FGF2 promotes the chemotherapy resistance in colon cancer cells through activating PI3K/Akt signaling pathway

Background:To investigate the role of fibroblast growth factor 2(FGF2)in chemotherapy resistance of colon cancer.Methods:An HCT116/5-fluorouracil(5-FU)-resistant cell line was established,and FGF2 levels were detected in a sensitive cell group(HCT116)and a resistant cell group(HCT1116-R)using different methods.Fibroblast growth factor 2 levels in the medium were determined by enzyme-linked immunoassay.The protein expressions of FGF2,fibroblast growth factor receptor 1(FGFR1),and phospho-FGFR1 were assessed by Western blotting,and FGF2 mRNA levels were detected by quantitative real-time polymerase chain reaction.Fibroblast growth factor 2 recombinant protein was added to sensitive cells,and FGFR inhibitor AZD4547 was added to resistant cells,and the cell survival rate was determined using the cell counting kit-8 method and the protein expressions of PI3K(phosphatidylinositol 3 kinase),p-PI3K(phospho-PI3K),Akt(protein kinase B),p-Akt(phospho-Akt),mammalian target of rapamycin(mTOR),p-mTOR(phospho-mTOR),Bad(Bcl-xL/Bcl-2-associated death promoter),NF-κB(nuclear factorκB),GSK-3(glycogen synthase kinase-3),FKHR(forkhead box protein O1),and PTEN(phosphatase and tensin homolog deleted on chromosome ten)were detected by Western blotting.Results:Fibroblast growth factor 2 protein and mRNA expression levels in the HCT116-R group were significantly higher than those in the HCT116 group.Fibroblast growth factor 2 increased the survival rate of HCT116 cells;improved tolerance to 5-FU;upregulated p-PI3K,p-Akt,and p-mTOR;and downregulated Bad.The FGFR inhibitor AZD4547 decreased cell survival rate and tolerance to 5-FU;downregulated p-PI3K,p-Akt,and p-mTOR expression;and upregulated Bad.Conclusions:Fibroblast growth factor 2 promotes chemotherapy tolerance in colon cancer cells by activating the Akt/mTOR and Akt/Bad signaling pathways downstream of PI3K.

CK2αcauses stemness and chemotherapy resistance in liver cancer through the Hedgehog signaling pathway

Background:Liver cancer is one of the major causes of cancer-related deaths globally.Cancer cell stem-ness and chemotherapy resistance contribute to the high mortality.Although evidence indicates that the alpha subunit of protein kinase 2(CK2α)is involved in several human cancers,its function in liver cancer remains unknown.In the present study,we aimed to elucidate the role of CK2αin liver cancer.Methods:We examined the role of CK2αregulation in stemness and chemotherapy resistance capacity of liver cancer cells.MTT assays,tumor sphere formation assays,RT-PCR,flow cytometry,Western blotting assay,clonogenicity assay,matrigel invasion assay and bioinformatics were conducted in this study.Results:CK2αexpression in the liver cancer tissues was notably upregulated compared with that in the corresponding non-tumorous tissues.The overexpression of CK2αpromoted tumor sphere formation,increased the percentage of CD133(+)and side population cells,caused the resistance of liver cancer cells to 5-FU treatment,increased the expression levels of NANOG,OCT4,SOX2,Gli1 and Ptch1,and enhanced the ability of CD133(+)cell clone formation and invasion.Consistently,the downregulation of CK2αhad the opposite effects.CK2αsilencing inhibited the Hedgehog pathway by reducing the expression of Gli1 and Ptch1.Mechanistically,CK2αregulation on liver cancer cell stemness and chemotherapy resistance was found to be involved in the Hedgehog signaling pathway.Conclusions:Our study may bring some new insights into the occurrence of liver cancer.Furthermore,these findings suggest that targeting CK2αmay be a novel therapeutic strategy for patients with liver cancer.

The DMRTA1-SOX2 positive feedback loop promotes progression and chemotherapy resistance of esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma(ESCC)is among the most prevalent causes of cancer-related death in patients worldwide.Resistance to immunotherapy and chemotherapy results in worse survival outcomes in ESCC.It is urgent to explore the underlying molecular mechanism of immune evasion and chemoresistance in ESCC.Here,we conducted RNA-sequencing analysis in ten ESCC tissues from cisplatin-based neoadjuvant chemotherapy patients.We found that DMRTA1 was extremely upregulated in the non-pathologic complete response(non-pCR)group.The proliferation rate of esophageal squamous carcinoma cells was markedly decreased after knockdown of DMRTA1 expression,which could increase cisplatin sensitivity in ESCC.Additionally,suppression of DMRTA1 could decrease the immune escape of esophageal squamous carcinoma cells.Further mechanistic studies suggest that DMRTA1 can promote its expression by binding to the promoter of SOX2,which plays important roles in the progression and chemoresistance of ESCC in the form of positive feedback.Therefore,DMRTA1 could be a potential target to suppress immune escape and overcome chemoresistance in ESCC.

