Circulating tumor cells shielded with extracellular vesicle-derived CD45 evade T cell attack to enable metastasis.

Circulating tumor cells (CTCs) are precursors of distant metastasis in a subset of cancer patients. A better understanding of CTCs heterogeneity and how these CTCs survive during hematogenous dissemination could lay the foundation for therapeutic prevention of cancer metastasis. It remains elusive how CTCs evade immune surveillance and elimination by immune cells. In this study, we unequivocally identified a subpopulation of CTCs shielded with extracellular vesicle (EVs)-derived CD45 (termed as CD45+ CTCs) that resisted T cell attack. A higher percentage of CD45+ CTCs was found to be closely correlated with higher incidence of metastasis and worse prognosis in cancer patients. Moreover, CD45+ tumor cells orchestrated an immunosuppressive milieu and CD45+ CTCs exhibited remarkably stronger metastatic potential than CD45- CTCs in vivo. Mechanistically, CD45 expressing on tumor surfaces was shown to form intercellular CD45-CD45 homophilic interactions with CD45 on T cells, thereby preventing CD45 exclusion from TCR-pMHC synapse and leading to diminished TCR signaling transduction and suppressed immune response. Together, these results pointed to an underappreciated capability of EVs-derived CD45-dressed CTCs in immune evasion and metastasis, providing a rationale for targeting EVs-derived CD45 internalization by CTCs to prevent cancer metastasis.

Utilizing non-coding RNA-mediated regulation of ATP binding cassette (ABC) transporters to overcome multidrug resistance to cancer chemotherapy.

Multidrug resistance (MDR) is one of the primary factors that produces treatment failure in patients receiving cancer chemotherapy. MDR is a complex multifactorial phenomenon, characterized by a decrease or abrogation of the efficacy of a wide spectrum of anticancer drugs that are structurally and mechanistically distinct. The overexpression of the ATP-binding cassette (ABC) transporters, notably ABCG2 and ABCB1, are one of the primary mediators of MDR in cancer cells, which promotes the efflux of certain chemotherapeutic drugs from cancer cells, thereby decreasing or abolishing their therapeutic efficacy. A number of studies have suggested that non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), play a pivotal role in mediating the upregulation of ABC transporters in certain MDR cancer cells. This review will provide updated information about the induction of ABC transporters due to the aberrant regulation of ncRNAs in cancer cells. We will also discuss the measurement and biological profile of circulating ncRNAs in various body fluids as potential biomarkers for predicting the response of cancer patients to chemotherapy. Sequence variations, such as alternative polyadenylation of mRNA and single nucleotide polymorphism (SNPs) at miRNA target sites, which may indicate the interaction of miRNA-mediated gene regulation with genetic variations to modulate the MDR phenotype, will be reviewed. Finally, we will highlight novel strategies that could be used to modulate ncRNAs and circumvent ABC transporter-mediated MDR.

A thermosensitive hydrogel formulation of phage and colistin combination for the management of multidrug-resistant Acinetobacter baumannii wound infections.

Chronic skin wounds are often associated with multidrug-resistant bacteria, impeding the healing process. Bacteriophage (phage) therapy has been revitalized as a promising strategy to counter the growing concerns of antibiotic resistance. However, phage monotherapy also faces several application drawbacks, such as a narrow host spectrum, the advent of resistant phenotypes and poor stability of phage preparations. Phage-antibiotic synergistic (PAS) combination therapy has recently been suggested as a possible approach to overcome these shortcomings. In the present study, we employed a model PAS combination containing a vB_AbaM-IME-AB2 phage and colistin to develop stable wound dressings of PAS to mitigate infections associated with Acinetobacter baumannii. A set of thermosensitive hydrogels were synthesized with varying amounts of Pluronic® F-127 (PF-127 at 15, 17.5 and 20 w/w%) modified with/without 3 w/w% hydroxypropyl methylcellulose (HPMC). Most hydrogel formulations had a gelation temperature around skin temperature, suitable for topical application. The solidified gels were capable of releasing the encapsulated phage and colistin in a sustained manner to kill bacteria. The highest bactericidal effect was achieved with the formulation containing 17.5% PF-127 and 3% HPMC (F5), which effectively killed bacteria in both planktonic (by 5.66 log) and biofilm (by 3 log) states and inhibited bacterial regrowth. Good storage stability of F5 was also noted with negligible activity loss after 9 months of storage at 4 °C. The ex vivo antibacterial efficacy of the F5 hydrogel formulation was also investigated in a pork skin wound infection model, where it significantly reduced the bacterial burden by 4.65 log. These positive outcomes warrant its further development as a topical PAS-wound dressing.

