Different strategies to overcome multidrug resistance in cancer

The risk of acquisition of resistance to chemotherapy remains a major hurdle in the management of various types of cancer patients. Several cellular and noncellular mechanisms are involved in developing both intrinsic and acquired resistance in cancer cells toward chemotherapy. This review covers the various multidrug resistance (MDR) mechanisms observed in cancer cells as well as the various strategies developed to overcome these MDR mechanisms. Extensive studies have been conducted during the last several decades to enhance the efficacy of chemotherapy by suppressing or evading these MDR mechanisms including the use of new anticancer drugs that could escape from the efflux reaction, MDR modulators or chemosensitizers, multifunctional nanocarriers, and RNA interference (RNAi) therapy.     

Nanomedicine targeting ferroptosis to overcome anticancer therapeutic resistance

A potential reason for the failure of tumor therapies is treatment resistance. Resistance to chemotherapy, radiotherapy, and immunotherapy continues to be a major obstacle in clinic, resulting in tumor recurrence and metastasis. The major mechanisms of therapy resistance are inhibitions of cell deaths, like apoptosis and necrosis, through drug inactivation and excretion, repair of DNA damage, tumor heterogeneity,or changes in tumor microenvironment, etc. Recent studies have shown that ferroptosi...     

Cancer stem cells: A review from origin to therapeutic implications

Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are elucidated as cells that can perpetuate themselves via autorestoration. These cells are highly resistant to current therapeutic approaches and are the main reason for cancer recurrence. Radiotherapy has made a lot of contributions to cancer treatment. However, despite continuous achievements, therapy resistance and tumor recurrence are still prevalent in most patients. This resistance might be partly related to the existence of CSCs. In the present study, recent advances in the investigation of different biological properties of CSCs, such as their origin, markers, characteristics, and targeting have been reviewed. We have also focused our discussion on radioresistance and adaptive responses of CSCs and their related extrinsic and intrinsic influential factors. In summary, we suggest CSCs as the prime therapeutic target for cancer treatment.     

Mechanisms and strategies to overcome multiple drug resistance in cancer

One of the major problems in chemotherapy is multidrug resistance (MDR) against anticancer drugs. ATP-binding cassette (ABC) transporters are a family of proteins that mediate MDR via ATP-dependent drug efflux pumps. Many MDR inhibitors have been identified, but none of them have been proven clinically useful without side effects. Efforts continue to discover not toxic MDR inhibitors which lack pharmacokinetic interactions with anticancer drugs. Novel approaches have also been designed to inhibit or circumvent MDR. In this review, the structure and function of ABC transporters and development of MDR inhibitors are described briefly including various approaches to suppress MDR mechanisms.     

Glioblastoma cancer stem cells: heterogeneity,microenvironment and related therapeutic strategies

Glioblastoma Multiforme (GBM) is an incurable malignancy. GBM patients have a short life expectancy despite aggressive therapeutic approaches based on surgical resection followed by adjuvant radiotherapy and concomitant chemotherapy. Glioblastoma growth is characterized by a high motility of tumour cells, their resistance to both chemo/radio‐therapy, apoptosis inhibition leading to failure of conventional therapy. Cancer Stem Cells (CSCs), identified in GBM as well as in many other cancer types, express the membrane antigen prominin‐1 (namely CD133). These cells and normal Neural Stem Cells (NSC) share surface markers and properties, i.e. are able to self‐renew and differentiate into multiple cell types. Stem cell self‐renewal depends on microenvironmental cues, including Extracellular Matrix (ECM) composition and cell types. Therefore, the role of microenvironment needs to be evaluated to clarify its importance in tumour initiation and progression through CSCs. The specific microenvironment of CSCs was found to mimic in part the vascular niche of normal stem cells. The targeting of GMB CSCs may represent a powerful treatment approach. Lastly, in GBM patients cancer‐initiating cells contribute to the profound immune suppression that in turn correlated with CSCs STAT3 (CD133 + ). Further studies of microenvironment are needed to better understand the origin of GMB/GBM CSCs and its immunosuppressive properties. Copyright © 2010 John Wiley & Sons, Ltd.     