Clinical significance of miRNA-106a in non-small cell lung cancer patients who received cisplatin combined with gemcitabine chemotherapy

Objective：Research has demonstrated that microRNA（miR）-106a is related to cisplatin resistance.We investigated the expression of miR-106a in the serum of patients with non-small cell lung cancer（NSCLC）and their sensitivity to chemotherapy by cisplatin combined with gemcitabine.Methods：Eighty-five NSCLC patients,who completed four cycles of gemcitabine and cisplatin chemotherapy,volunteered for this study and their serum samples were collected.Serum samples from 60 healthy subjects were used as controls.Real-time quantitative polymerase chain reaction（real-time q PCR）was used to quantify the level of miR-106a in the serum.Demographic and survival data of these patients were collected for the analysis.Results：The expression of miR-106a in the serum of NSCLC patients was significantly higher than that of healthy subjects（P＆lt;0.001）.The expression of miR-106a was not correlated with patients＇gender,age,tumor size,lymphatic metastasis,and pathological types;but was correlated with patients＇tumor staging（P=0.003）.After chemotherapy,serum miR-106a expression decreased in patients.The decrease in miR-106a expression in the chemotherapy-sensitive group was much higher than that in the chemotherapy-resistant group.Survival analysis shows that NSCLC patients with high expression of miR-106a have a poorer prognosis.The overall survival of NSCLC patients in the chemotherapy-sensitive group was significantly higher than that in the chemotherapy-resistant group.Conclusions：High expression of miR-106a may be involved in the development of NSCLC.Mi R-106a has significance in the prognosis of NSCLC.The level of miR-106a in the serum can be a useful parameter in screening for drug resistance during cisplatin-based chemotherapy.

MGMT activated by Wnt pathway promotes cisplatin tolerance through inducing slow-cycling cells and nonhomologous end joining in colorectal cancer

Chemotherapy resistance plays a pivotal role in the prognosis and therapeutic failure of patients with colorectal cancer(CRC).Cisplatin(DDP)-resistant cells exhibit an inherent ability to evade the toxic chemotherapeutic drug effects which are characterized by the activation of slow-cycle programs and DNA repair.Among the elements that lead to DDP resistance,O^(6)-methylguanine(O^(6)-MG)-DNA-methyltransferase(MGMT),a DNA-repair enzyme,performs a quintessential role.In this study,we clarify the significant involvement of MGMT in conferring DDP resistance in CRC,elucidating the underlying mechanism of the regulatory actions of MGMT.A notable upregulation of MGMT in DDP-resistant cancer cells was found in our study,and MGMT repression amplifies the sensitivity of these cells to DDP treatment in vitro and in vivo.Conversely,in cancer cells,MGMT overexpression abolishes their sensitivity to DDP treatment.Mechanistically,the interaction between MGMT and cyclin dependent kinase 1(CDK1)inducing slow-cycling cells is attainted via the promotion of ubiquitination degradation of CDK1.Meanwhile,to achieve nonhomologous end joining,MGMT interacts with XRCC6 to resist chemotherapy drugs.Our transcriptome data from samples of 88 patients with CRC suggest that MGMT expression is co-related with the Wnt signaling pathway activation,and several Wnt inhibitors can repress drug-resistant cells.In summary,our results point out that MGMT is a potential therapeutic target and predictive marker of chemoresistance in CRC.

Acidic/hypoxia dual-alleviated nanoregulators for enhanced treatment of tumor chemo-immunotherapy

Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO3 by a CaCO3-assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.

