Ovarian Cancer Drug Research Articles

Expression of integrin α-6 is associated with multi drug resistance and prognosis in ovarian cancer.

Ovarian cancer is a serious threat to women's health. Multidrug resistance is a major cause of post-treatment relapse, metastasis, and even mortality. This characteristic severely restricts the survival of patients with ovarian cancer. Integrin α-6 (ITGA6) is a member of the adhesion molecule family that conducts signals through interactions between the extracellular domain and the matrix, serving important roles in cell adhesion-mediated drug resistance, which is considered to have a critical function in ovarian cancer drug resistance. The association between ITGA6 and ovarian cancer multidrug resistance has been investigated only rarely, to the best of our knowledge. Using RT-qPCR and immunohistochemistry, it was identified that ITGA6 is a central drug resistance gene, and that its expression was upregulated in cisplatin-resistant SKOV3 (SKOV3/DDP2), cisplatin-resistant A2780 (A2780/DDP) cells, and in 54 cases of drug-resistant tissues, as compared with in the controls. Furthermore, bioinformatics and text mining performed by Coremine Medical (http://www.coremine.com/medical/#search) confirmed that ITGA6 was significantly associated with ovarian cancer and drug resistance. Additionally, the high expression of ITGA6 is associated with a poor outcome. The present study provides the basis for further understanding the role of ITGA6 in the regulation of drug resistance in ovarian cancer, and demonstrates that it could be a potential marker for the prognosis of ovarian cancer.

Cul4 E3 ubiquitin ligase regulates ovarian cancer drug resistance by targeting the antiapoptotic protein BIRC3

CRL4, a well-defined E3 ligase, has been reported to be upregulated and is proposed to be a potential drug target in ovarian cancers. However, the biological functions of CRL4 and the underlying mechanism regulating cancer chemoresistance are still largely elusive. Here, we show that CRL4 is considerably increased in cisplatin-resistant ovarian cancer cells, and CRL4 knockdown with shRNAs is able to reverse cisplatin-resistance of ovarian cancer cells. Moreover, CRL4 knockdown markedly inhibits the expression of BIRC3, one of the inhibitors of apoptosis proteins (IAPs). Besides, lower expression level of BIRC3 is associated with better prognosis of ovarian cancer patients, and BIRC3 knockdown in ovarian cancer cells can recover their sensitivity to cisplatin. More importantly, we demonstrate that CRL4 regulates BIRC3 expression by mediating the STAT3, but not the PI3K pathway. Therefore, our results identified CRL4 as an important factor in ovarian cancer chemoresistance, suggesting that CRL4 and BIRC3 may serve as novel therapeutic targets for relapsed patients after treatment with cisplatin and its derivative to overcome the bottle neck of ovarian cancer chemoresistance.

Photo-Cured Glycol Chitosan Hydrogel for Ovarian Cancer Drug Delivery.

In this study, we prepared an injectable drug delivery depot system based on a visible light-cured glycol chitosan (GC) hydrogel containing paclitaxel (PTX)-complexed beta-cyclodextrin (β-CD) (GC/CD/PTX) for ovarian cancer (OC) therapy using a tumor-bearing mouse model. The hydrogel depot system had a 23.8 Pa of storage modulus at 100 rad/s after visible light irradiation for 10 s. In addition, GC was swollen as a function of time. However, GC had no degradation with the time change. Eventually, the swollen GC matrix affected the releases of PTX and CD/PTX. GC/PTX and GC/CD/PTX exhibited a controlled release of PTX for 7 days. In addition, GC/CD/PTX had a rapid PTX release for 7 days due to improved water solubility of PTX through CD/PTX complex. In vitro cell viability tests showed that GC/CD/PTX had a lower cell viability percentage than the free PTX solution and GC/PTX. Additionally, GC/CD/PTX resulted in a superior antitumor effect against OC. Consequently, we suggest that the GC/CD system might have clinical potential for OC therapy by improving the water solubility of PTX, as PTX is included into the cavity of β-CD.

Dual-mode US/MRI nanoparticles delivering siRNA and Pt(iv) for ovarian cancer treatment.

