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.

The importance of epithelial-mesenchymal transition and autophagy in cancer drug resistance

Epithelial-mesenchymal transition(EMT)and autophagy are both known to play important roles in the development of cancer.Subsequently,these processes are now being utilised as targets for therapy.Cancer is globally one of the leading causes of death,and,despite many advances in treatment options,patients still face many challenges.Drug resistance in cancer-therapy is a large problem,and both EMT and autophagy have been shown to contribute.However,given the context-dependent role of these processes and the complexity of the interactions between them,elucidating how they both act alone and interact is important.In this review,we provide insight into the current landscape of the interactions of autophagy and EMT in the context of malignancy,and how this ultimately may affect drug resistance in cancer therapy.

Atom engineering-regulated in situ transition of Cu(Ⅰ)-Cu(Ⅱ)for efficiently overcoming cancer drug resistance

The search of highly efficient drugs for overcoming cancer drug resistance continues to be a challenge for scientists.Constructing a metal drug based in situ oxidation-state transition system to disturb the redox balance in cancer cells is a promising approach for overcoming cancer drug resistance.Inspired by natural redox-active copper enzyme centers,we developed a Cu(Ⅰ)-Cu(Ⅱ) in situ transition system in this work.Through atom engineering,we fine-tuned the thermodynamic stability of this system to investigate its anticancer activity.The results indicated that the synthetic Cu(Ⅰ)-Cu(Ⅱ) system could under-go in situ transition in vitro and in vivo,to disrupt the intracellular redox balance and trigger mitochondrial dysfunction and G2/M arrest,leading to apoptosis and overcoming cancer drug resistance.This study presents a feasible way to overcome cancer drug resistance by designing an in situ oxidation-state transition metal drug system.

Exploring near-infrared absorbing nanocarriers to overcome cancer drug resistance

One of the major obstacles of successful cancer therapy is cancer drug resistance.The unique tools and applications developed by nanomedicine provide new approaches to surmount this common limitation of current treatment regimens.Nanocarriers that absorb light in the near-infrared spectrum are particularly suitable for this purpose.These nanocarriers can produce heat,release drugs or stimulate the production of physiologically relevant compounds when illuminated with near-infrared light.The current review summarizes the causes contributing to cancer multidrug resistance.The major types of nanocarriers that have been developed in recent years to overcome these hurdles are described.We focus on nanoparticles that are responsive to near-infrared light and suitable to surmount cancer multidrug resistance.Our review concludes with the bottlenecks that currently restrict the use of nanocarriers in the clinic and an outlook on future directions.

MicroRNAs and cancer drug resistance: over two thousand characters in search of a role

MicroRNAs(miRNAs),a group of small regulatory noncoding RNAs,transformed our thinking on gene regulation.More than two thousand human miRNAs have been identified thus far.These bind imperfectly to the 3’-untranslated region of target mRNA and have been involved in several pathological conditions including cancer.In fact,major hallmarks of cancer,such as the cell cycle,cell proliferation,survival and invasion are modulated by miRNAs.Cancer drug resistance(CDR)has also been described as being modulated by miRNAs.CDR remains a burden for cancer therapy and patients’outcome,often resulting in more aggressive tumours that tend to metastasize to distant organs.In this review we discuss the role of miRNAs influencing drug metabolism and drug influx/efflux,two important mechanisms of CDR.

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

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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.

In situ-prepared homogeneous supramolecular organic framework drug delivery systems(sof-DDSs)：Overcoming cancer multidrug resistance and controlled release

Water-soluble three-dimensional porous supramolecular organic frameworks（SOFs） have been demonstrated as a new generation of homogeneous polycationic platforms for anti-cancer drug delivery.The new SOF drug delivery systems（sof-DDSs） can adsorb dianionic pemetrexed（PMX）,a clinically used chemotherapeutic agent instantaneously upon dissolving in water,which is driven by both electrostatic attraction and hydrophobicity.The in situ-prepared PMX@SOFs are highly stable and can avoid important release of the drug during plasm circulation and overcome the multidrug resistance of human breast MCF-7/Adr cancer cells to enter the cancer cells.Acidic microenvironment of cancer cells promotes the release of the drug in cancer cells.Both in vitro and in vivo studies have revealed that sofDDSs considerably improve the treatment efficacy of PMX,leading to 6-12-fold reduction of the IC50 values,as compared with that of PMX alone.The new drug delivery strategy omits the loading process required by most of reported nanoparticle-based delivery systems and thus holds promise for future development of low-cost drug delivery systems