Novel therapeutic strategies for targeting liver cancer stem cells

The cancer stem cell (CSC) hypothesis was first proposed over 40 years ago. Advances in CSC isolation were first achieved in hematological malignancies, with the first CSC demonstrated in acute myeloid leukemia. However, using similar strategies and technologies, and taking advantage of available surface markers, CSCs have been more recently demonstrated in a growing range of epithelial and other solid organ malignancies, suggesting that the majority of malignancies are dependent on such a compartment.Primary liver cancer consists predominantly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). It is believed that hepatic progenitor cells (HPCs) could be the origin of some HCCs and ICCs. Furthermore, stem cell activators such as Wnt/β-catenin, TGF-β, Notch and Hedgehog signaling pathways also expedite tumorigenesis, and these pathways could serve as molecular targets to assist in designing cancer prevention strategies. Recent studies indicate that additional factors such as EpCAM, Lin28 or miR-181 may also contribute to HCC progression by targeting HCC CSCs. Various therapeutic drugs that directly modulate CSCs have been examined in vivo and in vitro. However, CSCs clearly have a complex pathogenesis, with a considerable crosstalk and redundancy in signaling pathways, and hence targeting single molecules or pathways may have a limited benefit for treatment. Many of the key signaling molecules are shared by both CSCs and normal stem cells, which add further challenges for designing molecularly targeted strategies specific to CSCs but sparing normal stem cells to avoid side effects. In addition to the direct control of CSCs, many other factors that are needed for the maintenance of CSCs, such as angiogenesis, vasculogenesis, invasion and migration, hypoxia, immune evasion, multiple drug resistance, and radioresistance, should be taken into consideration when designing therapeutic strategies for HCC. Here we provide a brief review of molecular signaling in liver CSCs and present insights into new therapeutic strategies for targeting liver CSCs.     

Cancer stem cells: redefining the paradigm of cancer treatment strategies

Cancer has been known to arise from long-lived cells in the body and to possess properties in common with undifferentiated, embryonic cells. Recent findings of a population of cells in solid tumors resembling stem cells supports a stem cell model of cancer. A scheme in which all cancers initiate from "activated' stem cells helps bring together data from genetic, cell biology, and epidemiology studies. Cancer can arise from embryonic cells in the case of childhood tumors; hormone-activated stem cells in the case of breast cancer; and following chronic activation of stem cells caused by tissue damage. This scheme helps explain the failure of many cancer therapies, points out deficiencies in certain research approaches, and focuses the problem on a subset of cells that can be explicitly targeted, leading to more efficient therapy.     

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

The identification of cancer stem cells(CSCs) that are responsible for tumor initiation, growth, metastasis, and therapeutic resistance might lead to a new thinking on cancer treatments. Similar to stem cells,CSCs also display high resistance to radiotherapy and chemotherapy with genotoxic agents. Thus, conventional therapy may shrink the tumor volume but cannot eliminate cancer. Eradiation of CSCs represents a novel therapeutic strategy. CSCs possess a highly efficient DNA damage response(DDR) system, which is considered as a contributor to the resistance of these cells from exposures to DNA damaging agents. Targeting of enhanced DDR in CSCs is thus proposed to facilitate the eradication of CSCs by conventional therapeutics. To achieve this aim, a better understanding of the cellular responses to DNA damage in CSCs is needed. In addition to the protein kinases and enzymes that are involved in DDR, other processes that affect the DDR including chromatin remodeling should also be explored.     

Emerging strategies to overcome the resistance to current mTOR inhibitors in renal cell carcinoma

The mammalian target of rapamycin (mTOR) has emerged as an attractive cancer therapeutic target. Treatment of metastatic renal cell carcinoma (mRCC) has improved significantly with the advent of agents targeting the mTOR pathway, such as temsirolimus and everolimus. Unfortunately, a number of potential mechanisms that may lead to resistance to mTOR inhibitors have been proposed.In this paper, we discuss the mechanisms underlying resistance to mTOR inhibitors, which include the downstream effectors of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway, the activation of hypoxia-inducible factor (HIF), the PIM kinase family, PTEN expression, elevated superoxide levels, stimulation of autophagy, immune cell response and ERK/MAPK, Notch and Aurora signaling pathways. Moreover, we present an updated analysis of clinical trials available on PubMed Central and www.clinicaltrials.gov, which were pertinent to the resistance to rapalogs.The new frontier of inhibiting the mTOR pathway is to identify agents targeting the feedback loops and cross talks with other pathways involved in the acquired resistance to mTOR inhibitors. The true goal will be to identify biomarkers predictive of sensitivity or resistance to efficiently develop novel agents with the aim to avoid toxicities and to better choose the active drug for the right patient.     

