Breast Cancer Resistance Protein Expression and 5-Fluorouracil Resistance

Objective To filtrate breast cancer resistance protein （BCRP）-mediated resistant agents and to investigate clinical relationship between BCRP expression and drug resistance. Methods MTT assay was performed to filtrate BCRP-mediated resistant agents with BCRP expression cell model and to detect chemosensitivity of breast cancer tissue specimens to these agents. A high performance liquid chromatography （HPLC） assay was established, and was used to measure the relative dose of intracellular retention resistant agents. RT-PCR and immunohistochemistry （IHC） were employed to investigate the BCRP expression in breast cancer tissue specimens. Results MTT assay showed that the expression of BCRP increased with the increasing resistance of 5-fluorouracil （5-Fu） （P〈0.05, n=3） in the cell model, while HPLC assay indicated that the intracellular retention dose of 5-Fu was significantly correlated with the expression of BCRP （t=-0.897, P〈0.05, n=3）. A total of 140 breast cancer tissue specimens were collected. BCRP-positive expression was detected in forty-seven specimens by both RT-PCR and IHC. As shown by MTT assay subsequently, the resistance index （RI） of 47 BCRP-positive breast cancer tissue specimens to 5-Fu was 7-12 times as high as that of adjacent normal tissue samples. BCRP expression was related to 5-Fu resistance （R2=0.8124, P〈0.01）. Conclusion Resistance to 5-Fu can be mediated by BCRR Clinical chemotherapy for breast cancer patients can be optimized based on BCRP-positive expression.

Breast cancer resistance protein （Bcrp） and the testis--an unexpected turn of events

Breast cancer resistance protein （Bcrp） is an ATP-dependent efflux drug transporter. It has a diverse spectrum of hydrophilic and hydrophobic substrates ranging from anticancer, antiviral and antihypertensive drugs, to organic anions, antibiotics, phytoestrogens （e.g., genistein, daidzein, coumestrol）, xenoestrogens and steroids （e.g., dehydroepiandrosterone sulfate）. Bcrp is an integral membrane protein in cancer and normal cells within multiple organs （e.g., brain, placenta, intestine and testis） that maintains cellular homeostasis by extruding drugs and harmful substances from the inside of cells. In the brain, Bcrp is a major component of the blood- brain barrier located on endothelial cells near tight junctions （TJs）. However, Bcrp is absent at the Sertoli cell blood-testis barrier （BTB）; instead, it is localized almost exclusively to the endothelial TJ in microvessels in the interstitium and the peritubular myoid cells in the tunica propria. Recent studies have shown that Bcrp is also expressed stage specifically and spatiotemporally by Sertoli and germ cells in the seminiferous epithelium of rat testes, limited only to a testis-specific cell adhesion ultrastructure known as the apical ectoplasmic specialisation （ES） in stage VI-early VIII tubules. These findings suggest that Bcrp is equipped by late spermatids and Sertoli cells to protect late-stage spermatids completing spermiogenesis. Furthermore, Bcrp was found to be associated with F （filamentous）-actin and several actin regulatory proteins at the apical ES and might be involved in the organisation of actin filaments at the apical ES in stage VII-VIII tubules. These findings will be carefully evaluated in this brief review.

Treatment-induced neuroendocrine prostate cancer and de novo neuroendocrine prostate cancer:Identification,prognosis and survival,genetic and epigenetic factors

