Development Of Multidrug Resistance Research Articles

Long Non-Coding RNAs in Multidrug Resistance of Glioblastoma.

Glioblastoma, also known as glioblastoma multiforme, is the most aggressive brain tumor in adults. Despite the huge advance in developing novel therapeutic strategies for patients with glioblastoma, the appearance of multidrug resistance (MDR) against the common chemotherapeutic agents, including temozolomide, is considered as one of the important causes for the failure of glioblastoma treatment. On the other hand, recent studies have demonstrated the critical roles of long non-coding RNAs (lncRNAs), particularly in the development of MDR in glioblastoma. Therefore, this article aimed to review lncRNA’s contribution to the regulation of MDR and elucidate the underlying mechanisms in glioblastoma, which will open up new lines of inquiry in the treatment of glioblastoma.

MiR-26a Reverses Multidrug Resistance in Osteosarcoma by Targeting MCL1.

The multidrug resistance (MDR) acquired in human osteosarcoma is a huge obstacle for effective chemotherapy. Recently, microRNA-26a (miR-26a) has been associated with the pathogenesis and progression of osteosarcoma. However, whether it regulates MDR in osteosarcoma is unknown. We show here that miR-26a expression declines in chemoresistant osteosarcoma after neoadjuvant chemotherapy, and its expression correlates with clinical outcome. In addition, compared with sensitive parental cells, miR-26a expression also declines in osteosarcoma MDR cells, together suggesting a negative correlation between miR-26a expression and MDR development in osteosarcoma. We also show that the enforced expression of miR-26a reverses MDR in osteosarcoma cells, and conversely, miR-26a knockdown confers MDR in chemosensitive osteosarcoma cells treated with doxorubicin, methotrexate, or cisplatin. Mechanistically, miR-26a directly targets the pro-survival protein myeloid cell leukemia 1 (MCL1), and in turn, the enforced expression of MCL1 markedly antagonizes miR-26a-decreased MDR in osteosarcoma MDR cells, therefore demonstrating that miR-26a reverses MDR in osteosarcoma by targeting MCL1. Lastly, miR-26a reverses resistance to doxorubicin in osteosarcoma MDR cells xenografted in nude mice. Collectively, these results reveal a negative role and the underlying mechanism of miR-26a in the regulation of MDR in human osteosarcoma, implying a potential tactic of manipulating miR-26a for overcoming MDR in osteosarcoma chemotherapy.

Endoplasmic reticulum stress and oncomir-associated chemotherapeutic drug resistance mechanisms in breast cancer tumors.

Breast cancer, as a heterogenous malign disease among the top five leading causes of cancer death worldwide, is defined as by far the most common malignancy in women. It contributes to 25% of all cancer-associated deaths after menopause. Breast cancer is categorized based on the expression levels of cell surface and intracellular steroid receptors [estrogen, progesterone receptors, and human epidermal growth factor receptor (HER2)], and the treatment approaches frequently include antiestrogen, aromatase inhibitors, and Herceptin. However, the management and prevention strategies due to adverse side effects stress the patients. The unsuccessful treatments cause to raise the drug levels, leading to excessive toxic effects on healthy cells, and the development of multidrug-resistance (MDR) in the tumor cells against chemotherapeutic agents. MDR initially causes the tumor cells to gain a metastatic character, and subsequently, the patients do not respond adequately to treatment. Endoplasmic reticulum (ER) stress is one of the most important mechanisms supporting MDR development. ER stress-mediated chemotherapeutic resistance is very common in aggressive tumors. The in vitro and in vivo experiments on breast tumors indicate that ER stress-activated protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)- activating transcription factor (ATF4) signal axis plays an important role in the survival of tumors and metastasis. Besides, ER stress-associated oncogenic microRNAs (miRNAs) induce chemoresistance in breast tumors. We aimed to have a look at the development of resistance mechanisms due to ER stress as well as the involvement of ER stress-associated miRNA regulation following the chemotherapeutic regimen in the human breast tumors. We also aimed to draw attention to potential molecular markers and therapeutic targets.