As known to all, ovarian cancer ranks the most lethal of the gynecological malignancies. The antitumor drugs based on platinum are first-line chemotherapy drugs for ovarian cancer. However, their therapeutic efficiency is severely limited owing to dose-limiting toxicities of platinum. New theranostic strategies to overcome chemotherapy toxicity is highly desirable. Meanwhile, the real-time treating effect is not visible for doctors. Herein, we constructed PFH/siRNA/Fe3O4@Pt(iv) NPs-cRGD (NPs-cRGD) for precise theranostics against ovarian tumors with real-time imaging. The NPs-cRGD had a good storage stability and resisted the serum-induced aggregation, which was beneficial for drug delivery. Additionally, gel-retardation assay demonstrated that the NPs-cRGD exhibited great protection to siRNA to resist nuclease degradation. In vitro, the NPs-cRGD showed good dual-mode US/MRI imaging and the relative imaging research was also discussed. Moreover, the in vitro experiments indicated that the NPs-cRGD with US exhibited excellent antitumor therapeutic efficiency, resulting from the cRGD ligands and US exposure enhanced the cellular uptake efficiency. Thus, the dual-mode nanoparticles in this work may provide precious insight into the development of various multi-mode nanoplatforms delivering drugs or genes for precise theranostics against various cancer.

Evaluating class III antiarrhythmic agents as novel MYC targeting drugs in ovarian cancer

ObjectiveTo evaluate the utility of amiodarone and its derivative dronedarone as novel drug repositioning candidates in EOC and to determine the potential pathways targeted by these drugs. MethodsDrug-predict bioinformatics platform was used to assess the utility of amiodarone as a novel drug-repurposing candidate in EOC. EOC cells were treated with amiodarone and dronedarone. Cell death was assessed by Annexin V staining. Cell viability and cell survival were assessed by MTT and clonogenics assays respectively. c-MYC and mTOR/Akt axis were evaluated as potential targets. Effect on autophagy was determined by autophagy flux flow cytometry. Results“DrugPredict” bioinformatics platform ranked Class III antiarrhythmic drug amiodarone within the top 3.9% of potential EOC drug repositioning candidates which was comparable to carboplatin ranking in the top 3.7%. Amiodarone and dronedarone were the only Class III antiarrhythmic drugs that decreased the cellular survival of both cisplatin-sensitive and cisplatin-resistant primary EOC cells. Interestingly, both drugs induced degradation of c-MYC protein and decreased the expression of known transcriptional targets of c-MYC. Furthermore, stable overexpression of non-degradable c-MYC partially rescued the effects of amiodarone and dronedarone induced cell death. Dronedarone induced higher autophagy flux in EOC cells as compared to amiodarone with decreased phospho-AKT and phospho-4EBP1 protein expression, suggesting autophagy induction due to inhibition of AKT/mTOR axis with these drugs. Lastly, both drugs also inhibited the survival of EOC tumor-initiating cells (TICs). ConclusionsWe provide the first evidence of class III antiarrhythmic agents as novel c-MYC targeting drugs and autophagy inducers in EOC. Since c-MYC is amplified in >40% ovarian tumors, our results provide the basis for repositioning amiodarone and dronedarone as novel c-MYC targeting drugs in EOC with potential extension to other cancers.

ATL

Cisplatin and mitomycin C exert high activity towards BRCA1-deficient cells. This study aimed to evaluate the efficacy of a combination of these drugs in hereditary BRCA1-associated ovarian cancer (OC). Twelve OC patients, who could not be treated by primary debulking surgery owing to extensive tumor spread, were given neoadjuvant cisplatin (100 mg/m) and mitomycin C (10 mg/m) every 4 weeks for 3 (n = 9), 2 (n = 2), or 4 (n = 1) cycles. The decrease of tumor burden and complete surgical cytoreduction were achieved in all patients. Pathologic complete response, defined as the absence of tumor cells in surgically removed tissues, was observed in 2 (17%) of 12 cases. Retrospective analysis of 62 OC in BRCA1 mutation carriers subjected to conventional neoadjuvant chemotherapy schemes revealed 36 objective tumor responses (58%) and 37 instances (60%) of complete cytoreductive surgery; however, none of these patients demonstrated pathologic complete response. The combination of cisplatin plus mitomycin C showed promising results in BRCA1-driven OC and therefore deserves further clinical evaluation.