Molecular determinants of response to 5-fluorouracil-based chemotherapy in colorectal cancer: The undisputable role of microribonucleic acids

5-flurouracil(5-FU)-based chemotherapy is the main pharmacological therapy for advanced colorectal cancer(CRC).Despite significant progress in the treatment of CRC during the last decades,5-FU drug resistance remains the most important cause of failure in CRC therapy.Resistance to 5-FU is a complex and multistep process.Different mechanisms including microsatellite instability,increased expression level of key enzyme thymidylate synthase and its polymorphism,increased level of 5-FU-activating enzymes and mutation of TP53 are proposed as the main determinants of resistance to 5-FU in CRC cells.Recently,microribonucleic acids(miRNA)and their alterations were found to have a crucial role in 5-FU resistance.In this regard,the miRNA-mediated mechanisms of 5-FU drug resistance reside among the new fields of pharmacogenetics of CRC drug response that has not been completely discovered.Identification of the biological markers that are related to response to 5-FU-based chemotherapy is an emerging field of precision medicine.This approach will have an important role in defining those patients who are most likely to benefit from 5-FU-based chemotherapy in the future.Thereby,the identification of 5-FU drug resistance mechanisms is an essential step to predict and eventually overcome resistance.In the present comprehensive review,we will summarize the latest knowledge regarding the molecular determinants of response to 5-FU-based chemotherapy in CRC by emphasizing the role of miRNAs.

Difficult Conversations and Painful Decisions: When Should Patients with Progressive Cancer Stop Chemotherapy?

Introduction: The decision to stop anti-cancer treatment is fraught with many challenges for the oncologist, the patient, and their caregivers. This review examines the special considerations surrounding the decision to cease chemotherapy in terminally ill cancer patient. Methods: A comprehensive literature search was conducted to find relevant publications on chemotherapy cessation. A total of 2700 records were retrieved and 141 were identified as eligible for inclusion in this review. Results: Palliative chemotherapy does not achieve the goal of tumor-related symptom reduction for patients who have experienced progressive disease with more than two prior lines of chemotherapy. ECOG performance status is a crucial predictor of response to therapy and chemotherapy-related complications. Challenges to stopping chemotherapy at the end of life are multifactorial and are both patient and physician-driven. Racial, ethnic, and income-based disparities are seen in the timing and quality of end-of-life conversations offered by physicians to their patients. Conclusions: The decision to cease chemotherapy is one that should be approached with careful consideration and accurate information. Clear communication, compassion and empathy are important components to the therapeutic relationship. Early involvement of palliative care and clear conversations about prognosis and the expected utility of further chemotherapy is essential to conduct the best possible care for cancer patients at the end of life.

Blue LED promotes the chemosensitivity of human hepatoma to Sorafenib by inducing DNA damage

Background:Phototherapies based on sunlight,infrared,ultraviolet,visible,and laser-based treatments present advantages like high curative effects,small invasion,and negligible adverse reactions in cancer treatment.We aimed to explore the potential therapeutic effects of blue light emitting diode(LED)in human hepatoma cells and decipher the underlying cellular and molecular mechanisms.Methods:Wound healing and transwell assays were employed to probe the inhibition of the invasion and migration of hepatocellular carcinoma cells in the presence of blue LED.The sphere-forming test was used to evaluate the effect of LED blue light irradiation on cancer stem cell properties.Immunofluorescence and western blotting were used to detect the changes inγ-H2AX.The Cell Counting Kit-8 assay,5-ethynyl-2′-deoxyuridine staining,and colony formation assay were used to detect the combined effect of blue LED and sorafenib on cell proliferation inhibition.Results:We demonstrated that the irradiation of blue LED light in hepatoma cells could lead to cell proliferation reduction along with the increase of cell apoptosis.Simultaneously,blue LED irradiation also markedly suppressed the migration and invasion ability of human hepatoma cells.Sphere formation analysis further revealed the decreased cancer stemness of hepatoma cells upon blue LED irradiation.Mechanistically,blue LED irradiation significantly promoted the expression of the phosphorylation of the core histone protein H2AX(γ-H2AX),a sensitive molecular marker of DNA damage.In addition,we found that the combined treatment of blue LED irradiation and sorafenib increased cancer cell sensitivity to sorafenib.Conclusion:Collectively,we demonstrated that blue LED irradiation exhibited anti-tumor effects on liver cancer cells by inducing DNA damage and could enhance chemosensitivity of cancer cells,which represents a potential approach for human hepatoma treatment.