Molecular Study of Class1 and 2 Integrons in Methicillin-resistant Staphylococcus Aureus

Background and Aim: Methicillin-Resistant Staphylococcus aureus (MRSA) had appeared in the last few decades and became a significant health problem. The study aimed to evaluate the prevalence of class 1 and class 2 integrons among MRSA clinical isolates from different healthcare-associated infections (HAIs) and the prevalence of multi-drug resistance (MDR) in these isolates. Materials and Methods: Two hundred Staphylococcus aureus (S. aureus) isolates from different HAIs were evaluated for the presence of the mecA gene, class 1 (intI1) and class 2 (intI2) integrons via the polymerase chain reaction (PCR) beside the determination of antibiotics sensitivity. Results: MRSA was determined by resistance to cefoxitin in 152 isolates (76%) of isolated S. aureus. The molecular study showed the prevalence of mecA, intI1, and intI2 genes among the isolated MRSA strains as follows: 100%, 70.4%, 13.1, respectively, and there were 12 isolates (7.9%) that had both intI1 and intI2 genes. There was a significant high incidence of resistance to gentamicin (P=0.01), amikacin (P=0.005), tobramycin (P=0.035), erythromycin (P=0.035), clindamycin (P=0.08), levofloxacin (P=0.0001) and ciprofloxacin (P=0.0001) in MRSA strains positive for intI1 and/or intI2 genes compared to MRSA strains negative for intI genes and non-methicillin resistant S. aureus (Non- MRSA) strains. There was a significantly high prevalence of MDR among MRSA strains positive for intI1 and/or intI2 genes (62.8%) compared to MRSA strains negative for intI genes (28.8%) and Non- MRSA strains (8.3%), (P=0.0001). Conclusion: The present study revealed a high prevalence of MRSA strains among S. aureus clinical isolates with a high prevalence of the mecA gene in those isolates. There was also a high prevalence of intI1gene but not intI2 gene. The mecA and intI genes were associated with the development of MDR in S. aureus.

CD13: A Key Player in Multidrug Resistance in Cancer Chemotherapy.

Cancer is one of the most serious diseases that are harmful to human health. Systemic chemotherapy is an optimal therapeutic strategy for the treatment of cancer, but great difficulty has been encountered in its administration in the form of multidrug resistance (MDR). As an enzyme on the outer cell surface, CD13 is documented to be involved in the MDR development of tumor cells. In this review, we will focus on the role of CD13 in MDR generation based on the current evidence.

Royleanone Derivatives From Plectranthus spp. as a Novel Class of P-Glycoprotein Inhibitors.

Cancer is among the leading causes of death worldwide. One of the most challenging obstacles in cancer treatment is multidrug resistance (MDR). Overexpression of P-glycoprotein (P-gp) is associated with MDR. The growing incidence of cancer and the development of MDR drive the search for novel and more effective anticancer drugs to overcome the MDR problem. Royleanones are natural bioactive compounds frequently found in Plectranthus spp. The cytotoxic diterpene 6,7-dehydroroyleanone (1) is the main component of the P. madagascariensis (Pers.) Benth. essential oil, while 7α-acetoxy-6β-hydroxyroyleanone (2) can be isolated from acetonic extracts of P. grandidentatus Gürke. The reactivity of the natural royleanones 1 and 2 was explored to obtain a small library of new P-gp inhibitors. Four new derivatives (6,7-dehydro-12-O-tert-butyl-carbonate-royleanone (20), 6,7-dehydro-12-O-methylroyleanone (21), 6,7-dehydro-12-O-benzoylroyleanone (22), and 7α-acetoxy-6β-hydroxy-12-O-benzoylroyleanone (23) were obtained as pure with overall modest to excellent yields (21–97%). P-gp inhibition potential of the derivatives 20–23 was evaluated in human non-small cell lung carcinoma NCI-H460 and its MDR counterpart NCI-H460/R with the P-gp overexpression, through MTT assay. Previously prepared diterpene 7α-acetoxy-6β-benzoyloxy-12-O-(4-chloro)benzoylroyleanone (4), has also been tested. The P-gp inhibiting effects of compounds 1–4 were also assessed through a Rhodamine 123 accumulation assay. Derivatives 4 and 23 have significant P-gp inhibitory potential. Regarding stability and P-gp inhibition potential, results suggest that the formation of benzoyl esters is a more convenient approach for future derivatives with enhanced effect on the cell viability decrease. Compound 4 presented higher anti-P-gp potential than the natural diterpenes 1, 2, and 3, with comparable inhibitory potential to Dexverapamil. Moreover, derivative 4 showed the ability to sensitize the resistant NCI-H460/R cells to doxorubicin.