Wnt/b-catenin signaling plays an ever-expanding role in stem cell self-renewal,tumorigenesis and cancer chemoresistance

Wnt signaling transduces evolutionarily conserved pathways which play important roles in initiating and regulating a diverse range of cellular activities,including cell proliferation,calcium homeostasis,and cell polarity.The role of Wnt signaling in controlling cell proliferation and stem cell self-renewal is primarily carried out through the canonical pathway,which is the best-characterized the multiple Wnt signaling branches.The past 10 years has seen a rapid expansion in our understanding of the complexity of this pathway,as many new components of Wnt signaling have been identified and linked to signaling regulation,stem cell functions,and adult tissue homeostasis.Additionally,a substantial body of evidence links Wnt signaling to tumorigenesis of cancer types and implicates it in the development of cancer drug resistance.Thus,a better understanding of the mechanisms by which dysregulation of Wnt signaling precedes the development and progression of human cancer may hasten the development of pathway inhibitors to augment current therapy.This review summarizes and synthesizes our current knowledge of the canonical Wnt pathway in development and disease.We begin with an overview of the components of the canonical Wnt signaling pathway and delve into the role this pathway has been shown to play in stemness,tumorigenesis,and cancer drug resistance.Ultimately,we hope to present an organized collection of evidence implicating Wnt signaling in tumorigenesis and chemoresistance to facilitate the pursuit of Wnt pathway modulators that may improve outcomes of cancers in which Wnt signaling contributes to aggressive disease and/or treatment resistance.

Cell-mediated and cell membrane-coated nanoparticles for drug delivery and cancer therapy

Nanotechnology-based drug delivery platforms have been developed over the last two decades because of their favorable features in terms of improved drug bioavailability and stability.Despite recent advancement in nanotechnology platforms,this approach still falls short to meet the complexity of biological systems and diseases,such as avoiding systemic side effects,manipulating biological interactions and overcoming drug resistance,which hinders the therapeutic outcomes of the NP-based drug delivery systems.To address these issues,various strategies have been developed including the use of engineered cells and/or cell membrane-coated nanocarriers.Cell membrane receptor profiles and characteristics are vital in performing therapeutic functions,targeting,and homing of either engineered cells or cell membrane-coated nanocarriers to the sites of interest.In this context,we comprehensively discuss various cell-and cell membrane-based drug delivery approaches towards cancer therapy,the therapeutic potential of these strategies,and the limitations associated with engineered cells as drug carriers and cell membrane-associated drug nanocarriers.Finally,we review various cell types and cell membrane receptors for their potential in targeting,immunomodulation and overcoming drug resistance in cancer.

Molecular mechanisms of docetaxel resistance in prostate cancer

Docetaxel(DTX)chemotherapy offers excellent initial response and confers significant survival benefit in patients with castration-resistant prostate cancer(CRPC).However,the clinical utility of DTX is compromised when primary and acquired resistance are encountered.Therefore,a more thorough understanding of DTX resistance mechanisms may potentially improve survival in patients with CRPC.This review focuses on DTX and discusses its mechanisms of resistance.We outline the involvement of tubulin alterations,androgen receptor(AR)signaling/AR variants,ERG rearrangements,drug efflux/influx,cancer stem cells,centrosome clustering,and phosphoinositide 3-kinase/AKT signaling in mediating DTX resistance.Furthermore,potential biomarkers for DTX treatment and therapeutic strategies to circumvent DTX resistance are reviewed.

Molecular mechanisms of enzalutamide resistance in prostate cancer

An estimated 30,000 men in the United States will die of metastatic prostate cancer(PCa)each year due to the development of therapy resistance,most notably resistance to second-generation antiandrogen enzalutamide.The vast majority of PCa is driven by the androgen receptor(AR).Enzalutamide is an AR antagonist,which extends patient survival and is widely used in the clinic for the treatment of castration-resistant prostate cancer(CRPC);however,many patients will have primary or develop acquired resistance and continue to progress.Characterization of the molecular mechanisms of enzalutamide resistance provides insight into potentially efficacious therapies for enzalutamide-resistant CRPC(ER-CRPC).Understanding these mechanisms is critical for the identification of biomarkers predictive of therapy resistance and the development of therapeutic strategies to target ER-CRPC.