Theaflavin-3,3′-digallate inhibits ovarian cancer stem cells via suppressing Wnt/β-Catenin signaling pathway

Recent evidence indicates that ovarian cancer stem cells (CSCs) are responsible for ovarian cancer recurrence and drug resistance, resulting in the low long-term survival rate of patients with advanced ovarian cancer. We aimed to study the inhibitory effect of theaflavin-3,3′-digallate (TF3), a black tea polyphenol on ovarian CSCs. Here, we showed that TF3 inhibited the proliferation of A2780/CP70 and OVCAR3 tumorshpere cells by suppressing their cell viability and colony formation capacity. TF3 inhibited the tumorsphere formation capacity of A2780/CP70 and OVCAR3 CSCs in serum-free and non-adherent conditions. TF3 inhibited A2780/CP70 and OVCAR3 CSCs isolated from tumorspheres by decreasing their cell viability and upregulating the protein expression of caspase-3 and -7 in the cells. We also revealed that TF3 inhibited ovarian CSCs through Wnt/β-catenin signaling pathway. Our results suggested that TF3 could inhibit ovarian CSCs and might be a potential agent for eradicating ovarian cancer.

The Diagnostic and Prognostic Role of Serum MicroRNAs in Ovarian Cancer

AimSummarize the research progress of serum miRNAs in clinical application for early diagnosis and prognosis of ovarian cancer. MethodsReview of the recently published literature these was conducted. We selected reviews and clinical researches from different scientific societies.ResultsThe abnormal expression of serum miRNAs has a certain clinical value in theearly diagnosis of ovarian cancer. Many miRNAs, which are involved in regulating ovarian cancer cell growth, migration, and drug resistance, are also closely related to the patients’ survival rate and affect the prognostic condition of the patients. So the serum miRNAs may be useful diagnostic and prognostic biomarkers.Conclusions Studies have shown that serum miRNAs has the tumor specificity and high stability, enabling it has the potential for early diagnosis, prognosis and sensitivity to chemotherapy. However, the researches on serum miRNAs is still at the primary stage, further researches is needed for application of serum miRNAs in early diagnosis and prognosis of ovarian cancer.

Mechanism of Cepharanthine Cytotoxicity in Human Ovarian Cancer Cells.

Cepharanthine (CEP), a medicinal product derived from Stephania cephalantha Hayata, possesses a potent cytotoxicity against several types of cancers. Recently, we have found that CEP could efficiently inhibit the growth of mutated p53 colon cancer cells, which are often resistant to commonly used chemotherapeutic agents. In this study, we evaluated the cytotoxic effect and the underlying mechanisms of CEP on both chemosensitive CaOV-3 and chemoresistant OVCAR-3 ovarian cancer cell lines. The present study demonstrated that CEP significantly inhibited the growth of CaOV-3 and OVCAR-3 cells in a time- and concentration-dependent manner. CEP arrested CaOV-3 and OVCAR-3 cells in the G1 phase and S phase of cell cycle, respectively. Western blot analysis demonstrated that CEP markedly increased the expression of p21Waf1 protein and decreased the expression of cyclins A and D proteins in both CaOV-3 and OVCAR-3 cells. Additionally, CEP triggered apoptotic cell death in OVCAR-3 cells. Taken together, the above results suggest that CEP is a promising anticancer drug for ovarian cancer.

Abstract A58: Transcription factor SREBP2 mediates ovarian cancer drug resistance and recurrence