Tamoxifen induces stem-like phenotypes and multidrug resistance by altering epigenetic regulators in ERα+ breast cancer cells.

To understand the mechanism underlying tamoxifen-induced multidrug resistance (MDR) and stem-like phenotypes in breast cancer cells, we treated the MCF-7 cells with 4-hydroxy-tamoxifen (TAM) for 6 months continuously and established MCF-7 tamoxifen resistance (TR) phenotypes. In the present study, the following methods were used: cell viability assay, colony formation, cell cycle analysis, ALDEFLUOR assay, mammosphere formation assay, chromatin immunoprecipitation (ChIP) assay, PCR array, western blot analysis and quantitative reverse transcription polymerase chain reaction (QRT-PCR). The expression of ERα was significantly higher in MCF7-TR cells when compared with parental MCF-7 cells. MCF7-TR cells exposed to TAM showed a significant increase in the proliferation and rate of colony formation. The number of cancer stem cells was higher in MCF7-TR cells as observed by the increase in the number of ALDH+ cells. Furthermore, the number of mammospheres formed from the FACS-sorted ALDH+ cells was higher in MCF7-TR cells. Using PCR array analysis, we were able to identify that the long-term exposure of TAM leads to alterations in the epigenetic and MDR stem cell marker genes. Furthermore, western blot analysis demonstrated elevated levels of Notch-1 expression in MCF-TR cells compared with MCF-7 cells. Chromatin immunoprecipitation (ChIP) assay revealed that Notch-1 enhanced the cyclin D1 expression significantly in these cells. In addition, we observed that MCF7-TR cells were resistant to doxorubicin but not the MCF-7 cells. In the present study, we conclude that the treatment with tamoxifen induces multiple epigenetic alterations that lead to the development of MDR and stem-like phenotypes in breast cancers. Therefore, our study provides better insights to develop novel treatment regime to control the progression of breast cancer.

DJ-1 is involved in the multidrug resistance of SGC7901 gastric cancer cells through PTEN/PI3K/Akt/Nrf2 pathway.

Gastric cancer is a common malignancy worldwide. The occurrence of multidrug resistance (MDR) is the major obstacle for effective gastric cancer chemotherapy. In this study, the in-depth molecular mechanism of the DJ-1-induced MDR in SGC7901 gastric cancer cells was investigated. The results showed that DJ-1 expression level was higher in MDR variant SGC7901/VCR cells than that in its parental SGC7901 cells. Moreover, DJ-1 overexpression conferred the MDR phenotype to SGC7901 cells, while DJ-1 knockdown in SGC7901/VCR cells induced re-sensitization to adriamycin, vincristine, cisplatin, and 5-fluorouracil. These results suggested that DJ-1 mediated the development of MDR in SGC7901 gastric cancer cells. Importantly, further data revealed that the activation of PI3k/Akt and Nrf2 signaling pathway were required for the DJ-1-induced MDR phenotype in SGC7901 gastric cancer cells. Meanwhile, we found that PI3k/Akt pathway was activated probably through DJ-1 directly binding to and negatively regulating PTEN, consequently resulting in Nrf2 phosphorylation and activation, and thereby inducing Nrf2-dependent P-glycoprotein (P-gp) and Bcl-2 expressions in the DJ-1-mediated MDR of SGC7901 gastric cancer cells. Overall, these results revealed that activating PTEN/PI3K/Akt/Nrf2 pathway and subsequently upregulating P-gp and Bcl-2 expression could be a critical mechanism by which DJ-1 mediates the development of MDR in SGC7901 gastric cancer cells. The new findings may be helpful for understanding the mechanisms of MDR in gastric cancer cells, prompting its further investigation as a molecular target to overcome MDR.