Plasma proteome profiling reveals biomarkers of chemotherapy resistance in patients with advanced colorectal cancer

Colorectal cancer(CRC)is one of the most common cancers.Patients with advanced CRC can only rely on chemotherapy to improve outcomes.However,primary drug resistance frequently occurs and is difficult to predict.Changes in plasma protein composition have shown potential in clinical diagnosis.Thus,it is urgent to identify potential protein biomarkers for primary resistance to chemotherapy for patients with CRC.Automatic sample preparation and high-throughput analysis were used to explore potential plasma protein biomarkers.Drug susceptibility testing of circulating tumor cells(CTCs)has been investigated,and the relationship between their values and protein expressions has been discussed.In addition,the differential proteins in different chemotherapy outcomes have been analyzed.Finally,the potential biomarkers have been detected via enzyme-linked immunosorbent assay(ELISA).Plasma proteome of 60 CRC patients were profiled.The correlation between plasma protein levels and the results of drug susceptibility testing of CTCs was performed,and 85 proteins showed a significant positive or negative correlation with chemotherapy resistance.Forty-four CRC patients were then divided into three groups according to their chemotherapy outcomes(objective response,stable disease,and progressive disease),and 37 differential proteins were found to be related to chemotherapy resistance.The overlapping proteins were further investigated in an additional group of 79 patients using ELISA.Protein levels of F5 and PROZ significantly increased in the progressive disease group compared to other outcome groups.Our study indicated that F5 and PROZ proteins could represent potential biomarkers of resistance to chemotherapy in advanced CRC patients.

The Expression of NF-Kappa B Family Protein and Its Relationship with Drug Resistance in Breast Cancer Cell Lines

Objective: To study the expression of NFκB family protein in breast cancer cell lines and the relationship between NFκB family protein and the drug resistance.Methods: Expression of P65, IκB-α in 14 breast cancer cell lines and P50 in 11 breast cancer cell lines was detected by Western blot. The sensitivity of the cells to ADM was determined by MTT.Results: 1κB-α located mainly in the cytoplasm. P65 and P50 were in both of cytoplasm and nucleus. The expression level of P50 was higher than that of P65, especially in nucleus. MTT assay showed that IC50 was three-fold higher in the cell lines which expressed P50 in nucleus than those P50 negative in nucleus, but no difference was found in the expression of P65.Conclusion: The expression of P50 in nucleus may predict the chemotherapy resistance in breast cancer, so it can be used as an indicator to predict the prognosis. The expression of P50 is more often in breast cancer, and it may play a more important role in the chemotherapy resistance than other NFκB family members. Key words breast cancer - NFκB - chemotherapy resistance

The Expression of IMF-Kappa B Family Protein and Its Relationship with Drug Resistance in Breast Cancer Cell Lines

Objective: To study the expression of NFκB family protein in breast cancer cell lines and the relationship between NFκB family protein and the drug resistance. Methods: Expression of P65, IκB-α in 14 breast cancer cell lines and P50 in 11 breast cancer cell lines was detected by Western blot. The sensitivity of the cells to ADM was determined by MTT. Results: IκB-α located mainly in the cytoplasm. P65 and P50 were in both of cytoplasm and nucleus. The expression level of P50 was higher than that of P65, especially in nucleus. MTT assay showed that IC50 was three-fold higher in the cell lines which expressed P50 in nucleus than those P50 negative in nucleus, but no difference was found in the expression of P65. Conclusion: The expression of P50 in nucleus may predict the chemotherapy resistance in breast cancer, so it can be used as an indicator to predict the prognosis. The expression of P50 is more often in breast cancer, and it may play a more important role in the chemotherapy resistance than other NFκB family members.

Bcl-2 degradation is an additional pro-apoptotic effect of polo-like kinase inhibition in cholangiocarcinoma cells

To examine the influence on apoptotic mechanisms following inhibition of polo-like kinases as therapeutically approach for cholangiocellular cancer treatment.METHODSAs most cholangiocarcinomas are chemotherapy-resistant due to mechanisms preventing tumor cell death, we investigated the effect of Cisplatin on cholangiocellular carcinoma (CCA) cell lines KMCH-1 and Mz-Ch-1. Polo-like kinases (PLK) are important regulators of the cell cycle and their inhibition is discussed as a potential therapy while PLK inhibition can regulate apoptotic mediators. Here, cells were treated with PLK inhibitor BI6727 (Volasertib), Cisplatin, and in combination of both compounds. Cell viability was assessed by MTT; apoptosis was measured by DAPI staining and caspase-3/-7 assay. Western blot and qRT-PCR were used to measure expression levels of apoptosis-related molecules Bax and Bcl-2.RESULTSThe cell viability in the CCA cell lines KMCH-1 and Mz-Ch-1 was reduced in all treatment conditions compared to vehicle-treated cells. Co-treatment with BI6727 and cisplatin could even enhance the cytotoxic effect of cisplatin single treatment. Thus, co-treatment of cisplatin with BI6727 could slightly enhance the cytotoxic effect of the cisplatin in both cell lines whereas there was evidence of increased apoptosis induction solely in Mz-Ch-1 as compared to KMCH-1. Moreover, PLK inhibition decreases protein levels of Bcl-2; an effect that can be reversed by the proteasomal degradation inhibitor MG-132. In contrast, protein levels of Bax were not found to be altered by PLK inhibition. These findings indicate that cytotoxic effects of Cisplatin in Mz-Ch-1 cells can be enhanced by cotreatment with BI6727.CONCLUSIONIn conclusion, BI6727 treatment can sensitize CCA cells to cisplatin-induced apoptosis with proteasomal Bcl-2 degradation as an additional pro-apoptotic effect.

