhances the chemosensitivity of Cisplatin on endometrial cancer by inhibiting ROS-mediated expression of drug-resistance genes.

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Nanoparticle-based drug delivery systems with platinum drugs for overcoming cancer drug resistance

Journal of Materials Chemistry B ◽

10.1039/d1tb00753j ◽

2021 ◽

Author(s):

Peng Xie ◽

Yushu Wang ◽

Dengshuai Wei ◽

Lingpu Zhang ◽

Bin Zhang ◽

...

Keyword(s):

Drug Delivery ◽

Drug Resistance ◽

Drug Delivery Systems ◽

Delivery Systems ◽

Cancer Drug ◽

Platinum Drugs ◽

Effective Strategy ◽

Platinum Drug ◽

Cancer Drug Resistance ◽

Platinum Drug Resistance

The mechanisms of chemoresistance and nanoparticle-based drug delivery systems for platinum drugs were detailed summarized in this review. The current combination therapy provided an effective strategy to overcome the platinum drug resistance.

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MMP-7 Serum and Tissue Levels Are Associated with Poor Survival in Platinum-Treated Bladder Cancer Patients

Diagnostics ◽

10.3390/diagnostics11010048 ◽

2020 ◽

Vol 11 (1) ◽

pp. 48

Author(s):

Tibor Szarvas ◽

Michèle J. Hoffmann ◽

Csilla Olah ◽

Eszter Szekely ◽

Andras Kiss ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Patients ◽

Cell Lines ◽

Checkpoint Inhibitors ◽

Serum Concentrations ◽

Serum Samples ◽

Poor Overall Survival ◽

Platinum Sensitivity ◽

Therapeutic Decisions ◽

Platinum Based Chemotherapy

Chemotherapy resistance is a main cause of therapeutic failure and death in bladder cancer. With the approval of immune checkpoint inhibitors, prediction of platinum treatment became of great clinical importance. Matrix metalloproteinase-7 (MMP-7) was shown to be involved in cisplatin resistance. Therefore, tissue and circulating MMP-7 levels were evaluated in 124 bladder cancer patients who received postoperative platinum-based chemotherapy. Tissue MMP-7 levels were analyzed by immunohistochemistry in 72 formalin-fixed, paraffin-embedded chemo-naïve tumor samples, while MMP-7 serum concentrations were determined in 132 serum samples of an independent cohort of 52 patients. MMP-7 tissue and serum levels were correlated with clinicopathological and follow-up data. MMP-7 gene expression was determined by RT-qPCR in 20 urothelial cancer cell lines and two non-malignant urothelial cell lines. MMP-7 was overexpressed in RT-112 and T-24 cells by stable transfection, to assess its functional involvement in platinum sensitivity. High MMP-7 tissue expression and pretreatment serum concentrations were independently associated with poor overall survival (tissue HR = 2.296, 95%CI = 1.235–4.268 and p = 0.009; serum HR = 2.743, 95%CI = 1.258–5.984 and p = 0.011). Therefore, MMP-7 tissue and serum analysis may help to optimize therapeutic decisions. Stable overexpression in RT-112 and T-24 cells did not affect platinum sensitivity.

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Mortalin/glucose-regulated protein 75 promotes the cisplatin-resistance of gastric cancer via regulating anti-oxidation/apoptosis and metabolic reprogramming

Cell Death Discovery ◽

10.1038/s41420-021-00517-w ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Yi Dai ◽

Fan Li ◽

Yuwen Jiao ◽

Guoguang Wang ◽

Tian Zhan ◽

...