Dental stem cells: The role of biomaterials and scaffolds in developing novel therapeutic strategies

Dental stem cells(DSCs) are self-renewable cells that can be obtained easily from dental tissues, and are a desirable source of autologous stem cells. The use of DSCs for stem cell transplantation therapeutic approaches is attractive due to their simple isolation, high plasticity, immunomodulatory properties, and multipotential abilities. Using appropriate scaffolds loaded with favorable biomolecules, such as growth factors, and cytokines, can improve the proliferation, differentiation, migration, and functional capacity of DSCs and can optimize the cellular morphology to build tissue constructs for specific purposes. An enormous variety of scaffolds have been used for tissue engineering with DSCs. Of these, the scaffolds that particularly mimic tissue-specific micromilieu and loaded with biomolecules favorably regulate angiogenesis, cell-matrix interactions, degradation of extracellular matrix, organized matrix formation, and the mineralization abilities of DSCs in both in vitro and in vivo conditions. DSCs represent a promising cell source for tissue engineering, especially for tooth, bone, and neural tissue restoration. The purpose of the present review is to summarize the current developments in the major scaffolding approaches as crucial guidelines for tissue engineering using DSCs and compare their effects in tissue and organ regeneration.     

Cancer stem cells as a therapeutic target in bladder cancer

Bladder cancer is one of the most prevalent genitourinary cancers responsible for about 150,000 deaths per year worldwide. Currently, several treatments, such as endoscopic and open surgery, appended by local or systemic immunotherapy, chemotherapy, and radiotherapy are used to treat this malignancy. However, the differences in treatment outcome among patients suffering from bladder cancer are considered as one of the important challenges. In recent years, cancer stem cells, representing a population of undifferentiated cells with stem-cell like properties, have been eyed as a major culprit for the high recurrence rate in superficial papillary bladder cancer. Cancer stem cells have been reported to be resistant to conventional treatments, such as chemotherapy, radiation, and immunotherapy, which induce selective pressure on tumoral populations resulting in selection and growth of the resistant cells. Therefore, targeting the therapeutic aspects of cancer stem cells in bladder cancer may be promising. In this study, we briefly discuss the biology of bladder cancer and then address the possible relationship between molecular biology of bladder cancer and cancer stem cells. Subsequently, the mechanisms of resistance applied by cancer stem cells against the conventional therapeutic tools, especially chemotherapy, are discussed. Moreover, by emphasizing the biomarkers described for cancer stem cells in bladder cancer, we have provided, described, and proposed targets on cancer stem cells for therapeutic interventions and, finally, reviewed some immunotargeting strategies against bladder cancer stem cells.     

Cancer stem cells in prostate adenocarcinoma: a target for new anticancer strategies

Prostate cancer (PC) is major common malignancy in males in most industrialized Western countries, where it is the most commonly diagnosed cancer affecting men after middle age (>50 years). Over 90% of PC patients with incurable disease respond to primary treatment, which consists of intervention to lower serum testosterone. However, the duration of response is short (12-33 months) and in almost all patients, is followed by the emergence of a phenotype resistant to androgen deprivation in therapy (known as hormone or androgen-resistant PC). Considerable research efforts have been directed towards the identification of markers associated with the initiation and progression of PC, yet there is little consensus about the target cell within prostate epithelium that is susceptible to malignant transformation. Stem cells may represent a major target for mutations leading to cancer as their longevity assures continued presence during the long latency between carcinogenic agents exposure and cancer development. Therefore in order to allow the development of more effective treatment strategies for PC, a better understanding of the molecular changes that underlie cancer stem cells is required.     

