Overcoming drug resistance in pancreatic cancer

Introduction: Pancreatic cancer has the worst survival rate of all cancers. The current standard care for metastatic pancreatic cancer is gemcitabine, however, the success of this treatment is poor and overall survival has not improved for decades. Drug resistance (both intrinsic and acquired) is thought to be a major reason for the limited benefit of most pancreatic cancer therapies.

Areas covered: Previous studies have indicated various mechanisms of drug resistance in pancreatic cancer, including changes in individual genes or signaling pathways, the influence of the tumor microenvironment, and the presence of highly resistant stem cells. This review summarizes recent advances in the mechanisms of drug resistance in pancreatic cancer and potential strategies to overcome this.

Expert opinion: Increasing drug delivery efficiency and decreasing drug resistance is the current aim in pancreatic cancer treatment, and will also benefit the treatment of other cancers. Understanding the molecular and cellular basis of drug resistance in pancreatic cancer will lead to the development of novel therapeutic strategies with the potential to sensitize pancreatic cancer to chemotherapy, and to increase the efficacy of current treatments in a wide variety of human cancers.     

Overcoming multiple drug resistance in cancer using polymeric micelles

ABSTRACT

Introduction: A major concern that limits the success of cancer chemotherapy is multidrug resistance (MDR). The drug resistance mechanisms are either host related or tumor related. The host tumor interacting factors also contribute to MDR. Multifunctional polymeric micelles offer several advantages in circumventing MDR due to their design, selectivity, and stability in cancer microenvironment.

Areas covered: The review is broadly divided into two parts: the first part covers MDR and its mechanisms; the second part covers multifunctional polymeric micelles in combating MDR through its state-of-the-art design. This part covers various strategies like use of P-gp transporter inhibitors, TPGS, pH & thermo-sensitive, and siRNA for selectivity of PMs against multidrug-resistant tumors.

Expert opinion: Numerous approaches have been tested using polymeric micelles to overcome MDR tumors. However, these are either limited to only in-vitro investigations and/or preliminary preclinical models and do not investigate the underlying biological mechanism. Hence, there exists an unmet need to perform fundamental research that focuses on studying the underlying mechanism and preclinical/clinical testing of the micellar formulations.     

Overcoming drug resistance by regulating nuclear receptors

Drug resistance involves multiple mechanisms. Multidrug resistance (MDR) is the leading cause of treatment failure in cancer therapy. Elevated levels of MDR proteins [members of the ATP-binding cassette (ABC) transporter family] increase cellular efflux and decrease the effectiveness of chemotherapeutic agents. As a salvage approach to overcome drug resistance, inhibitors of MDR proteins have been developed, but have had limited success mainly due to undesired toxicities. Nuclear receptors (NRs), including pregnane X receptor (PXR), regulate the expression of proteins (including MDR proteins) involved in drug metabolism and drug clearance, suggesting that it is possible to overcome drug resistance by regulating NR. This review discusses the progress in the development of MDR inhibitors, with a focus on MDR1 inhibitors. Recent development of PXR antagonists to pharmacologically modulate PXR is also reviewed. The review proposes that selectively preventing the elevation of MDR levels by regulating NRs rather than non-selectively inhibiting the MDR activity by using MDR inhibitors can be a less toxic approach to overcome drug resistance during cancer therapy.     

Overcoming multidrug resistance in human cancer cells by natural compounds

Multidrug resistance is a phenomenon whereby tumors become resistant to structurally unrelated anticancer drugs. P-glycoprotein belongs to the large ATP-binding cassette (ABC) transporter superfamily of membrane transport proteins. P-glycoprotein mediates resistance to various classes of anticancer drugs including vinblastine, daunorubicin, and paclitaxel, by actively extruding the drugs from the cells. The quest for inhibitors of anticancer drug efflux transporters has uncovered natural compounds, including (-)-epigallocatechin gallate, curcumin, capsaicin, and guggulsterone, as promising candidates. In this review, studies on the effects of natural compounds on P-glycoprotein and anticancer drug efflux transporters are summarized.     