Erratum: CM082 Enhances the Efficacy of Chemotherapeutic Drugs by Inhibiting the Drug Efflux Function of ABCG2.

[This corrects the article DOI: 10.1016/j.omto.2019.12.007.].

Circumvention of Gefitinib Resistance by Repurposing Flunarizine via Histone Deacetylase Inhibition.

Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) for treating advanced non-small cell lung cancer (NSCLC). However, drug resistance seriously impedes the clinical efficacy of gefitinib. This study investigated the repositioning of the non-oncology drug capable of inhibiting histone deacetylases (HDACs) to overcome gefitinib resistance. A few drug candidates were identified using the in silico repurposing tool "DRUGSURV" and tested for HDAC inhibition. Flunarizine, originally indicated for migraine prophylaxis and vertigo treatment, was selected for detailed investigation in NSCLC cell lines harboring a range of different gefitinib resistance mechanisms (EGFR T790M, KRAS G12S, MET amplification, or PTEN loss). The circumvention of gefitinib resistance by flunarizine was further demonstrated in an EGFR TKI (erlotinib)-refractory patient-derived tumor xenograft (PDX) model in vivo. The acetylation level of cellular histone protein was increased by flunarizine in a concentration- and time-dependent manner. Among the NSCLC cell lines evaluated, the extent of gefitinib resistance circumvention by flunarizine was found to be the most pronounced in EGFR T790M-bearing H1975 cells. The gefitinib-flunarizine combination was shown to induce the apoptotic protein Bim but reduce the antiapoptotic protein Bcl-2, which apparently circumvented gefitinib resistance. The induction of Bim by flunarizine was accompanied by an increase in the histone acetylation and E2F1 interaction with the BIM gene promoter. Flunarizine was also found to upregulate E-cadherin but downregulate the vimentin expression, which subsequently inhibited cancer cell migration and invasion. Importantly, flunarizine was also shown to significantly potentiate the tumor growth suppressive effect of gefitinib in EGFR TKI-refractory PDX in vivo. The findings advocate for the translational application of flunarizine to circumvent gefitinib resistance in the clinic.

Drug Repurposing to Circumvent Immune Checkpoint Inhibitor Resistance in Cancer Immunotherapy.

Immune checkpoint inhibitors (ICI) have achieved unprecedented clinical success in cancer treatment. However, drug resistance to ICI therapy is a major hurdle that prevents cancer patients from responding to the treatment or having durable disease control. Drug repurposing refers to the application of clinically approved drugs, with characterized pharmacological properties and known adverse effect profiles, to new indications. It has also emerged as a promising strategy to overcome drug resistance. In this review, we summarized the latest research about drug repurposing to overcome ICI resistance. Repurposed drugs work by either exerting immunostimulatory activities or abolishing the immunosuppressive tumor microenvironment (TME). Compared to the de novo drug design strategy, they provide novel and affordable treatment options to enhance cancer immunotherapy that can be readily evaluated in the clinic. Biomarkers are exploited to identify the right patient population to benefit from the repurposed drugs and drug combinations. Phenotypic screening of chemical libraries has been conducted to search for T-cell-modifying drugs. Genomics and integrated bioinformatics analysis, artificial intelligence, machine and deep learning approaches are employed to identify novel modulators of the immunosuppressive TME.

Sequential treatment effects on phage-antibiotic synergistic application against multi-drug-resistant Acinetobacter baumannii.