Abstract 6326: Global changes in alternative mRNA polyadenylation profile promote the development of multidrug resistance (MDR) to chemotherapy in colon cancer

Abstract Aim: The study investigated the global changes in mRNA alternative polyadenylation (APA) profile associated with MDR development in colon cancer cells. Background: Polyadenylation is a crucial step needed for the maturation of eukaryotic mRNAs. APA refers to the production of different mRNA isoforms bearing varying length of 3'-untranslated region (3'UTR), where key RNA regulatory elements are found. APA usually eliminates the distal end of the 3'UTR, thus allowing the escape from the predominantly repressive effect from longer 3'UTR. Colon cancer is a leading cause of cancer-related death worldwide. MDR, which is usually associated with overexpression of ATP-binding cassette efflux transporters including ABCG2, is a major unresolved obstacle to successful cancer chemotherapy. We have previously reported that ABCG2 mRNA is more stable in MDR colon cancer cells. Interestingly, the increase in mRNA stability is tied to a missing microRNA binding site (miR-519c) due to the shortening of ABCG2 mRNA 3'UTR in drug resistant cells. Thus microRNA-mediated mRNA degradation and/or protein translation block are relieved, thereby leading to ABCG2 overexpression. A remarkable feature of 3'UTR APA is that it can be regulated globally, thus simultaneously affecting numerous mRNA transcripts. While ABCG2 mRNA 3'UTR is shortened in MDR colon cancer cells, the global changes in APA profile of other transcripts during the course of MDR development have not been reported. Method: Differential APA signature and specific APA-regulated mRNAs were evaluated in two pairs of sensitive and MDR colon cancer cell lines by RNA sequencing. APA profiles were assessed from the RNA-Seq datasets by using the bioinformatics tool “DaPars”. Altered 3'UTR isoforms of a few differentially expressed mRNAs were validated by 3'RACE assay and 3'UTR isoform specific PCR analysis. The genes were subjected to Gene Ontology (GO) analysis to identify relevant molecular pathways and biological processes. Result: APA profiles of two pairs of drug resistant ABCG2-overexpressing colon cancer cell line (S1-M1-80 & SW620 Flv100) versus their parental cells (S1 & SW620) were compared at the global scale from their sequenced RNA samples. By GO analysis using the PANTHER Platform, mRNA transcripts exhibiting 3'UTR shortening in S1-M1-80 and SW620 Flv100 versus their respective parental cells were enriched in biological processes including “transport and catabolism”, “cell growth and death”, and “cell motility” by GO terms. Genes ranked at the top of the list are mostly direct or indirect targets of the Wnt-β-catenin signaling pathway. Wnt signaling is a crucial pathway for mediating metastasis and therapeutic resistance. Conclusion: Global changes of APA in gene regulation may contribute to the development of MDR in colon cancer. Further investigation is warranted to elucidate the mechanisms leading to APA. Modulation of the APA machinery may help eradicate MDR cancer cells. Citation Format: Kenneth KW To. Global changes in alternative mRNA polyadenylation profile promote the development of multidrug resistance (MDR) to chemotherapy in colon cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6326.

Repurposing Tyrosine Kinase Inhibitors to Overcome Multidrug Resistance in Cancer: A Focus on Transporters and Lysosomal Sequestration.