Genomics and cancer drug resistance

Cellular drug resistance is a major obstacle in cancer therapy. Mechanisms of resistance can be associated with altered expression of ATP-binding cassette (ABC) family of transporters on cell membrane transporters, the most common cause of multi-drug resistance (MDR), but can also include alterations of DNA repair pathways, resistance to apoptosis and target modifications. Anti-cancer treatments may be divided into different categories based on their purpose and action: chemotherapeutic agents damage and kill dividing cells; hormonal treatments prevent cancer cells from receiving signals essential for their growth; targeted drugs are a relatively new cancer treatment that targets specific proteins and pathways that are limited primarily to cancer cells or that are much more prevalent in cancer cells; and antibodies function by either depriving the cancer cells of necessary signals or by causing their direct death. In any case, resistance to anticancer therapies leads to poor prognosis of patients. Thus, identification of novel molecular targets is critical in development of new, efficient and specific cancer drugs. The aim of this review is to describe the impact of genomics in studying some of the most critical pathways involved in cancer drug resistance and in improving drug development. We shall also focus on the emerging role of microRNAs, as key gene expression regulators, in drug resistance. Finally, we shall address the specific mechanisms involved in resistance to tyrosine kinase inhibitors in chronic myeloid leukemia.     

Overcoming treatment resistance in HER2-positive breast cancer: potential strategies

Human epidermal growth factor receptor (HER)-2 overexpression or amplification occurs in about 20% of all breast cancers and results in a worse prognosis. Nevertheless, anti-HER2 treatments have recently been developed, resulting in dramatic improvements in the clinical outcome of patients with HER2-positive breast cancer. Trastuzumab has shown efficacy in early and advanced breast cancer treatment and lapatinib is currently approved for the treatment of advanced disease. Other anti-HER2 agents are being investigated. Mechanisms of resistance to trastuzumab treatment include crosstalk with heterologous receptors and amplification of HER2 signalling; amplification of the phosphoinositide 3-kinase (PI3K)/AKT pathway; alteration in binding of trastuzumab to HER2; and loss of HER2 expression. Proposed mechanisms of resistance to lapatinib involve derepression and/or activation of compensatory survival pathways through increased PI3K/AKT or estrogen receptor (ER) signalling. Several strategies to overcome resistance to anti-HER2 treatment are in different phases of development and include treatment with pertuzumab, T-DM1 and mammalian target of rapamycin (mTOR) inhibitors.     

Supermolecular drug challenge to overcome drug resistance in cancer cells

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Overcoming multidrug resistance in gram-negative bacteria

The incidence of Gram-negative pathogens resistant to multiple antibiotics and multiple classes of antibiotics is increasing and the resultant deficit in effective therapeutic agents emphasizes the urgent need for novel agents and novel therapeutic approaches to the treatment of Gram-negative infectious disease. While developing versions of existing agents able to overcome resistance, or targeting resistance itself are strategies being considered to deal with multidrug resistance, genomic approaches will ultimately provide a multitude of novel targets for the development of new classes of agents likely to be unaffected by existing resistance mechanisms. The use of 'natural' antibacterials such as cationic antimicrobial peptides and bacteriophage as therapeutic agents is also being pursued. With an increased understanding of the infection process, immunomodulation and vaccinology are increasingly useful approaches to infectious disease management in the face of increasing antimicrobial resistance. Finally, there is a need to rigorously implement appropriate prescribing and infection control practices, to minimize the risk of resistance development and spread. Clearly, the antibiotic era has not heralded the defeat of infectious disease and prudent use of novel therapies is imperative if we are to avoid entering the post-antimicrobial era.     

Overcoming platinum resistance in ovarian carcinoma

Importance of the field: Ovarian cancer remains a deadly malignancy because most patients develop recurrent disease that is resistant to chemotherapy, including platinum. Because response rates for current treatment regimens are relatively similar and unfortunately low, no standard chemotherapy for platinum-resistant ovarian cancer exists.

