Autophagy and multidrug resistance in cancer

Multidrug resistance(MDR) occurs frequently after long-term chemotherapy, resulting in refractory cancer and tumor recurrence.Therefore, combatting MDR is an important issue. Autophagy, a self-degradative system, universally arises during the treatment of sensitive and MDR cancer. Autophagy can be a double-edged sword for MDR tumors: it participates in the development of MDR and protects cancer cells from chemotherapeutics but can also kill MDR cancer cells in which apoptosis pathways are inactive. Autophagy induced by anticancer drugs could also activate apoptosis signaling pathways in MDR cells, facilitating MDR reversal. Therefore, research on the regulation of autophagy to combat MDR is expanding and is becoming increasingly important. We summarize advanced studies of autophagy in MDR tumors, including the variable role of autophagy in MDR cancer cells.

The reversal of antineoplastic drug resistance in cancer cells by B-elemene

Multidrug resistance(MDR), deined as the resistance of cancer cells to compounds with diverse structures and mechanisms of actions, signiicantly limits the eicacy of antitumor drugs. A major mechanism that mediates MDR in cancer is the overexpression of adenosine triphosphate(ATP)?binding cassette transporters. These transporters bind to their respective substrates and catalyze their elux from cancer cells, thereby lowering the intracellular concentra?tions of the substrates and thus attenuating or even abolishing their eicacy. In addition, cancer cells can become resistant to drugs via mechanisms that attenuate apoptosis and cell cycle arrest such as alterations in the p53, check point kinase, nuclear factor kappa B, and the p38 mitogen?activated protein kinase pathway. In this review, we discuss the mechanisms by which β?elemene, a compound extracted from Rhizoma zedoariae that has clinical antitumor eicacy, overcomes drug resistance in cancer.

ATP-binding cassette subfamily B member 1 (ABCB1) and subfamily C member 10(ABCC1O) are not primary resistance factors for cabazitaxel

Introduction:ATP-binding cassette subfamily B member 1(ABCB1) and subfamily C member 10(ABCCIO) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substances and chemotherapeutic drugs out of cells.Cabazitaxel is a novel taxane that differs from paclitaxel by its lower affinity for ATP-binding cassette(ABC) transporters.Methods:We determined the effects of cabazitaxel,a novel tubulin-binding taxane,and paclitaxel on paclitaxelresistant,ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells and paclitaxel-resistant,ABCC10-overexpressing HEK293/ABCC10 cells by calculating the degree of drug resistance and measuring ATPase activity of the ABCB1 transporter.Results:Decreased resistance to cabazitaxel compared with paclitaxel was observed in KB-C2,LLC-MDR1-WT,and HEK293/ABCC10 cells.Moreover,cabazitaxel had low efficacy,whereas paclitaxel had high efficacy in stimulating the ATPase activity of ABCB1,indicating a direct interaction of both drugs with the transporter.Conclusion:ABCB1 and ABCC10 are not primary resistance factors for cabazitaxel compared with paclitaxel,suggesting that cabazitaxel may have a low affinity for these efflux transporters.

Recent advances regarding the role of ABC subfamily C member 10(ABCC10) in the efflux of antitumor drugs

ABCC10,also known as multidrug-resistant protein 7(MRP7),is the tenth member of the C subfamily of the ATP-binding cassette(ABC) superfamily.ABCC10 mediates multidrug resistance(MDR) in cancer cells by preventing the intracellular accumulation of certain antitumor drugs.The ABCC10 transporter is a 171-kDa protein that is localized on the basolateral cell membrane.ABCC10 is a broad-specificity transporter of xenobiotics,including antitumor drugs,such as taxanes,epothilone B,vinca alkaloids,and cytarabine,as well as modulators of the estrogen pathway,such as tamoxifen.In recent years,ABCC10 inhibitors,including cepharanthine,lapatinib,erlotinib,nilotinib,imatinib,sildenafil,and vardenafil,have been reported to overcome ABCC10-mediated MDR.This review discusses some recent and clinically relevant aspects of the ABCC10 drug efflux transporter from the perspective of current chemotherapy,particularly its inhibition by tyrosine kinase inhibitors and phosphodiesterase type 5 inhibitors.