Bacteriophage (phage) therapy, exploiting phages which are the natural enemies of bacteria, has been re-introduced to treat multidrug-resistant (MDR) bacterial infections. However, some intrinsic drawbacks of phages are overshadowing their clinical use, particularly the narrow host spectrum and rapid emergence of resistance upon treatment. The use of phage-antibiotic combinations exhibiting synergistic bacterial killing [termed 'phage-antibiotic synergy' (PAS)] has therefore been proposed. It is well reported that the types and doses of phages and antibiotics are critical in achieving PAS. However, the impact of treatment order has received less research attention. As such, this study used an Acinetobacter baumannii phage vB_AbaM-IME-AB2 and colistin as a model PAS combination to elucidate the order effects in-vitro. While application of the phage 8 h before colistin treatment demonstrated the greatest antibacterial synergy, it failed to prevent the development of phage resistance. On the other hand, simultaneous application and antibiotic followed by phage application were able to suppress/delay the development of resistance effectively, and simultaneous application demonstrated superior antibacterial and antibiofilm activities. Further in-vivo investigation is required to confirm the impact of treatment order on PAS.

BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications.

The mammalian bromodomain and extra-terminal domain (BET) family of proteins consists of four conserved members (Brd2, Brd3, Brd4, and Brdt) that regulate numerous cancer-related and immunity-associated genes. They are epigenetic readers of histone acetylation with broad specificity. BET proteins are linked to cancer progression due to their interaction with numerous cellular proteins including chromatin-modifying factors, transcription factors, and histone modification enzymes. The spectacular growth in the clinical development of small-molecule BET inhibitors underscores the interest and importance of this protein family as an anticancer target. Current approaches targeting BET proteins for cancer therapy rely on acetylation mimics to block the bromodomains from binding chromatin. However, bromodomain-targeted agents are suffering from dose-limiting toxicities because of their effects on other bromodomain-containing proteins. In this review, we provided an updated summary about the evolution of small-molecule BET inhibitors. The design of bivalent BET inhibitors, kinase and BET dual inhibitors, BET protein proteolysis-targeting chimeras (PROTACs), and Brd4-selective inhibitors are discussed. The novel strategy of targeting the unique C-terminal extra-terminal (ET) domain of BET proteins and its therapeutic significance will also be highlighted. Apart from single agent treatment alone, BET inhibitors have also been combined with other chemotherapeutic modalities for cancer treatment demonstrating favorable clinical outcomes. The investigation of specific biomarkers for predicting the efficacy and resistance of BET inhibitors is needed to fully realize their therapeutic potential in the clinical setting.

CD39/CD73/A2AR pathway and cancer immunotherapy.

Cancer development is closely associated with immunosuppressive tumor microenvironment (TME) that attenuates antitumor immune responses and promotes tumor cell immunologic escape. The sequential conversion of extracellular ATP into adenosine by two important cell-surface ectonucleosidases CD39 and CD73 play critical roles in reshaping an immunosuppressive TME. The accumulated extracellular adenosine mediates its regulatory functions by binding to one of four adenosine receptors (A1R, A2AR, A2BR and A3R). The A2AR elicits its profound immunosuppressive function via regulating cAMP signaling. The increasing evidence suggests that CD39, CD73 and A2AR could be used as novel therapeutic targets for manipulating the antitumor immunity. In recent years, monoclonal antibodies or small molecule inhibitors targeting the CD39/CD73/A2AR pathway have been investigated in clinical trials as single agents or in combination with anti-PD-1/PD-L1 therapies. In this review, we provide an updated summary about the pathophysiological function of the adenosinergic pathway in cancer development, metastasis and drug resistance. The targeting of one or more components of the adenosinergic pathway for cancer therapy and circumvention of immunotherapy resistance are also discussed. Emerging biomarkers that may be used to guide the selection of CD39/CD73/A2AR-targeting treatment strategies for individual cancer patients is also deliberated.

Repurposing of triamterene as a histone deacetylase inhibitor to overcome cisplatin resistance in lung cancer treatment.