Neuroendocrine prostate cancer(NEPC)shows an aggressive behavior compared to prostate cancer(PCa),also known as prostate adenocarcinoma.Scanty foci in PCa can harbor genetic alternation that can arise in a heterogeneity of prostate cancer.NEPC may arise de novo or develop following androgen deprivation therapy(ADT).NEPC that arise following ADT has the nomenclature“treatmentemerging/induced NEPC(t-NEPC)”.t-NEPC would be anticipated in castration resistant prostate cancer(CRPC)and metastatic PCa.t-NEPC is characterized by low or absent androgen receptor(AR)expression,independence of AR signaling,and gain of neuroendocrine phenotype.t-NEPC is an aggressive metastatic tumor,develops from PCa in response to drug induced ADT,and shows very short response to conventional therapy.t-NEPC occurs in 10%-17%of patients with CRPC.De novo NEPC is rare and is accounting for less than 2%of all PCa.The molecular mechanisms underlying the trans-differentiation from CRPC to t-NEPC are not fully elucidated.Sphingosine kinase 1 plays a significant role in t-NEPC development.Although neuroendocrine markers:Synaptophysin,chromogranin A,and insulinoma associated protein 1(INSM1)are expressed in t-NEPC,they are non-specific for diagnosis,prognosis,and follow-up of therapy.t-NEPC shows enriched genomic alteration in tumor protein P53(TP53)and retinoblastoma 1(RB1).There are evidences suggest that t-NEPC might develop through epigenetic evolution.There are genomic,epigenetic,and transcriptional alterations that are reported to be involved in development of t-NEPC.Knock-outs of TP53 and RB1 were found to contribute in development of t-NEPC.PCa is resistant to immunotherapy,and at present there are running trials to approach immunotherapy for PCa,CRPC,and t-NEPC.

Modulation of breast cancer resistance protein mediated atypical multidrug resistance using RNA interference delivered by adenovirus

Clinical multidrug resistance ( MDR ) of malignancies to many antineoplasticagents is the major obstacle in the successful treatment of cancer. The emergence of breast cancerresistance protein ( BCRP), a member of the adenosine triphosphate ( ATP ) binding cassette ( ABC )transporter family, has necessitated the development of antagonists. To overcome the BCRP-mediatedatypical MDR, RNA interference (RNAi) delivered by adenovirus targeting BCRP mRNA was used toinhibit the atypical MDR expression by infecting MCF-7/MX100 cell lines with constructed RNAiadenovirus.

Adaptive pathways and emerging strategies overcoming treatment resistance in castration resistant prostate cancer

The therapies available for prostate cancer patients whom progress from hormonesensitive to castration resistant prostate cancer include both systemic drugs,including docetaxel and cabazitaxel,and drugs that inhibit androgen signaling such as enzalutamide and abiraterone.Unfortunately,it is estimated that up to 30%of patients have primary resistance to these treatments and over time even those who initially respond to therapy will eventually develop resistance and their disease will continue to progress regardless of the presence of the drug.Determining the mechanisms involved in the development of resistance to these therapies has been the area of intense study and several adaptive pathways have been uncovered.Androgen receptor(AR)mutations,expression of AR-V7(or other constitutively active androgen receptor variants),intracrine androgen production and overexpression of androgen synthesis enzymes such as Aldo-Keto Reductase Family 1,Member C3(AKR1C3)are among the many mechanisms associated with resistance to anti-androgens.In regards to the taxanes,one of the key contributors to drug resistance is increased drug efflux through ATP Binding Cassette Subfamily B Member 1(ABCB1).Targeting these resistance mechanisms using different strategies has led to various levels of success in overcoming resistance to current therapies.For instance,targeting AR-V7 with niclosamide or AKR1C3 with indomethacin can improve enzalutamide and abiraterone treatment.ABCB1 transport activity can be inhibited by the dietary constituent apigenin and antiandrogens such as bicalutamide which in turn improves response to docetaxel.A more thorough understanding of how drug resistance develops will lead to improved treatment strategies.This review will cover the current knowledge of resistance mechanisms to castration resistant prostate cancer therapies and methods that have been identified which may improve treatment response.

MicroRNA-216a: a potential therapeutic target for drug resistance and recurrent of liver cancer

The Editor welcomes submissions for possible publication in the Letters to the Editor section.Letters commenting on an article published in the Journal or other interesting pieces will be considered if they are received within 6 weeks of the time the article was published.Authors of the article being commented on will be given an opportunity to offer a timely response to the letter.Authors of letters will be notified that the letter has been received.Unpublished letters cannot be returned.