Keyword(s):

Gastric Cancer ◽

Cisplatin Resistance ◽

Meta Analysis ◽

Acquired Resistance ◽

Hypoxia Inducible Factor ◽

Metabolic Reprogramming ◽

Platinum Resistance ◽

Related Factor ◽

Platinum Drug ◽

Glucose Regulated Protein

AbstractPlatinum drug treatment is one of the most predominant chemotherapeutic strategies for patients with gastric cancer (GC). However, the therapeutic effect is less than satisfactory, largely due to the acquired resistance to platinum drugs. Therefore, a better understanding of the underlying mechanisms can greatly improve the therapeutic efficacy of GC. In this study, we aimed to investigate the chemo-resistance related functions/mechanisms and clinical significance of glucose-regulated protein 75 (GRP75) in GC. Here, our data showed that compared with SGC7901 cells, the expression of GRP75 was markedly higher in cisplatin-resistance cells (SGC7901CR). Knockdown of GRP75 abolished the maintenance of mitochondrial membrane potential (MMP) and inhibited the nuclear factor erythroid-2-related factor 2 (NRF2), phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), hypoxia-inducible factor 1α (HIF-1α), and c-myc, which resulted in blocking the activation of their downstream targets. These processes attenuated the anti-oxidation/apoptosis abilities and altered the metabolic reprogramming in SGC7901CR cells, leading to re-sensitizing these cells to cisplatin. However, overexpression of GRP75 in SGC7901 cells caused the opposite effects. A xenografts model confirmed the abovementioned results. In GC patients receiving platinum chemotherapy and a meta-analysis, a high level of GRP75 was positively associated with aggressive characteristics and poor prognosis including but not limited to gastrointestinal cancers, and was an independent predictor for overall survival. Collectively, our study indicated that GRP75 was involved in the cisplatin-resistance of GC and that GRP75 could be a potential therapeutic target for restoring the drug response in platinum-resistance cells and a useful additive prognostic tool in guiding clinical management of GC patients.

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Sab concentrations indicate chemotherapeutic susceptibility in ovarian cancer cell lines

Biochemical Journal ◽

10.1042/bcj20180603 ◽

2018 ◽

Vol 475 (21) ◽

pp. 3471-3492 ◽

Cited By ~ 4

Author(s):

Iru Paudel ◽

Sean M. Hernandez ◽

Gilda M. Portalatin ◽

Tara P. Chambers ◽

Jeremy W. Chambers

Keyword(s):

Ovarian Cancer ◽

Cell Lines ◽

Ovarian Cancer Cell ◽

Prognostic Biomarker ◽

Chemotherapeutic Agents ◽

Mitochondrial Outer Membrane ◽

Expression Data ◽

Apoptotic Pathway ◽

Gynecological Malignancy ◽

Ovarian Cancer Cell Lines

The occurrence of chemotherapy-resistant tumors makes ovarian cancer (OC) the most lethal gynecological malignancy. While many factors may contribute to chemoresistance, the mechanisms responsible for regulating tumor vulnerability are under investigation. Our analysis of gene expression data revealed that Sab, a mitochondrial outer membrane (MOM) scaffold protein, was down-regulated in OC patients. Sab-mediated signaling induces cell death, suggesting that this apoptotic pathway is diminished in OC. We examined Sab expression in a panel of OC cell lines and found that the magnitude of Sab expression correlated to chemo-responsiveness; wherein, OC cells with low Sab levels were chemoresistant. The Sab levels were reflected by a corresponding amount of stress-induced c-Jun N-terminal kinase (JNK) on the MOM. BH3 profiling and examination of Bcl-2 and BH3-only protein concentrations revealed that cells with high Sab concentrations were primed for apoptosis, as determined by the decrease in pro-survival Bcl-2 proteins and an increase in pro-apoptotic BH3-only proteins on mitochondria. Furthermore, overexpression of Sab in chemoresistant cells enhanced apoptotic priming and restored cellular vulnerability to a combination treatment of cisplatin and paclitaxel. Contrariwise, inhibiting Sab-mediated signaling or silencing Sab expression in a chemosensitive cell line resulted in decreased apoptotic priming and increased resistance. The effects of silencing on Sab on the resistance to chemotherapeutic agents were emulated by the silencing or inhibition of JNK, which could be attributed to changes in Bcl-2 protein concentrations induced by sub-chronic JNK inhibition. We propose that Sab may be a prognostic biomarker to discern personalized treatments for OC patients.

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