Areas covered in this review: A systematic literature review of clinical studies published between January 2005 and March 2010 was conducted using search engines, PubMed and MEDLINE with the entry keywords ‘ovarian cancer’ and ‘platinum resistance’. This search revealed 40 clinical trials (1793 patients).

What the reader will gain: Gemcitabine was the most common drug used in clinical trials reporting higher response rates, ≥ +1 SD of overall response rate (5 out of 8). Gemcitabine-based combination therapy showed an average response rate of 27.2% (95% CI, 22.4 – 32.0). Combination of gemcitabine and pegylated liposomal doxorubicin (PLD) was the most common regimen (n = 3) and was associated with possible additive effects in platinum-resistant ovarian cancer patients: response rate, gemcitabine alone 6.1%, PLD alone 19.8%, and gemcitabine with PLD 28.7% (95% CI, 20.4 – 37.0), respectively.

Take home message: Analysis of recent clinical trials showed that gemcitabine-based combination chemotherapy was associated with the highest antitumor effects in platinum-resistant ovarian cancer patients during the study period.     

Mechanism of EGER-related cancer drug resistance

Drug resistance in cancer arises from a complex range of biochemical and molecular events, which ultimately result in tumor cell survival. Identifying key genes and signal pathways involved in the molecular mechanisms of drug resistance is essential for establishment of new drug targets for preventing further resistance development and spreading. Epidermal growth factor receptor (EGFR) was the first growth factor receptor proposed as a target for cancer therapy. Significant progress in studying EGFR gene expression and mutation has been made in understanding the molecular events involved in EGFR-targeted agents. Recently, some individual chromosomal features such as EGFR copy number variation were demonstrated as new aspects related to drug sensitivity. Identifying these functional regulators of drug resistance will benefit therapeutic decision-making. In this study, we describe an extensive investigation of the published literature on mutation, amplification, and expression of EGFR and its downstream signaling that directly contribute to EGFR inhibitor resistance, including the gene status of KRAS, BRAF, PIK3CA, PTEN, MEK, and AKT on response to therapy. Analysis of these gene signatures identified reveals general modes of action of multicomponent therapies and the mechanisms of specific drug combinations, highlights the potential value of molecular interaction profiles in the discovery of novel therapies, and provides more information for personalized cancer medicine.     

Overcoming antimicrobial resistance by targeting resistance mechanisms

Three mechanisms of antimicrobial resistance predominate in bacteria: antibiotic inactivation, target site modification, and altered uptake by way of restricted entry and/or enhanced efflux. Many of these involve enzymes or transport proteins whose activity can be targeted directly in an attemptto compromise resistance and, thus, potentiate antimicrobial activity. Alternatively, novel agents unaffected by these resistance mechanisms can be developed. Given the ongoing challenge posed by antimicrobial resistance in bacteria, targeting resistance in this way may be our best hope at prolonging the antibiotic era.     

Animal models of pancreatic cancer for drug research

Background: The operative and conservative results of therapy in pancreatic ductal adenocarcinoma remain appallingly poor. This underlines the demand for further research for effective anticancer drugs. The various animal models remain the essential method for the determination of efficacy of substances during preclinical phase. Objective: Unfortunately, most of these tested substances showed a good efficacy in pancreatic carcinoma in the animal model but were not confirmed during the clinical phase. Methods: The available literature in PubMed, Medline, Ovid and secondary literature was searched regarding the available animal models for drug testing against pancreatic cancer. The models were analyzed regarding their pros and cons in anticancer drug testing. Conclusion: The different modifications of the orthotopic model (especially in mice) seem at present to be the best model for anticancer testing in pancreatic carcinoma. The value of genetically engineered animal model (GEM) and syngeneic models is on debate. A good selection of the model concerning the questions supposed to be clarified may improve the comparability of the results of animal experiments compared to clinical trials.     