PURPOSE: Cisplatin is the core chemotherapeutic drug used for first-line treatment of advanced non-small cell lung cancer (NSCLC). However, drug resistance is severely hindering its clinical efficacy. This study investigated the circumvention of cisplatin resistance by repurposing non-oncology drugs with putative histone deacetylase (HDAC) inhibitory effect. METHODS: A few clinically approved drugs were identified by a computational drug repurposing tool called "DRUGSURV" and evaluated for HDAC inhibition. Triamterene, originally indicated as a diuretic, was chosen for further investigation in pairs of parental and cisplatin-resistant NSCLC cell lines. Sulforhodamine B assay was used to evaluate cell proliferation. Western blot analysis was performed to examine histone acetylation. Flow cytometry was used to examine apoptosis and cell cycle effects. Chromatin immunoprecipitation was conducted to investigate the interaction of transcription factors to the promoter of genes regulating cisplatin uptake and cell cycle progression. The circumvention of cisplatin resistance by triamterene was further verified in a patient-derived tumor xenograft (PDX) from a cisplatin-refractory NSCLC patient. RESULTS: Triamterene was found to inhibit HDACs. It was shown to enhance cellular cisplatin accumulation and potentiate cisplatin-induced cell cycle arrest, DNA damage, and apoptosis. Mechanistically, triamterene was found to induce histone acetylation in chromatin, thereby reducing the association of HDAC1 but promoting the interaction of Sp1 with the gene promoter of hCTR1 and p21. Triamterene was further shown to potentiate the anti-cancer effect of cisplatin in cisplatin-resistant PDX in vivo. CONCLUSION: The findings advocate further clinical evaluation of the repurposing use of triamterene to overcome cisplatin resistance.

Exosome secretion from hypoxic cancer cells reshapes the tumor microenvironment and mediates drug resistance.

Hypoxia is a common phenomenon in solid tumors as the poorly organized tumor vasculature cannot fulfill the increasing oxygen demand of rapidly expanding tumors. Under hypoxia, tumor cells reshape their microenvironment to sustain survival, promote metastasis, and develop resistance to therapy. Exosomes are extracellular vesicles secreted by most eukaryotic cells, including tumor cells. They are enriched with a selective collection of nucleic acids and proteins from the originating cells to mediate cell-to-cell communication. Accumulating evidence suggests that exosomes derived from tumor cells play critical roles in modulating the tumor microenvironment (TME). Hypoxia is known to stimulate the secretion of exosomes from tumor cells, thereby promoting intercellular communication of hypoxic tumors with the surrounding stromal tissues. Exosome-mediated signaling pathways under hypoxic conditions have been reported to cause angiogenesis, invasion, metastasis, drug resistance, and immune escape. Recently, the programmed cell death ligand-1 (PD-L1) has been reported to reside as a transmembrane protein in tumor exosomes. Exosomal PD-L1 was shown to suppress T cell effector function in the TME and cause drug resistance to immune checkpoint therapy. This review provides an update about the pivotal role of tumor-derived exosomes in drug resistance to chemotherapy and immunotherapy, particularly under hypoxic conditions. Emerging strategies that target the exosomes in the hypoxic TME to enhance the antitumor efficacy are discussed.

Mesenchymal Epithelial Transition (MET): A Key Player in Chemotherapy Resistance and an Emerging Target for Potentiating Cancer Immunotherapy.

The MET protein is a cell surface receptor tyrosine kinase predominately expressed in epithelial cells. Upon binding of its only known ligand, hepatocyte growth factor (HGF), MET homodimerizes, phosphorylates, and stimulates intracellular signalling to drive cell proliferation. Amplification or hyperactivation of MET is frequently observed in various cancer types and it is associated with poor response to conventional and targeted chemotherapy. More recently, emerging evidence also suggests that MET/HGF signalling may play an immunosuppressive role and it could confer resistance to cancer immunotherapy. In this review, we summarized the preclinical and clinical evidence of MET's role in drug resistance to conventional chemotherapy, targeted therapy, and immunotherapy. Previous clinical trials investigating MET-targeted therapy in unselected or METoverexpressing cancers yielded mostly unfavourable results. More recent clinical studies focusing on MET exon 14 alterations and MET amplification have produced encouraging treatment responses to MET inhibitor therapy. The translational relevance of MET inhibitor therapy to overcome drug resistance in cancer patients is discussed.

WITHDRAWN: Pretomanid for the treatment of Mycobacterium tuberculosis: Evidence on the development and clinical roles.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

The Influence of Formulation Components and Environmental Humidity on Spray-Dried Phage Powders for Treatment of Respiratory Infections Caused by Acinetobacter baumannii.