Tyrosine kinase inhibitors (TKIs) are being increasingly used to treat various malignancies. Although they were designed to target aberrant tyrosine kinases, they are also intimately linked with the mechanisms of multidrug resistance (MDR) in cancer cells. MDR-related solute carrier (SLC) and ATB-binding cassette (ABC) transporters are responsible for TKI uptake and efflux, respectively. However, the role of TKIs appears to be dual because they can act as substrates and/or inhibitors of these transporters. In addition, several TKIs have been identified to be sequestered into lysosomes either due to their physiochemical properties or via ABC transporters expressed on the lysosomal membrane. Since the development of MDR represents a great concern in anticancer treatment, it is important to elucidate the interactions of TKIs with MDR-related transporters as well as to improve the properties that would prevent TKIs from diffusing into lysosomes. These findings not only help to avoid MDR, but also help to define the possible impact of combining TKIs with other anticancer drugs, leading to more efficient therapy and fewer adverse effects in patients.

Celecoxib Prevents Doxorubicin-Induced Multidrug Resistance in Canine and Mouse Lymphoma Cell Lines.

Background: Treatment of malignancies is still a major challenge in human and canine cancer, mostly due to the emergence of multidrug resistance (MDR). One of the main contributors of MDR is the overexpression P-glycoprotein (Pgp), which recognizes and extrudes various chemotherapeutics from cancer cells. Methods: To study mechanisms underlying the development of drug resistance, we established an in vitro treatment protocol to rapidly induce Pgp-mediated MDR in cancer cells. Based on a clinical observation showing that a 33-day-long, unplanned drug holiday can reverse the MDR phenotype of a canine diffuse large B-cell lymphoma patient, our aim was to use the established assay to prevent the emergence of drug resistance in the early stages of treatment. Results: We showed that an in vitro drug holiday results in the decrease of Pgp expression in MDR cell lines. Surprisingly, celecoxib, a known COX-2 inhibitor, prevented the emergence of drug-induced MDR in murine and canine lymphoma cell lines. Conclusions: Our findings suggest that celecoxib could significantly improve the efficiency of chemotherapy by preventing the development of MDR in B-cell lymphoma.

Perplexing Role of P-Glycoprotein in Tumor Microenvironment.

Development of multidrug resistance (MDR) still remains a major obstacle to the long-term success of cancer therapy. P-glycoprotein (P-gp) is a well-identified membrane transporter with capability to efflux drug molecules out of the cancer cell leading to reduced efficiency of chemotherapy. Cancer cells upregulate P-gp expression as an adaptive response to evade chemotherapy mediated cell death. While several P-gp inhibitors have been discovered by in silico and pre-clinical studies, very few have successfully passed all phases of the clinical trials. Studies show that application of P-gp inhibitors in cancer therapy regimen following development of MDR achieved limited beneficial outcomes. While, the non-specific substrate binding to P-gp has made the drug-design a challenge, a bigger perplexing challenge comes from its role in tumor immunology. Expression of P-gp was noted immune cell phenotypes with apparently antagonistic functionality. Both pro-tumor MΦ2-macrophages and, anti-tumor NK-cell and Th17/CD4+T cell subsets have shown enhanced expression of P-gp. While drug based inhibition of P-gp in pro-tumor immune cell phenotypes could promote tumor elimination, however, it would not be a rational choice to exert inhibition of P-gp on anti-tumor immune cell phenotypes. This mutually exclusive paradigm of P-gp functionality requires a more comprehensive and detailed understanding of its role in tumor microenvironment with active interplay of cancer and immune cells in the tumor mileu. In this review, we focus on the current understanding of the role of P-gp in cancer cells and immune cells and finally attempt to highlight some caveats in the current understanding of its role in comprehensive tumor microenvironment along with challenges in the development of P-gp inhibitors toward anti-cancer therapy.