Sulindac sulfide selectively increases sensitivity of ABCC1 expressing tumor cells to doxorubicin and glutathione depletion

ATP-binding cassette（ABC） transporters ABCC1（MRP1）,ABCB1（P-gp）,and ABCG2（BCRP） contribute to chemotherapy failure.The primary goals of this study were to characterize the efficacy and mechanism of the nonsteroidal anti-inflammatory drug（NSAID）,sulindac sulfide,to reverse ABCC1 mediated resistance to chemotherapeutic drugs and to determine if sulindac sulfide can influence sensitivity to chemotherapeutic drugs independently of drug efflux.Cytotoxicity assays were performed to measure resistance of ABC-expressing cell lines to doxorubicin and other chemotherapeutic drugs.NSAIDs were tested for the ability to restore sensitivity to resistance selected tumor cell lines,as well as a large panel of standard tumor cell lines.Other experiments characterized the mechanism by which sulindac sulfide inhibits ABCC1 substrate and co-substrate（GSH） transport in isolated membrane vesicles and intact cells.Selective reversal of multi-drug resistance（MDR）,decreased efflux of doxorubicin,and fluorescent substrates were demonstrated by sulindac sulfide and a related NSAID,indomethacin,in resistance selected and engineered cell lines expressing ABCC 1,but not ABCB 1 or ABCG2.Sulindac sulfide also inhibited transport of leukotriene C_4 into membrane vesicles.Sulindac sulfide enhanced the sensitivity to doxorubicin in 24 of 47 tumor cell lines,including all melanoma lines tested（7-7）.Sulindac sulfide also decreased intracellular GSH in ABCC1 expressing cells,while the glutathione synthesis inhibitor,BSO,selectively increased sensitivity to sulindac sulfide induced cytotoxicity.Sulindac sulfide potently and selectively reverses ABCC1-mediated MDR at clinically achievable concentrations.ABCC1 expressing tumors may be highly sensitive to the direct cytotoxicity of sulindac sulfide,and in combination with chemotherapeutic drugs that induce oxidative stress.

Design,synthesis and biological evaluation of selective survivin inhibitors

The differential distribution between cancer cells and normal adult tissues makes survivin a very attractive cancer drug target. We have previously reported a series of novel selective survivin inhibitors with the most potent compound MX 106 reaching nanomolar activity in several cancer cell lines. Further optimization of the MX 106 scaffold leads to the discovery of more potent and more selective survivin inhibitors. Various structural modifications were synthesized and their anticancer activities were evaluated to determine the structure activity relationships for this MX 106 scaffold. In vitro anti-proliferative assays using two human melanoma cell lines showed that several new analogs have improved potency compared to MX 106. Very interestingly, these new analogs generally showed significantly higher potency against P-glycoprotein overexpressed cells compared with the corresponding parental cells, suggesting that these compounds may strongly sensitize tumors that have high expressions of the Pglycoprotein drug efflux pumps. Western blotting analysis confirmed that the new MX 106 analogs maintained their mechanism of actions by selectively suppressing survivin expression level among major inhibitors of apoptotic proteins and induced strong apoptosis in melanoma tumor cells.

Nanotechnology-based delivery systems to overcome drug resistance in cancer

Cancer nanomedicine is defined as the application of nanotechnology and nanomaterials for the formulation of cancer therapeutics that can overcome the impediments and restrictions of traditional chemotherapeutics.Multidrug resistance(MDR)in cancer cells can be defined as a decrease or abrogation in the efficacy of anticancer drugs that have different molecular structures and mechanisms of action and is one of the primary causes of therapeutic failure.There have been successes in the development of cancer nanomedicine to overcome MDR;however,relatively few of these formulations have been approved by the United States Food and Drug Administration for the treatment of cancer.This is primarily due to the paucity of knowledge about nanotechnology and the fundamental biology of cancer cells.Here,we discuss the advances,types of nanomedicines,and the challenges regarding the translation of in vitro to in vivo results and their relevance to effective therapies.