BioPerine Encapsulated Nanoformulation for Overcoming Drug-Resistant Breast Cancers

The evolving dynamics of drug resistance due to tumor heterogeneity often creates impediments to traditional therapies making it a challenging issue for cancer cure.Breast cancer often faces challenges of current therapeutic interventions owing to its multiple complexities and high drug resistivity,for example against drugs like trastuzumab and tamoxifen.Drug resistance in the majority of breast cancer is often aided by the overtly expressed P-glycoprotein(P-gp)that guides in the rapid drug efflux of chemotherapy drugs.Despite continuous endeavors and ground-breaking achievements in the pursuit of finding better cancer therapeutic avenues,drug resistance is still a menace to hold back.Among newer therapeutic approaches,the application of phytonutrients such as alkaloids to suppress P-gp activity in drug-resistant cancers has found an exciting niche in the arena of alternative cancer therapies.In this work,we would like to present a black pepper alkaloid derivative known as Bio Perine-loaded chitosan(CS)-polyethylene glycol(PEG)coated polylactic acid(PLA)hybrid polymeric nanoparticle to improve the bioavailability of Bio Perine and its therapeutic efficacy in suppressing P-gp expression in MDA-MB 453 breast cancer cell line.Our findings revealed that the CS-PEG-Bio PerinePLA nanoparticles demonstrated a smooth spherical morphology with an average size of316 nm,with improved aqueous solubility,and provided sustained Bio Perine release.The nanoparticles also enhanced in vitro cytotoxicity and downregulation of P-gp expression in MDA-MB 453 cells compared to the commercial inhibitor verapamil hydrochloride,thus promising a piece of exciting evidence for the development of Bio Perine based nano-drug delivery system in combination with traditional therapies as a crucial approach to tackling multi-drug resistance in cancers.

Mismatch repair enzyme expression in primary and castrate resistant prostate cancer

Objective:Although the utility of immunohistochemistry(IHC)for assessing mismatch repair(MMR)protein expression has been demonstrated in solid tumors including primary prostate cancer(PCa),its utility has not been assessed in castration-resistant PCa(CRPC).Methods:Tissue microarrays were constructed from 127 radical prostatectomies and 155 CRPC metastases from 50 patients.MMR(MLH1,MSH2,MSH6,and PMS2)expression was assessed by IHC and gene expression arrays.Associations between MMR protein expression in PCa and CRPC and biochemical recurrence(BCR)or time from diagnosis to death respectively were determined.Results:There was no correlation between levels of MMR protein and BCR.Absence of MSH2 and MSH6 was the most pronounced at 15%and 22%in PCa and 17.8%and 16%in CRPC patients,respectively.MSH2 and MSH6 protein were absent in 9.4%and 8%of PCa and CRPC respectively.Absence of individual MMR proteins did not correlate with BCR or time from diagnosis to death.However absent MSH2/MSH6 in CRPC was associated with shorter time to death(pZ0.0006).Loss of MSH2 was verified at the gene expression level.This finding correlated with microsatellite instability previously reported in this CRPC cohort.

Role of androgen receptor splice variants in prostate cancer metastasis

Prostate cancer(PCa)is one of the most lethal cancers in western countries.Androgen receptor(AR)signaling pathway plays a key role in PCa progression.Despite the initial effectiveness of androgen deprivation therapy(ADT)for treatment of patients with advanced PCa,most of them will develop resistance to ADT and progress to metastatic castration resistant prostate cancer(mCRPC).Constitutively transcriptional activated AR splice variants(AR-Vs)have emerged as critical players in the development and progression of mCRPC.Among AR-Vs identified to date,AR-V7(a.k.a.AR3)is one of the most abundant and frequently found in both PCa cell lines and in human prostate tissues.Most of functional studies have been focused on AR-V7/AR3 and revealed its role in regulation of survival,growth,differentiation and migration in prostate cells.In this review,we will summarize our current understanding of regulation of expression and activity of AR-Vs in mCRPC.