A liquid biopsy to detect multidrug resistance and disease burden in multiple myeloma

Multiple myeloma is an incurable cancer of bone marrow plasma cells, with a 5-year survival rate of 43%. Its incidence has increased by 126% since 1990. Treatment typically involves high-dose combination chemotherapy, but therapeutic response and patient survival are unpredictable and highly variable—attributed largely to the development of multidrug resistance (MDR). MDR is the simultaneous cross-resistance to a range of unrelated chemotherapeutic agents and is associated with poor prognosis and survival. Currently, no clinical procedures allow for a direct, continuous monitoring of MDR. We identified circulating large extracellular vesicles (specifically microparticles (MPs)) that can be used to monitor disease burden, disease progression and development of MDR in myeloma. These MPs differ phenotypically in the expression of four protein biomarkers: a plasma-cell marker (CD138), the MDR protein, P-glycoprotein (P-gp), the stem-cell marker (CD34); and phosphatidylserine (PS), an MP marker and mediator of cancer spread. Elevated levels of P-gp+ and PS+ MPs correlate with disease progression and treatment unresponsiveness. Furthermore, P-gp, PS and CD34 are predominantly expressed in CD138− MPs in advanced disease. In particular, a dual-positive (CD138−P-gp+CD34+) population is elevated in aggressive/unresponsive disease. Our test provides a personalised liquid biopsy with potential to address the unmet clinical need of monitoring MDR and treatment failure in myeloma.

Wnt-β-catenin Signaling Pathway, the Achilles' Heels of Cancer Multidrug Resistance.

Most of the anticancer chemotherapies are hampered via the development of multidrug resistance (MDR), which is the resistance of tumor cells against cytotoxic effects of multiple chemotherapeutic agents. Overexpression and/or over-activation of ATP-dependent drug efflux transporters is a key mechanism underlying MDR development. Moreover, enhancement of drug metabolism, changes in drug targets and aberrant activation of the main signaling pathways, including Wnt, Akt and NF-κB are also responsible for MDR. In this study, we have reviewed the roles of Wnt signaling in MDR as well as its potential therapeutic significance. Pubmed and Scopus have been searched using Wnt, β-catenin, cancer, MDR and multidrug resistance as keywords. The last search was done in March 2019. Manuscripts investigating the roles of Wnt signaling in MDR or studying the modulation of MDR through the inhibition of Wnt signaling have been involved in the study. The main focus of the manuscript is regulation of MDR related transporters by canonical Wnt signaling pathway. Wnt signaling has been involved in several pathophysiological states, including carcinogenesis and embryonic development. Wnt signaling is linked to various aspects of MDR including P-glycoprotein and multidrug resistance protein 1 regulation through its canonical pathways. Aberrant activation of Wnt/β- catenin signaling leads to the induction of cancer MDR mainly through the overexpression and/or over-activation of MDR related transporters. Accordingly, Wnt/β-catenin signaling can be a potential target for modulating cancer MDR.

Curcumin increases the sensitivity of K562/DOX cells to doxorubicin by targeting S100 calcium-binding protein A8 and P-glycoprotein.

The development of multidrug resistance (MDR) has seriously impeded the efficacy of drug treatment of chronic myeloid leukemia (CML). Recent studies have indicated that S100 calcium-binding protein A8 (S100A8) is associated with the occurrence and development of MDR. Traditional Chinese medicine may provide drugs with the potential to be used as multidrug resistance reversal agents with low toxicity and multi-target characteristics. The present study selected K562/DOX cells, a CML drug-resistant cell line, as a research model, and aimed to examine whether curcumin was able to reverse the resistance to doxorubicin (DOX), and elucidate the underlying molecular mechanisms. An MTT cytotoxicity assay indicated that curcumin at 0.5–2 µM reversed DOX resistance with a reversal index of 1.3–9.3. Western blot analysis revealed that curcumin treatment caused a downregulation of the expression of P-glycoprotein (P-gp) and S100A8 in a dose- and time-dependent manner. To study the internal association between S100A8 and P-gp, and the S100A8 role in drug resistance reversal, an RNA knockdown assay was conducted; however, S100A8 did not regulate the expression of P-gp or vice versa. After inhibiting the expression of S100A8 with specific small interfering RNA (si-S100A8), the sensitivity of K562/DOX cells to DOX was enhanced. In addition, si-S100A8 did not increase the intracellular accumulation of DOX, but increased the intracellular free calcium ion content, and the expression and activity of apoptosis-associated proteins, thereby inducing apoptosis. In conclusion, the present study suggested that inhibition of S100A8 expression increased DOX-induced apoptosis, and curcumin acted independently on S100A8 and P-gp to exert its drug resistance reversal effects