Abstract Ovarian cancer, the most lethal gynecologic malignancy, has a poor prognosis. Existing chemotherapies are challenged by the emergence of drug resistance and metastasis of tumor cells, which obstruct sustained, relapse-free patient cures. Resistance can emerge from pre-existing mutations, secondary mutations, or other nongenetic mechanisms or metabolic adaptations. SREBPs are necessary for cell survival in low-nutrient conditions. SREBP1 predominantly regulates fatty acid and glycolysis while SREBP2 regulates cholesterol metabolism. SREBP2 is a sterol sensitive transcription factor regulating cholesterol homeostasis including the expression of LDLR and HMGCR. Recent reports suggest that SREBP2 may promote mesenchymal and stem-cell states. These observations support our working hypothesis that the regulation of cholesterol and fatty acids through SREBP2 is critical for drug tolerance, resistance, and viability of a cancer stem cell population. We further hypothesize that drug-tolerant ovarian cancer cells depend on SREBP2 to re-enter the cell cycle and proliferate. To test this hypothesis, we assessed the importance of SREBP2 in an in vitro drug tolerant model. Ovarian cancer cells were treated with high concentrations of paclitaxel for 1 week and the surviving cells were examined. SREBP2, HMGCR, and related factors were significantly upregulated in these surviving drug-tolerant cells. To evaluate the function of SREBP2 in drug-tolerant cells, stable cell lines targeting the SREBF2 gene using CRISPR technology were created in OVCAR8. Using this SREBF2-KD line, we assessed the response of ovarian cancer cells to drug treatment under different environments. SREBF2-KD cells were more sensitive to statin and paclitaxel in low-sterol environments compared to control cells. These observations highlight the need for SREBP2 in stressed conditions for cancer cells to survive drug treatment. Moreover, after treatment with high concentrations of paclitaxel, SREBF2-KD cells grew back significantly slower compared to control cells. To characterize the mechanisms controlled by SREBP2, we examined the effects on the cell cycle. We have observed a significant change in the distribution of the cell cycle phases between SREBF2-KD and control cells treated with paclitaxel, which suggests an important role for SREBP2 in ovarian cancer cells’ exit from cell cycle arrest after chemotherapy. To further examine the role of SREBP2 in drug resistance and tumor relapse, we are currently extending these in vitro observations to in vivo models. In summary, our study illustrates the crucial role of cholesterol pathway for ovarian cancer not only under stress conditions such as chemotherapy, but also in return to a high proliferative state upon recurrence. These data suggest that targeting SREBP2 may represent a new approach for sequential therapy to eliminate cancer cells that survive initial treatment. Citation Format: Galina Karashchuk, Alexander S. Brodsky. Transcription factor SREBP2 mediates ovarian cancer drug resistance and recurrence. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A58.

PO-106 Downregulation of MYPT increases tumorigenesis and resistance to platin drugs in ovarian cancer

IntroductionIn recent years, the molecular mechanisms involved in the development of ovary tumours have been studied, although little is known about the high resistance of these tumours to conventional therapies. We found that the expression of myosin phosphatase-targeting subunit 1 (MYPT1), which has been related to cancer progression, in tumour ovary samples versus normal tissues was reduced, as was also the overall survival of ovary tumour patients. MYPT1 is a known regulator of protein phosphatase 1 (PP1C), which is known to play critical roles controlling the phosphorylation states of diverse substrates in different locations and various steps of cell division.Material and methodsTo characterise the implication of MYPT1 in ovary cancer, we generated two MYPT1 knock-down ovary cancer cell lines from SKOV3 and OVCAR8 commercial cell lines and checked MYPT1 protein and mRNA levels. In additiion, we analysed tumorigenesis using different in vitro approaches: growth curves, colony formation assays, percentage of holoclones and capacity to generate tumorspheres. We also analysed several stem cell markers by FACS and RT-qPCR, as well as resistance to treatment with platin drugs in vitro (IC50) and in vivo using xenografts.Results and discussionsThe study of tumorigenesis in SKOV3 and OVCAR8 ovary tumour cell lines demonstrates that down-regulation of MYPT increases resistance to platin drugs treatment both in vivo and in vitro. Moreover, MYPT down-regulation increases tumour growth in vitro and in vivo, the ability to generate tumorspheres, and the percentage of holoclones. In addition, MYPT depletion increases several stem cell features in ovary cells lines.ConclusionAltogether, our data demonstrates that down-regulation of MYPT1 increases the resistance to platin drugs therapies, possibly because it is responsible for the increase in tumorigenesis and de-differentiation of ovarian tumour to a stem-cell phenotype.