Efficacy of pemetrexed combined with erlotinib/gefitinib in advanced non-small cell lung cancer patients during tyrosine kinase inhibitor treatment

Objective We aimed to evaluate the efficacy and safety of pemetrexed combined with erlotinib/gefitinib in advanced non-small cell lung cancer(NSCLC) patients during tyrosine kinase inhibitor(TKI) treatment. Methods Thirty-two patients with advanced NSCLC were divided into two groups. Patients in the control group received continuous daily epidermal growth factor receptor tyrosine kinase inhibitor(EGFRTKI) treatment, and patients in the experimental group received continuous daily EGFR-TKI along with pemetrexed treatment, which was administered on day 1 at 500 mg/m2. Erlotinib(150 mg) or gefitinib(250 mg) was administered daily from day 1 to day 21, with a cycle of every 21 days. Dexamethasone, folic acid, and vitamin B12 were also administered during the treatment. The endpoint of the primary study was the disease control rate. Results The objective response rate was 21.9%(95% CI: 7.6% to 36.3%) in the control group, whereas the disease control rate was 84.4%(95% CI: 71.8% to 97.0%) in the experimental group. The median progression-free survival was 6.2(95% CI: 2.4 to 10.0). Grades 3 or 4 adverse effects of leucopenia(15.6%), neutropenia(12.5%), anemia(3.1%), and nausea or vomiting(3.1%) were found in the experimental group.Conclusion The administration of pemetrexed combined with erlotinib or gefitinib showed a higher efficacy in TKI-resistant NSCLC patients. Further, the adverse effects of this drug combination were well tolerated by the patients. Pemetrexed combined with TKI treatment might provide a satisfactory therapeutic strategy for advanced NSCLC patients after TKI treatment.

New developments in the treatment of castration resistant prostate cancer

In the past 5 years, the treatment and understanding of metastatic castrate resistant prostate cancer （CRPC） have improved dramatically. Our understanding of the mechanisms of castration resistance has allowed for the development of new drugs to target prostate cancer, and our understanding of genetic mutations may give us new tools with which to more accurately diagnose and be able to predict the course of this heterogeneous disease. This article summarizes the recent advances in the understanding of the development of CRPC, as well as the new drugs and targets, which have evolved from this basic research.

The effective transfection of a low dose of negatively charged drug-loaded DNA-nanocarriers into cancer cells via scavenger receptors

DNA-nanotechnology-based nano-architecture scaffolds based on circular strands were designed in the form of DNA-nanowires(DNA-NWs) as a polymer of DNA-triangles. Circularizing a scaffold strand(84-NT) was the critical step followed by annealing with various staple strands to make stiff DNAtriangles. Atomic force microcopy(AFM), native polyacrylamide gel electrophoresis(PAGE), UVanalysis, MTT-assay, flow cytometry, and confocal imaging were performed to assess the formulated DNA-NWs and cisplatin(CPT) loading. The AFM and confocal microscopy images revealed a uniform shape and size distribution of the DNA-NWs, with lengths ranging from 2 to 4 mm and diameters ranging from 150 to 300 nm. One sharp band at the top of the lane(500 bp level) with the loss of electrophoretic mobility during the PAGE(native) gel analysis revealed the successful fabrication of DNA-NWs. The loading efficiency of CPT ranged from 66.85% to 97.35%. MTT and flow cytometry results showed biocompatibility of the blank DNA-NWs even at 95% concentration compared with the CPT-loaded DNANWs. The CPT-loaded DNA-NWs exhibited enhanced apoptosis(22%) compared to the apoptosis(7%)induced by the blank DNA-NWs. The release of CPT from the DNA-NWs was sustained at < 75% for 6 h in the presence of serum, demonstrating suitability for systemic applications. The IC_(50) of CPT@DNA-NWs was reduced to 12.8 nM CPT, as compared with the free CPT solution exhibiting an IC_(50) of 51.2 n M.Confocal imaging revealed the targetability, surface binding, and slow internalization of the DNA-NWs in the scavenger-receptor-rich cancer cell line(HepG2) compared with the control cell line.

Radium-223 and metastatic castration-resistant prostate cancer: All that glitters is not gold

After being approved by the National Drug Agency in several countries, Radium-223 (Ra-223) is gaining wide acceptance in the treatment of bone metastatic castration resistant prostate cancer. The exact mechanism of action remain unclear: The established model of direct alpha-particle irradiation from the remodelling bone surface, where Ra-223 accumulates, surrounding the tumor foci can explain a lethal effect only on metastatic microdeposits, but not on higher tumor burden. According to the &#x0201c;pre-metastatic niche model&#x0201d;, it is likely that Ra-223 targets several non-tumoral cell types of the tumor microenvironment involved in the complex mechanism of cancer bone homing and colonization. A deeper insight into this hypothetical mechanism will lead to a more accurate dosimetric approach and to find optimal sequencing and/or combination with the other therapeutic options.