The feasibility of using respirable bacteriophage (phage) powder to treat lung infections has been demonstrated in animal models and clinical studies. This work investigated the influence of formulation compositions and excipient concentrations on the aerosol performance and storage stability of phage powder. An anti-Acinetobacter baumannii phage vB_AbaM-IME-AB406 was incorporated into dry powders consisting of trehalose, mannitol and L-leucine for the first time. The phage stability upon the spray-drying process, room temperature storage and powder dispersion under different humidity conditions were assessed. In general, powders prepared with higher mannitol content (40% of the total solids) showed a lower degree of particle merging and no sense of stickiness during sample handling. These formulations also provided better storage stability of phage with no further titer loss after 1 month and <1 log titer loss in 6 months at high excipient concentration. Mannitol improved the dispersibility of phage powders, but the in vitro lung dose dropped sharply after exposure to high-humidity condition (65% RH) for formulations with 20% mannitol. While previously collected knowledge on phage powder preparation could be largely extended to formulate A. baumannii phage into inhalable dry powders, the environmental humidity may have great impacts on the stability and dispersion of phage; therefore, specific attention is required when optimizing phage powder formulations for global distribution.

Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies.

Lung cancer is the leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors, including monoclonal antibodies against programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), have dramatically improved the survival and quality of life of a subset of non-small cell lung cancer (NSCLC) patients. Multiple predictive biomarkers have been proposed to select the patients who may benefit from the immune checkpoint inhibitors. EGFR-mutant NSCLC is the most prevalent molecular subtype in Asian lung cancer patients. However, patients with EGFR-mutant NSCLC show poor response to anti-PD-1/PD-L1 treatment. While small-molecule EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for EGFR-mutant NSCLC, acquired drug resistance is severely limiting the long-term efficacy. However, there is currently no further effective treatment option for TKIs-refractory EGFR-mutant NSCLC patients. The reasons mediating the poor response of EGFR-mutated NSCLC patients to immunotherapy are not clear. Initial investigations revealed that EGFR-mutated NSCLC has lower PD-L1 expression and a low tumor mutational burden, thus leading to weak immunogenicity. Moreover, the use of PD-1/PD-L1 blockade prior to or concurrent with osimertinib has been reported to increase the risk of pulmonary toxicity. Furthermore, emerging evidence shows that PD-1/PD-L1 blockade in NSCLC patients can lead to hyperprogressive disease associated with dismal prognosis. However, it is difficult to predict the treatment toxicity. New biomarkers are urgently needed to predict response and toxicity associated with the use of PD-1/PD-L1 immunotherapy in EGFR-mutated NSCLC. Recently, promising data have emerged to suggest the potentiation of PD-1/PD-L1 blockade therapy by anti-angiogenic agents and a few other novel therapeutic agents. This article reviews the current investigations about the poor response of EGFR-mutated NSCLC to anti-PD-1/PD-L1 therapy, and discusses the new strategies that may be adopted in the future.

An overview of rational design of mRNA-based therapeutics and vaccines.

INTRODUCTION: Messenger RNA (mRNA)-based therapeutics and vaccines have emerged as a disruptive new drug class for various applications, including regenerative medicine, cancer treatment, and prophylactic and therapeutic vaccinations. AREAS COVERED: This review provides an update about the rational structure-based design of various formats of mRNA-based therapeutics. The authors discuss the recent advances in the mRNA modifications that have been used to enhance stability, promote translation efficiency and regulate immunogenicity for specific applications. EXPERT OPINION: Extensive research efforts have been made to optimize mRNA constructs and preparation procedures to unleash the full potential of mRNA-based therapeutics and vaccines. Sequence optimization (untranslated region and codon usage), chemical engineering of nucleotides and modified 5'cap, and optimization of in vitro transcription and mRNA purification protocols have overcome the major obstacles (instability, delivery, immunogenicity and safety) hindering the clinical applications of mRNA therapeutics and vaccines. The optimized design parameters should not be applied as default to different biological systems, but rather individually optimized for each mRNA sequence and intended application. Further advancement in the mRNA design and delivery technologies for achieving cell type- and organ site-specificity will broaden the scope and usefulness of this new class of drugs.

Aldehyde Dehydrogenase 2 Mediates Alcohol-Induced Colorectal Cancer Immune Escape through Stabilizing PD-L1 Expression.