Therapeutic strategies of dual-target small molecules to overcome drug resistance in cancer therapy

Despite some advances in targeted therapeutics of human cancers, curative cancer treatment still remains a tremendous challenge due to the occurrence of drug resistance. A variety of underlying resistance mechanisms to targeted cancer drugs have recently revealed that the dual-target therapeutic strategy would be an attractive avenue. Compared to drug combination strategies, one agent simultaneously modulating two druggable targets generally shows fewer adverse reactions and lower toxicity. As a consequence, the dual-target small molecule has been extensively explored to overcome drug resistance in cancer therapy. Thus, in this review, we focus on summarizing drug resistance mechanisms of cancer cells, such as enhanced drug efflux, deregulated cell death, DNA damage repair, and epigenetic alterations. Based upon the resistance mechanisms, we further discuss the current therapeutic strategies of dual-target small molecules to overcome drug resistance, which will shed new light on exploiting more intricate mechanisms and relevant dual-target drugs for future cancer therapeutics.     

Bacterial strategies to overcome insect defences

Recent genetic and molecular analyses have revealed how several strategies enable bacteria to persist and overcome insect immune defences. Genetic and genomic tools that can be used with Drosophila melanogaster have enabled the characterization of the pathways that are used by insects to detect bacterial invaders and combat infection. Conservation of bacterial virulence factors and insect immune repertoires indicates that there are common strategies of host invasion and pathogen eradication. Long-term interactions of bacteria with insects might ensure efficient dissemination of pathogens to other hosts, including humans.     

Cancer stem cells: the lessons from pre-cancerous stem cells

How a cancer is initiated and established remains elusive despite all the advances in decades of cancer research. Recently the cancer stem cell (CSC) hypothesis has been revived, challenging the long-standing model of "clonal evolution" for cancer development and implicating the dawning of a potential cure for cancer [1]. The recent identification of precancerous stem cells (pCSCs) in cancer, an early stage of CSC development, however, implicates that the "clonal evolution" is not contradictory to the CSC hypothesis, but is rather an aspect of the process of CSC development [2]. The discovery of pCSC has revealed and will continue to reveal the volatile properties of CSC with respects to their phenotype, differentiation and tumorigenic capacity during initiation and progression. Both pCSC and CSC might also serve as precursors of tumor stromal components such as tumor vasculogenic stem/progenitor cells (TVPCs). Thus, the CSC hypothesis covers the developing process of tumor-initiating cells (TIC) --> pCSC --> CSC --> cancer, a cellular process that should parallel the histological process of hyperplasia/metaplasia (TIC) --> precancerous lesions (pCSC) --> malignant lesions (CSC --> cancer). The embryonic stem (ES) cell and germline stem (GS) cell genes are subverted in pCSCs. Especially the GS cell protein piwil2 may play an important role during the development of TIC --> pCSC --> CSC, and this protein may be used as a common biomarker for early detection, prevention, and treatment of cancer. As cancer stem cell research is yet in its infancy, definitive conclusions regarding the role of pCSC can not be made at this time. However this review will discuss what we have learned from pCSC and how this has led to innovative ideas that may eventually have major impacts on the understanding and treatment of cancer.     

Cancer and stem cells

Being the second leading cause of death globally, cancer has been a long-standing and rapidly evolving focus of biomedical research and practice in the world. A tremendous effort has been made to understand the origin of cancer cells, the formation of cancerous tissues, and the mechanism by which they spread and relapse, but the disease still remains mysterious. Here, we made an attempt to scrutinize evidences that indicate the role of stem cells in tumorigenesis and metastasis, and cancer relapse. We also looked into the influence of cancers on stem cells, which in turn represent a major constituent of tumor microenvironment. Based on current understandings of the properties of (cancer) stem cells and their relation to cancers, we can foresee that novel therapeutic approaches would become the next wave of cancer treatment.     

Neural stem cells: plasticity and therapeutic potential

Previous studies have suggested that human umbilical cord blood (HUCB) may serve as a rich source of hematopoietic and nonhematopoietic stem cells and that conditions exist that can coax hematopoietic cells to express neural characteristics. In our laboratory, these cells were tested for several models of neurodegenerative diseases and spinal cord injuries. Through a series of transplantation studies we have begun to uncover the properties of HUCB‐derived cells in neuropoietic regions of the neonatal (1) and aging rodent brain. The systematic application of phenotyping approaches to characterize survival, migratory potential and morphologic properties of the differentiated HUCB progeny within normal/unaffected brain will serve as a base for understanding the potential effect of these cells in the diseased brain. Acknowledgements: Supported in part by R01 6155039 (TZ). HUCB cells were obtained from Saneron CCEL Therapeutics, Inc. and BioWhittaker, Inc.