Antimicrobial Stewardship in Hematological Patients at the intensive care unit: a global cross-sectional survey from the Nine-i Investigators Network.

A global cross-sectional survey was performed to gather data on the current treatment of infections caused by multidrug-resistant (MDR) bacteria among hematological patients admitted to ICUs worldwide. The survey was performed in April 2019 using an electronic platform (SurveyMonkey®) being distributed among 83 physicians and completed by 48 (57.8%) responders. ESBL Enterobacteriaceae, carbapenem-resistant K. pneumoniae and carbapenem-resistant P. aeruginosa were the main concerns. Previous MDR infection (34% of responders), MDR colonization (20%) and previous antibiotic exposure within the last 3months (20.5%) were considered the most relevant risk factors of bloodstream infection (BSI) due to MDR bacteria. In 48.8% of the ICUs, there was no antimicrobial stewardship (AMS) team focused on hematological patients. Updates on local epidemiology of MDR pathogens were provided in 98% of the centers, using phone or verbal communications (56.1% and 53.7%, respectively). In presence of febrile neutropenia, initial therapy consisted of anti-Gram-negative plus anti-Gram-positive antibiotics for 41% of participants. Antibiotic de-escalation and/or discontinuation of therapy were considered as a promising strategy for the prevention of MDR development (32.4%). Factors associated with antibiotic de-escalation were clinical improvement (43.6%) and neutrophil count recovery (12.8%). Infectious Disease consultation and AMS interventions were not determining factors for de-escalation decisions (more than 50% of responders). Infection control and educational programs were valued as necessary measures for implementation by ICU practitioners. These findings should guide future efforts on collaborative team working, improving compliance with adequate treatment protocols, implementing antimicrobial stewardship programs in critically ill hematological patients, and educational activities.

A Comprehensive Review on Medicinal Plants as Antimicrobial Therapeutics: Potential Avenues of Biocompatible Drug Discovery.

The war on multidrug resistance (MDR) has resulted in the greatest loss to the world’s economy. Antibiotics, the bedrock, and wonder drug of the 20th century have played a central role in treating infectious diseases. However, the inappropriate, irregular, and irrational uses of antibiotics have resulted in the emergence of antimicrobial resistance. This has resulted in an increased interest in medicinal plants since 30–50% of current pharmaceuticals and nutraceuticals are plant-derived. The question we address in this review is whether plants, which produce a rich diversity of secondary metabolites, may provide novel antibiotics to tackle MDR microbes and novel chemosensitizers to reclaim currently used antibiotics that have been rendered ineffective by the MDR microbes. Plants synthesize secondary metabolites and phytochemicals and have great potential to act as therapeutics. The main focus of this mini-review is to highlight the potential benefits of plant derived multiple compounds and the importance of phytochemicals for the development of biocompatible therapeutics. In addition, this review focuses on the diverse effects and efficacy of herbal compounds in controlling the development of MDR in microbes and hopes to inspire research into unexplored plants with a view to identify novel antibiotics for global health benefits.