THE EFFECTS OF MRP GENE mRNA OVEREXPRESSION ON THE PROGNOSIS IN LUNG CANCER PATIENTS

Objective To study the effects of multi- drug resistance associated protein gene (MRP gene)overexpression on the prognosis of patients with lung cancer. methods Paraffin - embedded tissues taken fromradical resection of 47 cases suffering from non - small cell lung cancer (NSCLC) were determined for theexpression of MRP gene mRNA by in situ hybridization using labelled digoxigenin probes combined withimmunohistochemistry. All the patients had been followed - up from 6 months to 3 years. Results Theoverexpression of MRP gene mRNA of all the 47 lung cancer specimens was found to be obviously related withsurvival time, effects of chemotherapy, recurrence or metastases after surgery, but not related with histology, tumorsize, node metastases, TNM stages, age and sex. Conclusion MRP gene mRNA expression is correlated with theprognosis of lung cancer patients and may be regarded as an indicator to forecast the prognosis and to choose thechemotherapy for lung cancer patients.

The Use of PSA Doubling Time to Predict Prognosis and the Use of PSA Response to Assess the Success for Prostate Cancer Patients Undergoing Docetaxel Chemotherapy

In the targeted therapy era, it is critical to know the certain points to start or discontinue chemotherapy for patients with castration resistant metastatic prostate cancer. The prognostic factors to determine this response are still not clear yet. We tried to find out if the PSA doubling time helps us to predict the patients who will benefit from docetaxel chemotherapy most, and also to question the value of the PSA response to chemotherapy. Retrospectively, 70 patients who had hormone refractory metastatic prostate cancer that were given at least 4 cycles of docetaxel chemotherapy between 2002 and 2015 were evaluated. After the onset of docetaxel, PSA response to therapy and overall survival rates were analyzed to figure out if these parameters were related to PSA doubling time. The only statistically significant prognostic parameter affecting overall survival was the best PSA response rate to docetaxel chemotherapy being over or under 50%. The most significant parameter that affects the PSA doubling time was the clinical stage at the time of diagnosis. PSA doubling time is not a useful predictive tool for predicting response to docetaxel. By means of overall survival, the clinical stage at the time of diagnosis was the best predictive tool for our cohort. The best PSA response rate to docetaxel chemotherapy was found to be a valuable parameter. The study being retrospective and the low number of patients included in this cohort can be the main weaknesses of this study. Further studies to determine which other factors can be useful are needed.

Cytoreductive surgery after recurrent epithelial ovarian cancer and at other timepoints

In this descriptive review we look at the role of surgery for advanced ovarian cancer at other timepoints apart from the initial cytoreduction for front-line therapy or interval cytoreductive surgery after neoadjuvant chemotherapy. The chief surgical problem to face after primary treatment is recurrent ovarian cancer. Of far more marginal concern are the second-look surgical procedures or the palliative efforts intended to resolve the patient's symptoms with no curative intent. The role of surgery in recurrent ovarian cancer remains poorly defi ned. Current data, albeit from non-randomized studies, nevertheless clearly support surgical cytoreduction in selected patients, a rarely curative expedient that invariably yields a marked survival advantage over chemotherapy alone. Despite these fi ndings, some consider it too early to adopt secondary cytoreduction as the standard care for patients with recurrent ovarian cancer and a randomized study is needed. Two ongoing randomized trials(Arbeitsgemeinschaft Gynkologische Onkologie-Desktop Ⅲ and Gynecologic Oncology Group 213) intend to verify the role of secondary cytoreduction for platinum-sensitive ovarian cancer compared with chemotherapy considered as standard care for these patients. We await the results of these two trials for a defi nitive answer to the matter.