Dostarlimab in the treatment of mismatch repair deficient recurrent or advanced endometrial cancer

Dostarlimab,a programmed death receptor-1(PD-1)-blocking IgG4 humanized monoclonal antibody,gained accelerated approval from the US Food and Drug Administration(FDA)in April 2021,and received a full approval in February 2023.Dostarlimab was approved for treating adult patients with mismatch repair deficient(dMMR)recurrent or advanced endometrial cancer(EC)that progressed during or after prior treatment who have no other suitable treatment options.Herein,we review the structure-based mechanism of action of dostarlimab and the results of a clinical study(GARNET;NCT02715284)to comprehensively clarify the efficacy and toxicity of the drug.The efficacy and safety of dostarlimab as monotherapy was assessed in a non-randomized,multicenter,open-label,multi-cohort trial that included 209 patients with dMMR recurrent or advanced solid tumors after receiving systemic therapy.Patients received 500 mg of dostarlimab intravenously every three weeks until they were given four doses.Then,patients received 1000 mg dostarlimab intravenously every six weeks until disease progression or unacceptable toxicity.The overall response rate,as determined by shrinkage in tumor size,was 41.6%(95%confidence interval[CI];34.9,48.6),with 34.7 months as the median response duration.In conclusion,dostarlimab is an immunotherapy-based drug that has shown promising results in adult patients with recurrent or advanced dMMR EC.However,its efficacy in other cancer subtypes,the development of resistance to monotherapy,and efficacy and safety in combination with other immunotherapeutic drugs have not yet been studied.

Progress in the studies on the molecular mechanisms associated with multidrug resistance in cancers

Chemotherapy is one of the important methods to treat cancer,and the emergence of multidrug resistance(MDR)is one major cause for the failure of cancer chemotherapy.Almost all anti-tumor drugs develop drug resistance over a period of time of application in cancer patients,reducing their effects on killing cancer cells.Chemoresistance can lead to a rapid recurrence of cancers and ultimately patient death.MDR may be induced by multiple mechanisms,which are associated with a complex process of multiple genes,factors,pathways,and multiple steps,and today the MDR-associated mechanisms are largely unknown.In this paper,from the aspects of protein–protein interactions,alternative splicing(AS)in pre-mRNA,non-coding RNA(ncRNA)mediation,genome mutations,variance in cell functions,and influence from the tumor microenvironment,we summarize the molecular mechanisms associated with MDR in cancers.In the end,prospects for the exploration of antitumor drugs that can reverse MDR are briefly discussed from the angle of drug systems with improved targeting properties,biocompatibility,availability,and other advantages.

Tumor cell plasticity in targeted therapy-induced resistance:mechanisms and new strategies

Despite the success of targeted therapies in cancer treatment,therapy-induced resistance remains a major obstacle to a completecure.Tumor cells evade treatments and relapse via phenotypic switching driven by intrinsic or induced cell plasticity.Severalreversible mechanisms have been proposed to circumvent tumor cell plasticity,including epigenetic modifications,regulation oftranscription factors,activation or suppression of key signaling pathways,as well as modification of the tumor environment.Epithelial-to-mesenchymal transition,tumor cell and cancer stem cell formation also serve as roads towards tumor cell plasticity.Corresponding treatment strategies have recently been developed that either target plasticity-related mechanisms or employcombination treatments.In this review,we delineate the formation of tumor cell plasticity and its manipulation of tumor evasionfrom targeted therapy.We discuss the non-genetic mechanisms of targeted drug-induced tumor cell plasticity in various types oftumors and provide insights into the contribution of tumor cell plasticity to acquired drug resistance.New therapeutic strategiessuch as inhibition or reversal of tumor cell plasticity are also presented.We also discuss the multitude of clinical trials that areongoing worldwide with the intention of improving clinical outcomes.These advances provide a direction for developing noveltherapeutic strategies and combination therapy regimens that target tumor cell plasticity.

Stellettin B renders glioblastoma vulnerable to poly (ADPribose) polymerase inhibitors via suppressing homologydirected repair

Dear Editor,Glioblastoma(GBM)is one of the most fatal brain tumors.Current first-line post-surgery regimens for GBM including radiotherapy and temozolomide(TMZ)chemotherapy show very limited efficacy.1,2 Novel therapeutic approaches for GBM patients are urgently needed.Natural products are important sources for drug discovery,especially in the field of cancer treatment.3 We previously isolated stellettin B(STELB)(Fig.1a)from marine sponge(Jaspis stellifera)and reported the remarkable and specific anticancer activities.Recently,a series of stellettins has been totally synthesized and the core chemical structure has been indicated.4 However,the specific mechanism and its role in regulating tumor biology remain largely unknown.