Abstract 5893: Expression and role of autophagy-associated p62 (SQSTM1) in multidrug-resistant ovarian cancer

Abstract Multidrug resistance is the major cause of treatment failure in ovarian cancer. p62 (SQSTM1) is a multifunctional protein involved in multiple cellular processes including proliferation, drug sensitivity and autophagy-associated cancer cell growth. p62 is a critical indicator of autophagic flux, which is inversely associated with autophagy activity. However, the role of p62 remains controversial in drug resistance in human ovarian cancer. In this study, we examined p62 expression by immunohistochemistry in a unique ovarian cancer tissue microarray (TMA), which was constructed with paired primary, metastatic, and recurrent tumor tissues from 26 individual patients. Results showed that both the metastatic and recurrent tumor tissues expressed less p62 than the patient-matched primary tumor. A significant inverse correlation has been found between p62 expression and both the disease free survival and overall survival. In addition, multidrug resistant cancer cell lines expressed lower levels of p62 as compared with their parental drug sensitive cell lines. Importantly, cell viabilities determined by MTT assay after exposure to different concentrations of paclitaxel showed inhibition of autophagy or accumulation of p62 enhances paclitaxel sensitivity in ovarian cancer drug resistant cells. Furthermore, the wound healing assay exhibited that inhibition of autophagy significantly decreased multidrug resistant ovarian cancer cell migration in vitro. Collectively, these data highlight that autophagy pathway may be a promising therapeutic target to prevent metastasis, recurrence and to reverse drug resistance in ovarian cancer. Citation Format: Jinglu Wang, Cassandra Garbutt, Francis J Hornicek, Zhenfeng Duan. Expression and role of autophagy-associated p62 (SQSTM1) in multidrug-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5893.

Chick chorioallantoic membrane assay as an in vivo model to study the effect of nanoparticle-based anticancer drugs in ovarian cancer

New therapy development is critically needed for ovarian cancer. We used the chicken egg CAM assay to evaluate efficacy of anticancer drug delivery using recently developed biodegradable PMO (periodic mesoporous organosilica) nanoparticles. Human ovarian cancer cells were transplanted onto the CAM membrane of fertilized eggs, resulting in rapid tumor formation. The tumor closely resembles cancer patient tumor and contains extracellular matrix as well as stromal cells and extensive vasculature. PMO nanoparticles loaded with doxorubicin were injected intravenously into the chicken egg resulting in elimination of the tumor. No significant damage to various organs in the chicken embryo occurred. In contrast, injection of free doxorubicin caused widespread organ damage, even when less amount was administered. The lack of toxic effect of nanoparticle loaded doxorubicin was associated with specific delivery of doxorubicin to the tumor. Furthermore, we observed excellent tumor accumulation of the nanoparticles. Lastly, a tumor could be established in the egg using tumor samples from ovarian cancer patients and that our nanoparticles were effective in eliminating the tumor. These results point to the remarkable efficacy of our nanoparticle based drug delivery system and suggests the value of the chicken egg tumor model for testing novel therapies for ovarian cancer.

Systematic Identification of Druggable Epithelial-Stromal Crosstalk Signaling Networks in Ovarian Cancer.

BackgroundBulk tumor tissue samples are used for generating gene expression profiles in most research studies, making it difficult to decipher the stroma–cancer crosstalk networks. In the present study, we describe the use of microdissected transcriptome profiles for the identification of cancer–stroma crosstalk networks with prognostic value, which presents a unique opportunity for developing new treatment strategies for ovarian cancer.MethodsTranscriptome profiles from microdissected ovarian cancer–associated fibroblasts (CAFs) and ovarian cancer cells from patients with high-grade serous ovarian cancer (n = 70) were used as input data for the computational systems biology program CCCExplorer to uncover crosstalk networks between various cell types within the tumor microenvironment. The crosstalk analysis results were subsequently used for discovery of new indications for old drugs in ovarian cancer by computational ranking of candidate agents. Survival analysis was performed on ovarian tumor–bearing Dicer/Pten double-knockout mice treated with calcitriol, a US Food and Drug Administration–approved agent that suppresses the Smad signaling cascade, or vehicle control (9–11 mice per group). All statistical tests were two-sided.ResultsActivation of TGF-β-dependent and TGF-β-independent Smad signaling was identified in a particular subtype of CAFs and was associated with poor patient survival (patients with higher levels of Smad-regulated gene expression by CAFs: median overall survival = 15 months, 95% confidence interval [CI] = 12.7 to 17.3 months; vs patients with lower levels of Smad-regulated gene expression: median overall survival = 26 months, 95% CI = 15.9 to 36.1 months, P = .02). In addition, the activated Smad signaling identified in CAFs was found to be targeted by repositioning calcitriol. Calcitriol suppressed Smad signaling in CAFs, inhibited tumor progression in mice, and prolonged the median survival duration of ovarian cancer–bearing mice from 36 to 48 weeks (P = .04).ConclusionsOur findings suggest the feasibility of using novel multicellular systems biology modeling to identify and repurpose known drugs targeting cancer–stroma crosstalk networks, potentially leading to faster and more effective cures for cancers.