DJ-1 overexpression confers the multidrug resistance phenotype to SGC7901 cells by upregulating P-gp and Bcl-2

Gastric cancer (GC) is one of the most malignant tumors with high incidence and mortality worldwide, and the multidrug resistance (MDR) often results in chemotherapy failure in GC. DJ-1 has been well indicated to be associated with drug resistance in multiple cancers. However, the role of DJ-1 in the MDR of gastric cancer cells and its possible mechanism remain to be elucidated. Therefore, the current study was investigated whether DJ-1 expression is differential in parental gastric cancer cell SGC7901 and vincristine (VCR)-induced gastric cancer MDR cell SGC7901/VCR, and whether DJ-1 plays a significant role in development of MDR in gastric cancer. The results showed that DJ-1 expression in SGC7901/VCR cells was significantly higher than its sensitive parental SGC7901 cells. Furthermore, DJ-1 overexpressed gastric cancer cell line SGC7901/LV-DJ-1 led to the increase of cell survival rate, the IC50 of chemotherapeutic drugs and number of cell clones as well as decrease of cell cycle G0/G1 phase ratio compared with its parental cells under the treatment of VCR, adriamycin (ADR), 5-Fluorouracil (5-FU) and cisplatin (DDP). However, the DJ-1 knockdown stable cell line SGC7901/VCR/shDJ-1 reversed the above mentioned series of MDR. Moreover, it was found that upregulation of DJ-1 protein expression promoted the pumping rate of GC cells to ADR and reduced the apoptotic index of GC cells treated with chemotherapeutic drugs by upregulating P-gp and Bcl-2. Similarly, knocking down DJ-1, P-gp or Bcl-2 displayed a converse effect. In conclusion, the current study demonstrated that DJ-1 overexpression confers the MDR phenotype to SGC7901 cells and this process is related to DJ-1 promoting active efflux of drugs and enhancing the anti-apoptotic ability of MDR GC cells by upregulating P-gp and Bcl-2.

Derivative of 5-cyano-6-phenylpyrimidin antagonizes ABCB1- and ABCG2-mediated multidrug resistance

Multidrug resistance (MDR) lead to inadequate response to chemotherapy and cause failure in cancer treatment. One of the targeted approaches to overcome MDR in cancer cells is interfering or inhibiting ATP binding cassette (ABC) transporters. Among all members in ABC transporters superfamily, ABCB1 (ABC transporter subfamily B #1) and ABCG2 (ABC transporter subfamily G #2) play an important role in the development of cancer MDR. In this study, we synthesized a novel 5-cyano-6-phenylpyrimidin derivative 479, which exhibited selective dual-activity in reversing MDR mediated by ABCB1 and ABCG2, without affecting MDR mediated by ABCC1 (ABC transporter subfamily C #1) and ABCC10 (ABC transporter subfamily C #10). Further mechanism studies demonstrated that 479 increased the accumulation of paclitaxel and mitoxantrone in cancer cells by interrupting the efflux function of transporters and stimulating ABCB1/ABCG2 ATPase activity. In silico study provided evidence that 479 formed multiple physiochemical bonds with the drug-binding pocket of ABCB1 and ABCG2. Overall, our results provide a promising prototype in designing potent dual reversal agents targeting ABCB1- and ABCG2-meidated MDR.

The effect of ATP-binding cassette (ABC) transporters in human cancers

Multi-drug resistance (MDR) can be defined as a negative effect on the drug-target relationships, decreasing in intracellular drug aggregation. ABC (ATP-binding cassette) are popular transporter proteins in the development of MDR. ABC proteins in the cell membrane structure reduce the therapeutic efficacy and cause drug resistance in cancer patients. Resistance to chemotherapy is a remarkable and important issue in the treatment of cancer patients. These drug resistance proteins interfere with the drugs administered to patients, resulting in a decrease in bioavailability of these drugs and a reduction in their passage through the blood-brain barrier. ABC transporters are the largest family of transmembrane proteins with 8 subfamilies assigned from A to G based on sequence and structural homology. In this review, general information about ABC proteins is mentioned and the role of ABC proteins causing MDR in cancers is also discussed.