Detailed resume of RNA m^(6)A demethylases

N6-Methyladenosine(m^(6)A) is the most abundant internal modification in eukaryotic mRNA,playing critical role in various bioprocesses. Like other epigenetic modifications, m^(6)A modification can be catalyzed by the methyltransferase complex and erased dynamically to maintain cells homeostasis. Up to now, only two m^(6)A demethylases have been reported, fat mass and obesity-associated protein(FTO)and alkylation protein AlkB homolog 5(ALKBH5), involving in a wide range of mRNA biological progress, including mRNA shearing, export, metabolism and stability. Furthermore, they participate in many significantly biological signaling pathway, and contribute to the progress and development of cancer along with other diseases. In this review, we focus on the studies about structure, inhibitors development and biological function of FTO and ALKBH5.

Microbiota in health and diseases

The role of microbiota in health and diseases is being highlighted by numerous studies since its discovery.Depending on the localized regions,microbiota can be classified into gut,oral,respiratory,and skin microbiota.The microbial communities are in symbiosis with the host,contributing to homeostasis and regulating immune function.However,microbiota dysbiosis can lead to dysregulation of bodily functions and diseases including cardiovascular diseases(CVDs),cancers,respiratory diseases.

Signaling pathways and therapeutic interventions in gastric cancer

Gastric cancer(GC)ranks fifth in global cancer diagnosis and fourth in cancer-related death.Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival,the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages,which leads to unsatisfactory prognosis and high recurrence rates.With the recent advances in genome analysis,biomarkers have been identified that have clinical importance for GC diagnosis,treatment,and prognosis.Modern molecular classifications have uncovered the vital roles that signaling pathways,including EGFR/HER2,p53,PI3K,immune checkpoint pathways,and cell adhesion signaling molecules,play in GC tumorigenesis,progression,metastasis,and therapeutic responsiveness.These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients.Nevertheless,the relative significance,temporal activation,interaction with GC risk factors,and crosstalk between these signaling pathways in GC are not well understood.Here,we review the regulatory roles of signaling pathways in GC potential biomarkers,and therapeutic targets with an emphasis on recent discoveries.Current therapies,including signaling-based and immunotherapies exploited in the past decade,and the development of treatment for GC,particularly the challenges in developing precision medications,are discussed.These advances provide a direction for the integration of clinical,molecular,and genomic profiles to improve GC diagnosis and treatments.

The epigallocatechin gallate derivative Y_6 reverses drug resistance mediated by the ABCB1 transporter both in vitro and in vivo

Previously, we reported that Y_6, a new epigallocatechin gallate derivative, is efficacious in reversing doxorubicin(DOX)–mediated resistance in hepatocellular carcinoma BEL-7404/DOX cells. In this study, we evaluated the efficacy of Y_6 in reversing drug resistance both in vitro and in vivo by determining its effect on the adenosine triphosphate-binding cassette protein B1 transporter(ABCB1 or P-glycoprotein, P-gp). Our results showed that Y_6 significantly sensitized cells overexpressing the ABCB1 transporter to anticancer drugs that are ABCB1 substrates. Y_6 significantly stimulated the adenosine triphosphatase activity of ABCB1. Furthermore, Y_6 exhibited a higher docking score as compared with epigallocatechin gallate inside the transmembrane domain of ABCB1. In addition, in the nude mousetumor xenograft model, Y_6(110 mg/kg, intragastric administration), in combination with doxorubicin(2 mg/kg, intraperitoneal injection), significantly inhibited the growth of BEL-7404/DOX cell xenograft tumors, compared to equivalent epigallocatechin gallate. In conclusion, Y_6 significantly reversed ABCB1-mediated multidrug resistance and its mechanisms of action may result from its competitive inhibition of the ABCB1 drug efflux function.

Establishment and characterization of arsenic trioxide resistant KB/ATO cells

Arsenic trioxide(ATO) is used as a chemotherapeutic agent for the treatment of acute promyelocytic leukemia. However, increasing drug resistance is reducing its efficacy. Therefore, a better understanding of ATO resistance mechanism is required. In this study, we established an ATO-resistant human epidermoid carcinoma cell line, KB/ATO, from its parental KB-3-1 cells. In addition to ATO, KB/ATO cells also exhibited cross-resistance to other anticancer drugs such as cisplatin, antimony potassium tartrate, and 6-mercaptopurine. The arsenic accumulation in KB/ATO cells was significantly lower than that in KB-3-1 cells. Further analysis indicated that neither application of P-glycoprotein inhibitor, breast cancer resistant protein(BCRP) inhibitor, or multidrug resistance protein 1(MRP1) inhibitor could eliminate ATO resistance. We found that the expression level of ABCB6 was increased in KB/ATO cells.In conclusion, ABCB6 could be an important factor for ATO resistance in KB/ATO cells. The ABCB6 level may serve as a predictive biomarker for the effectiveness of ATO therapy.