Annexin A2 promotion of hepatocellular carcinoma tumorigenesis via the immune microenvironment

Hepatocellular carcinoma(HCC) is the most common primary liver cancer with a dismal prognosis, especially when diagnosed at advanced stages. Annexin A2(ANXA2), is found to promote cancer progression and therapeutic resistance.However, the underlining mechanisms of ANXA2 in immune escape of HCC remain poorly understood up to now. Herein, we summarized the molecular function of ANXA2 in HCC and its relationship with prognosis. Furthermore, we tentatively elucidated the underlying mechanism of ANXA2 immune escape of HCC by upregulating the proportion of regulatory T cells and the expression of several inhibitory molecules, and by downregulating the proportion of natural killer cells and dendritic cells and the expression of several inhibitory molecules or effector molecules. We expect a lot of in-depth studies to further reveal the underlying mechanism of ANXA2 in immune escape of HCC in the future.

Expression of multidrug resistance proteins in retinoblastoma

AIM： To elucidate the mechanism of multidrug resistance in retinoblastoma, and to acquire more insights into in vivo drug resistance.METHODS： Three anticancer drug resistant Y79 human RB cells were generated against vincristine, etoposide or carboplatin, which are used for conventional chemotherapy in RB. Primary cultures from enucleated eyes after chemotherapy（PCNC） were also prepared. Their chemosensitivity to chemotherapeutic agents（vincristine, etoposide and carboplatin） were measured using MTT assay. Western blot analysis was performed to evaluate the expression of p53, Bcl-2 and various multidrug resistant proteins in retinoblastoma cells.RESULTS： Following exposure to chemotherapeutic drugs, PCNC showed less sensitivity to drugs. No significant changes observed in the p53 expression, whereas Bcl-2 expression was found to be increased in the drug resistant cells as well as in PCNC. Increased expression of P-glycoprotein（P-gp） was observed in drug resistant Y79 cells; however there was no significant change in the expression of P-gp found between primary cultures of primarily enucleated eyes and PCNC. Multidrug resistance protein 1（Mrp-1） expression was found to be elevated in the drug resistant Y79 cells as well as in PCNC. No significant change in the expression of lung resistance associatedprotein（Lrp） was observed in the drug resistant Y79 cells as well as in PCNC.CONCLUSION： Our results suggest that multidrug resistant proteins are intrinsically present in retinoblastoma which causes treatment failure in managing retinoblastoma with chemotherapy.

Current Progress of Phytomedicine in Glioblastoma Therapy

Glioblastoma multiforme,an intrusive brain cancer,has the lowest survival rate of all brain cancers.The chemotherapy utilized to prevent their proliferation and propagation is limited due to modulation of complex cancer signalling pathways.These complex pathways provide infiltrative and drug evading properties leading to the development of chemotherapy resistance.Therefore,the development and discovery of such interventions or therapies that can bypass all these resistive barriers to ameliorate glioma prognosis and survival is of profound importance.Medicinal plants are comprised of an exorbitant range of phytochemicals that have the broad-spectrum capability to target intrusive brain cancers,modulate anti-cancer pathways and immunological responses to facilitate their eradication,and induce apoptosis.These phytocompounds also interfere with several oncogenic proteins that promote cancer invasiveness and metastasis,chemotherapy resistance and angiogenesis.These plants are extremely vital for promising anti-glioma therapy to avert glioma proliferation and recurrence.In this review,we acquired recent literature on medicinal plants whose extracts/bioactive ingredients are newly exploited in glioma therapeutics,and also highlighted their mode of action and pharmacological profile.