Despite the great success of immunotherapy in a small subset of cancer patients, most colorectal cancer (CRC) patients do not respond to programmed cell death receptor 1 (PD-1) blockade immunotherapy. There is an urgent medical need to elucidate how cancer cells evade immune response and to develop novel means to boost the efficacy of immune checkpoint inhibitors. In this study, alcohol induces ligand programmed cell death receptor 1 (PD-L1) expression of CRC cells in vitro and in vivo. Alcohol exposure is shown to induce aldehyde dehydrogenase 2 (ALDH2) expression that is a crucial enzyme involved in alcohol metabolism, and low level of lymphocytes infiltration in the murine CRC model and patients. Intriguingly, ALDH2 and PD-L1 protein expression are positively correlated in tumor tissues from the CRC patients. Mechanistically, ALDH2 stabilizes PD-L1 protein expression by physically interacting with the intracellular segment of PD-L1 and inhibiting its proteasome-dependent degradation mediated by an E3 ubiquitin ligase Speckle Type POZ Protein (SPOP). Importantly, inhibition of ALDH2 reduces PD-L1 protein in CRC cells and promotes tumor-infiltrating T cells (TILs) infiltration, presumably leading to the significant potentiation of anti-PD-1 antibody efficacy in a mouse CT26 CRC model. The findings highlight a crucial role played by ALDH2 to facilitate alcohol-mediated tumor escape from immunity surveillance and promote tumor progression.

Development of thermosensitive hydrogel wound dressing containing Acinetobacter baumannii phage against wound infections.

With the emergence of multidrug resistance (MDR) bacteria, wound infection continues to be a challenging problem and represents a considerable healthcare burden. This study aims to evaluate the applicability of a phage loaded thermosensitive hydrogel in managing wound infections caused by MDR Acinetobacter baumannii, using IME-AB2 phage and MDR-AB2 as the model phage and bacteria, respectively. Excellent storage stability of the IME-AB2 phage in a ~18 wt% Poloxamer 407 (P407) hydrogel solution was first demonstrated with negligible titer loss (~0.5 log) in 24 months at 4 °C. The incorporated phage was released in a sustained manner with a cumulative release of 60% in the first 24 h. The in vitro bacterial killing efficiency of phage gel and phage suspension at 37 °C demonstrated >5 log10 CFU/ml reduction against A. baumannii. A comparable biofilm elimination capacity was also noted between the phage gel and phage suspension (59% and 45% respectively). These results suggested that the incorporation of phage into the hydrogel not only had insignificant impacts on the bacterial killing efficiency of phage, but also act as a phage depot to maintain higher phage titer at the infectious site for a prolong period for more effective treatment. We also found that the hydrogel formulation significantly suppressed microbial survival in an ex vivo wound infection model using pig skin (90% reduction in bacterial counts was achieved after 4 h treatment). In summary, our results demonstrated that the P407-based phage-loaded thermosensitive hydrogel is a simple and promising phage formulation for the management of wound infections.

Flavonoids Overcome Drug Resistance to Cancer Chemotherapy by Epigenetically Modulating Multiple Mechanisms.

Drug resistance is the major reason accounting for the treatment failure in cancer chemotherapy. Dysregulation of the epigenetic machineries is known to induce chemoresistance. It was reported that numerous genes encoding the key mediators in cancer proliferation, apoptosis, DNA repair, and drug efflux are dysregulated in resistant cancer cells by aberrant DNA methylation. The imbalance of various enzymes catalyzing histone post-translational modifications is also known to alter chromatin configuration and regulate multiple drug resistance genes. Alteration in miRNA signature in cancer cells also gives rise to chemoresistance. Flavonoids are a large group of naturally occurring polyphenolic compounds ubiquitously found in plants, fruits, vegetables and traditional herbs. There has been increasing research interest in the health-promoting effects of flavonoids. Flavonoids were shown to directly kill or re-sensitize resistant cancer cells to conventional anticancer drugs by epigenetic mechanisms. In this review, we summarize the current findings of the circumvention of drug resistance by flavonoids through correcting the aberrant epigenetic regulation of multiple resistance mechanisms. More investigations including the evaluation of synergistic anticancer activity, dosing sequence effect, toxicity in normal cells, and animal studies, are warranted to establish the full potential of the combination of flavonoids with conventional chemotherapeutic drugs in the treatment of cancer with drug resistance.