PD173074, a selective FGFR inhibitor, reverses MRP7 (ABCC10)-mediated MDR

Multidrug resistance protein 7(MRP7,ABCC10)is a recently identified member of the ATP-binding cassette(ABC)transporter family,which adequately confers resistance to a diverse group of antineoplastic agents,including taxanes,vinca alkaloids and nucleoside analogs among others.Clinical studies indicate an increased MRP7 expression in non-small cell lung carcinomas(NSCLC)compared to a normal healthy lung tissue.Recent studies revealed increased paclitaxel sensitivity in the Mrp7^(-/-)mouse model compared to their wild-type counterparts.This demonstrates that MRP7 is a key contributor in developing drug resistance.Recently our group reported that PD173074,a specific fibroblast growth factor receptor(FGFR)inhibitor,could significantly reverse P-glycoprotein-mediated MDR.However,whether PD173074 can interact with and inhibit other MRP members is unknown.In the present study,we investigated the ability of PD173074 to reverse MRP7-mediated MDR.We found that PD173074,at non-toxic concentration,could significantly increase the cellular sensitivity to MRP7 substrates.Mechanistic studies indicated that PD173074(1μmol/L)significantly increased the intracellular accumulation and in-turn decreased the efflux of paclitaxel by inhibiting the transport activity without altering expression levels of the MRP7 protein,thereby representing a promising therapeutic agent in the clinical treatment of chemoresistant cancer patients.

Epitranscriptomics and epiproteomics in cancer drug resistance:therapeutic implications

Drug resistance is a major hurdle in cancer treatment and a key cause of poor prognosis.Epitranscriptomics and epiproteomics are crucial in cell proliferation,migration,invasion,and epithelial–mesenchymal transition.In recent years,epitranscriptomic and epiproteomic modification has been investigated on their roles in overcoming drug resistance.In this review article,we summarized the recent progress in overcoming cancer drug resistance in three novel aspects:(i)mRNA modification,which includes alternative splicing,A-to-I modification and mRNA methylation;(ii)noncoding RNAs modification,which involves miRNAs,lncRNAs,and circRNAs;and(iii)posttranslational modification on molecules encompasses drug inactivation/efflux,drug target modifications,DNA damage repair,cell death resistance,EMT,and metastasis.In addition,we discussed the therapeutic implications of targeting some classical chemotherapeutic drugs such as cisplatin,5-fluorouridine,and gefitinib via these modifications.Taken together,this review highlights the importance of epitranscriptomic and epiproteomic modification in cancer drug resistance and provides new insights on potential therapeutic targets to reverse cancer drug resistance.

Repurposing FDA-approved drugs for SARS- CoV-2 through an ELISA-based screening for the inhibition of RBD/ACE2 interaction

Dear Editor,The ongoing coronavirus disease 2019(COVID-19)global pandemic is caused by a novel coronavirus,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which instigates severe and often fatal symptoms.As of September 4th,2020,more than 26 million cases of COVID-19 and almost 900,000 deaths have been reported to WHO.Based on Kissler and colleagues’modeled projections of future viral transmission scenarios,a resurgence in SARS-CoV-2 could occur over the next five years(Kissler et al.,2020).

MET inhibitor tepotinib antagonizes multidrug resistance mediated by ABCG2 transporter:In vitro and in vivo study

Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance(MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor,tepotinib, is a potent reversal agent for ABCB1-mediated MDR. In the present study, we reported for the first time that the MET inhibitor tepotinib can also reverse ABCG2-mediated MDR in vitro and in vivo by directly binding to the drug-binding site of ABCG2 and reversibly inhibiting ABCG2 drug efflux activity, therefore enhancing the cytotoxicity of substrate drugs in drug-resistant cancer cells. Furthermore, the ABCB1/ABCG2 double-transfected cell model and ABCG2 gene knockout cell model demonstrated that tepotinib specifically inhibits the two MDR transporters. In mice bearing drug-resistant tumors, tepotinib increased the intratumoral accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect. Therefore, our study provides a new potential of repositioning tepotinib as an ABCG2 inhibitor and combining tepotinib with substrate drugs to antagonize ABCG2-mediated MDR.