Mutations in the DNA polymerase binding pathway affect the immune microenvironment of patients with small-cell lung cancer and enhance the efficacy of platinum-based chemotherapy

Background:Small-cell lung cancer(SCLC)is characterized by its high malignancy and is associated with a poor prognosis.In the early stages of the disease,platinum-based chemotherapy is the recommended first-line treatment and has demonstrated efficacy.However,SCLC is prone to recurrence and is generally resistant to chemotherapy in its later stages.Methods:Here,we collected samples from SCLC patients who received platinum-based chemotherapy,performed genomic and transcriptomic analyses,and validated our results with publicly available data.Results:SCLC patients with DNA polymerase binding pathway mutations had an improved prognosis after platinum chemotherapy compared with patients without such mutations.Patients in the mutant(MT)group had higher infiltration of T cells,B cells,and M1 macrophages compared with patients without DNA polymerase binding pathway mutations.Conclusions:DNA polymerase binding pathway mutations can be used as prognostic markers for platinum-based chemotherapy in SCLC.

Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer,therapeutic treatment options for platinum-resistant ovarian cancer

The survival rates for women with ovarian cancer have shown scant improvement in recent years,with a 5-year survival rate of less than 40%for women diagnosed with advanced ovarian cancer.High-grade serous ovarian cancer(HGSOC)is the most lethal subtype where the majority of women develop recurrent disease and chemotherapy resistance,despite over 70%-80%of patients initially responding to platinum-based chemotherapy.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)signaling pathway regulates many vital processes such as cell growth,survival and metabolism.However,this pathway is frequently dysregulated in cancers including different subtypes of ovarian cancer,through amplification or somatic mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha(PIK3CA),amplification of AKT isoforms,or deletion or inactivation of PTEN.Further evidence indicates a role for the PI3K/AKT/mTOR pathway in the development of chemotherapy resistance in ovarian cancer.Thus,targeting key nodes of the PI3K/AKT/mTOR pathway is a potential therapeutic prospect.In this review,we outline dysregulation of PI3K signaling in ovarian cancer,with a particular emphasis on HGSOC and platinum-resistant disease.We review pre-clinical evidence for inhibitors of the main components of the PI3K pathway and highlight past,current and upcoming trials in ovarian cancers for different inhibitors of the pathway.Whilst no inhibitors of the PI3K/AKT/mTOR pathway have thus far advanced to the clinic for the treatment of ovarian cancer,several promising compounds which have the potential to restore platinum sensitivity and improve clinical outcomes for patients are under evaluation and in various phases of clinical trials.

ABCA1 is associated with the development of acquired chemotherapy resistance and predicts poor ovarian cancer outcome

Aim:This study investigated the ATP binding cassette(ABC)transporter(ABCA1,ABCB1,ABCB3,ABCC2 and ABCG2)expression in high grade serous ovarian cancer(HGSOC)tissues,cell lines and primary cells to determine their potential relationship with acquired chemotherapy resistance and patient outcome.Methods:ABC transporter mRNA and protein expression(ABCA1,ABCB1,ABCB3,ABCC2 and ABCG2)was assessed in publicly available datasets and in a tissue microarray(TMA)cohort of HGSOC at diagnosis,respectively.ABC transporter mRNA expression was also assessed in chemosensitive ovarian cancer cell lines(OVCAR-5 and CaOV3)versus matching cell lines with acquired carboplatin resistance and in primary HGSOC cells from patients with chemosensitive disease at diagnosis(n=10)as well as patients with acquired chemotherapy resistance at relapse(n=6).The effects of the ABCA1 inhibitor apabetalone in carboplatin-sensitive and-resistant cell lines were also investigated.Results:High ABCA1 mRNA and protein expression was found to be significantly associated with poor patient outcome.ABCA1 mRNA and protein levels were significantly increased in ovarian cancer cell lines(OVCAR-5 CBPR and CaOV3 CBPR)with acquired carboplatin resistance.ABCA1 mRNA was significantly increased in primary HGSOC cells obtained from patients with acquired chemotherapy resistance.Apabetalone treatment reduced ABCA1 protein expression and increased the sensitivity of both parental and carboplatin-resistant ovarian cancer cells to carboplatin.Conclusion: These results suggest that inhibiting ABCA1 transporter may be useful in overcoming acquired chemotherapy resistance and improving outcome for patients with HGSOC.

Imaging Tumors Resistance to Chemotherapy Circumvented with Nanoparticle

Malignant tumor is one of the most notorious diseases devastating human lives.