Identifying gene network rewiring by combining gene expression and gene mutation data.

Understanding how gene dependency networks rewire between different disease states is an important task in genomic research. Although many computational methods have been proposed to undertake this task via differential network analysis, most of them are designed for a predefined data type. With the development of the high throughput technologies, gene activity measurements can be collected from different aspects (e.g., mRNA expression and DNA mutation). Different data types might share some common characteristics and include certain unique properties. New methods are needed to explore the similarity and difference between differential networks estimated from different data types. In this study, we develop a new differential network inference model which identifies gene network rewiring by combining gene expression and gene mutation data. Similarity and difference between different data types are learned via a group bridge penalty function. Simulation studies have demonstrated that our method consistently outperforms the competing methods. We also apply our method to identify gene network rewiring associated with ovarian cancer platinum resistance. There are certain differential edges common to both data types and some differential edges unique to individual data types. Hub genes in the differential networks inferred by our method play important roles in ovarian cancer drug resistance.

Overcoming Ovarian Cancer Drug Resistance with a Cold Responsive Nanomaterial.

Drug resistance due to overexpression of membrane transporters in cancer cells and the existence of cancer stem cells (CSCs) is a major hurdle to effective and safe cancer chemotherapy. Nanoparticles have been explored to overcome cancer drug resistance. However, drug slowly released from nanoparticles can still be efficiently pumped out of drug-resistant cells. Here, a hybrid nanoparticle of phospholipid and polymers is developed to achieve cold-triggered burst release of encapsulated drug. With ice cooling to below ∼12 °C for both burst drug release and reduced membrane transporter activity, binding of the drug with its target in drug-resistant cells is evident, while it is minimal in the cells kept at 37 °C. Moreover, targeted drug delivery with the cold-responsive nanoparticles in combination with ice cooling not only can effectively kill drug-resistant ovarian cancer cells and their CSCs in vitro but also destroy both subcutaneous and orthotopic ovarian tumors in vivo with no evident systemic toxicity.

HOXB4 knockdown enhances the cytotoxic effect of paclitaxel and cisplatin by downregulating ABC transporters in ovarian cancer cells

Therapeutic effects of anti-cancer drugs for ovarian cancer were limited due to the rapid development of chemotherapy resistance. The aim of this study was to test whether knockdown of Homeobox B4 (HOXB4) enhanced the cytotoxic effect of paclitaxel and cisplatin in ovarian cancer cells. HOXB4 expressions at mRNA and protein levels were upregulated in Taxol-resistant A2780 (A2780/Taxol) and DDP-resistant SKOV-3 (SKOV-3/DDP) cells. HOXB4 knockdown enhanced the cytotoxic effects of Taxol and DDP in A2780/Taxol and SKOV-3/DDP cells, respectively. HOXB4 silencing suppressed the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and reduced the expression of ABCB1, ABCC1 and ABCG2 in ovarian cancer cells. PI3K inhibitor LY294002 or siRNA targeting Akt (si-Akt) treatment inhibited cell viability, decreased protein levels of ABCB1, ABCC1 and ABCG2, and increased LDH release in A2780/Taxol and SKOV-3/DDP cells. These findings revealed that HOXB4 knockdown enhanced the cytotoxic effects of Taxol and DDP by downregulating ABC transporters via inhibiting the PI3K/Akt pathway in ovarian cancer cells.