Near infrared light triggered nitric oxide releasing platform based on upconversion nanoparticles for synergistic therapy of cancer stem-like cells

Near infrared(NIR) light-driven nitric oxide(NO) release nano-platform based on upconversion nanoparticles(UCNPs) and light sensitive NO precursor Roussin's black salt(RBS) was fabricated to generate NO upon 808 nm irradiation. The application of 808 nm laser as the excitation source could achieve better penetration depth and avoid overheating problem. The combination of UCNPs and RBS could realize the on-demand release of NO at desired time and location by simply controlling the output of NIR laser.Cellular uptake results showed that more nanoparticles were internalized in cancer stem-like cells(CSCs)rather than non-CSCs. Therefore, a synergistic cancer therapy strategy to eradicate both CSCs and nonCSCs simultaneously was developed. Traditional chemo-drug could inhibit non-CSCs but has low killing efficiency in CSCs. However, we found that the combination of NO and chemotherapy could efficiently inhibit CSCs in bulk cells, including inhibiting mammosphere formation ability, decreasing CD44^+/CD24^- subpopulation and reducing tumorigenic ability. The mechanism studies confirmed that NO could not only induce apoptosis but also increase drug sensitivity by declining drug efflux in CSCs. This UCNPsbased platform may provide a new combinatorial strategy of NO and chemotherapy to improve cancer treatment.

Bulbine frutescens phytochemicals as novel ABC-transporter inhibitor:a molecular docking and molecular dynamics simulation study

Aim:The present in silico study aimed to evaluate the ATP-binding cassette(ABC)transporter inhibition potential of Bulbine frutescens(B.frutescens)phytochemicals.Methods:Several previous studies and databases were used to retrieve the ligands and target protein structure.The molecular docking study was performed using the Auto Dock Tools,and the GROMACS package was applied to accomplish molecular dynamics simulation.Results:Utilizing the molecular docking and simulation approach,~25 phytochemicals were screened against the ABC transporter protein.Docking score analysis revealed that B.frutescens phytochemical 4’-Demethylknipholone 2’-β-D-glucopyranoside exhibited strong binding on the ABC transporter protein with a minimum binding score-9.8 kcal/mol in comparison to the standard ABC transporter inhibitor diltiazem(-6.86 kcal/mol).Furthermore,molecular dynamics simulation for 4’-Demethylknipholone 2’-β-D-glucopyranoside showed an acceptable root mean square deviation,radius of gyration,root mean square fluctuation,and hydrogen bond,in addition to other lead compounds.Conclusion:The in-silico study demonstrated that B.frutescens phytochemical 4’-Demethylknipholone 2’-β-D-glucopyranoside possesses anti-drug resistance properties and requires further testing in preclinical settings.

Clinical significance of the loss of CD20 antigen on tumor cells in patients with relapsed or refractory follicular lymphoma

Aim:Anti-CD20 monoclonal antibody is a cornerstone therapy for follicular lymphoma.Following anti-CD20 therapy,a potential decrease in CD20 antigen,and therefore a loss of the tumor target might be expected.However,the incidence and clinical significance of CD20 loss on tumor cells in patients with relapsed or refractory follicular lymphoma are unknown.This study aims to investigate the incidence and outcome of patients with relapsed or refractory follicular lymphoma patients harboring the loss of the tumor target,CD20.Methods:All consecutive adult patients with relapsed or refractory follicular lymphoma referred to the Early Drug Department at Gustave Roussy were included.The main objectives were to assess the incidence and prognosis of the loss in expression of CD20 antigen on the surface of tumor cells on patient outcome.Results:Over the study period 2013-2018,131 patients were screened for clinical trials with B-cell malignancies in the early drug department of Gustave Roussy in France.Forty-four patients presented with relapsed or refractory follicular lymphoma and 32 had tumor biopsies at the time of relapse that were retained for analysis.The median(range)age was 67.5 years(55.3-75.3)and the median number of prior anti-cancer systemic therapies was 3(2-4).At the time of relapse,CD20 expression was positive in 84%of tumors(n=27)and negative in 16%of tumors(n=5).At a median follow-up of 18.3(0.6-83.3)months,CD20 negativity was associated with a poorer prognosis with a median overall survival of 8.9 months(95%CI:2.4-19.1)in comparison to CD20 positive patients(28.3 months,95%CI:25.1-75.3 months,P=0.019).Conclusion:The loss of the tumor target antigen,CD20,occurred in 16%of patients with relapse or refractory follicular lymphoma.Due to confounding factors in patients who received anti-CD20 immunotherapy,it was not possible to formally establish the prognostic significance of CD20 negativity.However,we suggest that a check for CD20 antigen positivity nevertheless be performed to adapt subsequent therapies for patients with relapsed or refractory follicular lymphoma.