Biomarkers and multiple drug resistance in breast cancer

Breast cancer, the most common form of cancer among women in North America and almost all of Europe, is a significant health problem in terms of both morbidity and mortality. It is estimated that each year this disease is diagnosed in over one million people worldwide and is the cause of more than 400,000 deaths. Although chemotherapy forms part of a successful treatment regime in many cases, as few as 50% patients may benefit from this, as a result of intrinsic or acquired multiple drug resistance (MDR). Through the use of in vitro cell culture models, a number of mechanisms of MDR have been identified; many, if not all, of which may contribute to breast cancer resistance in the clinical setting. This phenomenon is complicated by the likely multi-factorial nature of clinical resistance combined with the fact that, although apparently studied extensively in breast cancer, reported analyses have been performed using a range of analytical techniques; many on small sub-groups of patients, with different clinicopathological characteristics and receiving a range of therapeutic approaches. Larger defined studies, using standardised genomic and proteomics profiling approaches followed by functional genomics studies, are necessary in order to definitively establish the degree of complexity contributing to drug resistance and to identify novel therapeutic approaches - possibly involving chemotherapy, drug resistance modulators, and novel targeted therapies - to combat this disease.     

Glutathione and glutathione-dependent enzymes in cancer drug resistance

Genetic and biochemical evidence has demonstrated that glutathione and glutathione-dependent enzymes play a central role in cellular defence against toxic environmental agents. Modulation of cellular glutathione homeostasis can also have a profound effect on the sensitivity of cancer cells to a wide range of drugs used in chemotherapy. These effects are produced by multifactorial mechanisms that involve inactivation of toxic electrophiles by conjugation, modulation of cellular redox state, activation of drug transporter systems and regulation of cell signalling and repair pathways. New data demonstrating the importance of these pathways in cytoprotection and greater understanding of the mechanisms which regulate their function reveal a number of new targets for novel anti-cancer agents. It is critical, however, if these targets are to be exploited correctly that the dynamics of glutathione regulation are taken into account.     

长链非编码RNA HOTAIR在肿瘤多药耐药中的研究进展

HOX转录反义RNA（HOTAIR）是首个被发现的参与癌症进程的长链非编码RNA,并具有反式调控作用。HOTAIR在多种肿瘤中表达上调,不仅参与肿瘤细胞多药耐药（MDR）的形成,且与肿瘤的恶性程度和不良预后密切相关,因此HOTAIR有望成为逆转肿瘤耐药新靶点。对HOTAIR及其在肿瘤MDR方面的研究进展做一综述,以期为逆转肿瘤MDR的新药设计与研发提供思路。     

Overcoming resistance with designer immunotoxins

Normal human serum contains apolipoprotein L-I (apoL-I), which lyses African trypanaosomes. Resistant forms, such as Trypanosoma brucei rhodesiense express apoL-I-neutralising serum resistance-associated protein, which enables this parasite to infect humans and cause human African trypanosomiasis. This paper describes the construction of a mutant apoL-I conjugated to a nanobody that targets the variant surface glycoprotein of trypanosomes. Treatment with this engineered immunotoxin has resulted in both alleviating and curative effects on chronic and acute infections of mice with normal human serum-resistant and -sensitive trypanosomes.     

Overcoming multidrug resistance with nanomedicines

Introduction: Cancer remains the leading cause of death worldwide. Numerous therapeutic strategies that include smart biological treatments toward specific cellular pathways are being developed. Yet, inherent and acquired multidrug resistance (MDR) to chemotherapeutic drugs remains the major obstacle in effective cancer treatments.

Areas covered: Herein, we focused on an implementation of nanoscale drug delivery strategies (nanomedicines) to treat tumors that resist MDR. Specifically, we briefly discuss the MDR phenomenon and provide structural and functional characterization of key proteins that account for MDR. We next describe the strategies to target tumors using nanoparticles and provide a mechanistic overview of how changes in the influx:efflux ratio result in overcoming MDR.

Expert opinion: Various strategies have been applied in preclinical and clinical settings to overcome cancer MDR. Among them are the use of chemosensitizers that aim to sensitize the cancer cells to chemotherapeutic treatment and the use of nanomedicines as delivery vehicles that can increase the influx of drugs into cancer cells. These strategies can enhance the therapeutic response in resistant tumors by bypassing efflux pumps or by increasing the nominal amounts of therapeutic payloads into the cancer cells at a given time point.