LDR reverses DDP resistance in ovarian cancer cells by affecting ERCC-1, Bcl-2, Survivin and Caspase-3 expressions

BackgroundOvarian cancer is the most frequent cause of death resulting from malignant gynecological tumors. After surgical intervention, cisplatin (DDP) is a major chemotherapy drug for ovarian cancer, but the ovarian cancer cells tend to develop DDP resistance in the clinical setting. Tumor cells are sensitive to low-dose radiation (LDR). However, how the LDR therapy improves the effects of chemotherapy drugs on ovarian cancer is not well understood. This study aimed to explore this issue. MethodsThe SKOV3/DDP cells were divided into 3 groups, including low-dose group, conventional-dose group, and control group (no radiation). Cell counting kit-8 assay was performed to measure cell proliferation. Flow cytometric analysis was then utilized to quantify the apoptosis with classical Annexin V/propidium iodide co-staining. And Real-time quantitative PCR and western blot were eventually used to analyze the mRNA and protein levels of excision repair cross complementing-group 1 (ERCC1), B-cell lymphoma 2 (Bcl-2), Survivin and Caspase-3, respectively. ResultsThe IC50 value of DDP in the low-dose group was significantly lower compared with the other two groups. Compared with the conventional-dose group and control group, LDR treatment resulted in significantly more apoptosis. Besides, LDR treatment significantly decreased the mRNA and protein expression of ERCC1, Bcl-2, and Survivin, and enhanced the mRNA and protein expression of Caspase-3 compared with the other two groups. ConclusionsLDR reversed DDP resistance in SKOV3/DDP cells possibly by suppressing ERCC1, Bcl-2, and Survivin expressions, and increasing Caspase-3 expression.

Enhanced Chemotherapeutic Efficacy of Paclitaxel Nanoparticles Co-delivered with MicroRNA-7 by Inhibiting Paclitaxel-Induced EGFR/ERK pathway Activation for Ovarian Cancer Therapy

Chemotherapy-induced activation of cell survival pathways leads to drug resistance. MicroRNAs (miRNAs) post-transcriptionally regulate gene expression in many biological pathways. Paclitaxel (PTX) is one of the first-line chemotherapy drugs for ovarian cancer, and it induces the activation of the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) pathway that leads to tumor cell proliferation, survival, invasion, and drug resistance. MicroRNA-7 (miR-7) has the ability to suppress the EGFR/ERK pathway. To sensitize chemotherapy, we developed monomethoxy(poly(ethylene glycol))-poly(d,l-lactide- co-glycolide)-poly(l-lysine) nanoparticles for the simultaneous co-delivery of PTX and miR-7. The resulting PTX/miR-7 nanoparticles (P/MNPs) protect miRNA from degradation, possess a sequential and controlled release of drugs, improve the transfection efficiency of miRNA, decrease the half-maximal inhibitory concentration of PTX, and increase the apoptosis of ovarian cancer cells. The chemotherapeutic efficacy of PTX is prominently enhanced in vitro and in vivo via the inhibition of PTX-induced EGFR/ERK pathway activation by miR-7. Our studies in P/MNPs reveal a novel paradigm for a dual-drug-delivery system of chemotherapeutics and gene therapy in treating cancers.

Frontline therapy of ovarian cancer: trials and tribulations.

The current article reviews the advances and challenges in the fight with cancer and the hope for cure, with a focus on clinical trials, at the one time with the best outcomes; first-line therapy. To date there have been four great stories that bridge inception to development of new drugs in ovarian cancer: Serendipitous insight into the role of platinum, discovery of taxanes, understanding the microenvironment and angiogenesis, and following the science in the development of Poly (ADP-Ribose) Polymerase (PARP) inhibitors. There is a fundamental difference between overall survival (OS), simply living longer; and eradicating disease, cure. The scientific underpinning of both our understanding and the recent developments encourages an optimistic view of the remaining hurdles. There has been an unprecedented explosion in the number of new drugs approved for the treatment of ovarian cancer with three new classes of agent, and five new drugs receiving food and drug administration approval in the last 3 years (Fig. 2). Getting the right drug truly transforms patients' experience with the seminal event being the development of imatinib in CML. In 1980, an average patient would have lived only 3 years, and now they only live 3 years less than a full lifespan [Bower et al. (2016). J Clin Oncol 34:2851].