Supramolecular host-guest nanosystems for overcoming cancer drug resistance

Cancer drug resistance has become one of the main challenges for the failure of chemotherapy,greatly limiting the selection and use of anticancer drugs and dashing the hopes of cancer patients.The emergence of supramolecular host-guest nanosystems has brought the field of supramolecular chemistry into the nanoworld,providing a potential solution to this challenge.Compared with conventional chemotherapeutic platforms,supramolecular host-guest nanosystems can reverse cancer drug resistance by increasing drug uptake,reducing drug efflux,activating drugs,and inhibiting DNA repair.Herein,we summarize the research progress of supramolecular host-guest nanosystems for overcoming cancer drug resistance and discuss the future research direction in this field.It is hoped that this review will provide more positive references for overcoming cancer drug resistance and promoting the development of supramolecular host-guest nanosystems.

New mechanisms of multidrug resistance: an introduction to the Cancer Drug Resistance special collection

Cancer Drug Resistance publishes contributions to understanding the biology and consequences of mechanisms that interfere with successful treatment of cancer. Since virtually all patients who die of metastatic cancer have multidrug-resistant tumors, improved treatment will require an understanding of the mechanisms of resistance to design therapies that circumvent these mechanisms, exploit these mechanisms, or inactivate these multidrug resistance mechanisms. One example of a resistance mechanism is the expression of ATP-binding cassette efflux pumps, but unfortunately, inhibition of these transporters has not proved to be the solution to overcome multidrug resistance in cancer. Other mechanisms that confer multidrug resistance, and the confluence of multiple different mechanisms (multifactorial multidrug resistance) have been identified, and it is the goal of this Special Collection to expand this catalog of potential multidrug resistance mechanisms, to explore novel ways to overcome resistance, and to present thoughtful reviews on the problem of multidrug resistance in cancer.

Mobilization of hematopoietic progenitor cells in patients with liver cirrhosis

AIM:To test the hypothesis that liver cirrhosis is associated with mobilization of hematopoietic progenitor cells. METHODS:Peripheral blood samples from 72 patients with liver cirrhosis of varying etiology were analyzed by flow cytometry.Identified progenitor cell subsets were immunoselected and used for functional assays in vitro. Plasma levels of stromal cell-derived factor-1(SDF-1) were measured using an enzyme linked immunosorbent assay.RESULTS:Progenitor cells with a CD133 + /CD45 + CD14 + phenotype were observed in 61%of th patients.Between 1%and 26%of the peripheral bloo mononuclear cells(MNCs)displayed this phenotype Furthermore,a distinct population of c-kit + progenito cells(between 1%and 38%of the MNCs)could b detected in 91%of the patients.Additionally,18% of the patients showed a population of progenito cells(between 1%and 68%of the MNCs)that wa characterized by expression of breast cancer resistanc protein-1.Further phenotypic analysis disclosed tha the circulating precursors expressed CXC chemokin receptor 4,the receptor for SDF-1.In line with thi finding,elevated plasma levels of SDF-1 were presen in all patients and were found to correlate with th number of mobilized CD133 + progenitor cells.

Pharmacological role of efflux transporters: Clinical implications for medication use during breastfeeding

The World Health Organisation recommends exclusive breastfeeding for the first six months of an infant’s life and in combination with solid food thereafter. This recommendation was introduced based on research showing numerous health benefits of breastfeeding for both the mother and the infant. However, there is always concern regarding the transfer of medications from mother to their breastfed baby via milk. Pharma-cokinetic properties of a drug are usually used to pre-dict its transferability into breast milk. Although most drugs are compatible with breastfeeding, cases of toxic drug exposure have been reported. This is thought to be due to active transport mechanisms whereby effux transporter proteins expressed in the epithelial cells of the mammary gland actively secrete drugs into milk. An example of such effux transporters including the breast cancer resistance protein which is strongly induced during lactation and this could result in contamination of milk with the substrates of this transporter which may place the suckling infant at risk of toxicity. Furthermore, there is little known about the substrate specifcity of most effux transporters as we have highlighted in this review. There also exists some degree of contradiction between in vivo and in vitro studies which makes it difficult to conclusively predict outcomes and drug-drug interactions.