Chemotherapy remains the cornerstone of cancer treatment; however, its efficacy is frequently compromised by the development of chemoresistance. Multidrug resistance (MDR), characterized by the refractoriness of cancer cells to a wide array of chemotherapeutic agents, presents a significant barrier to achieving successful and sustained cancer remission. One critical factor contributing to this chemoresistance is the overexpression of ATP-binding cassette (ABC) transporters. Furthermore, additional mechanisms, such as the malfunctioning of apoptosis, alterations in DNA repair systems, and resistance mechanisms inherent to cancer stem cells, exacerbate the issue. Intriguingly, microRNAs (miRNAs) have demonstrated potential in modulating chemoresistance by specifically targeting ABC transporters, thereby offering promising new avenues for overcoming drug resistance. This narrative review aims to elucidate the molecular underpinnings of drug resistance, with a particular focus on the roles of ABC transporters and the regulatory influence of miRNAs on these transporters.

Cervical cancer (CC) and ovarian cancer (OC) are among the most common gynecological cancers with significant mortality in women, and their incidence is increasing. In addition to the prominent role of the malignant aspect of these cancers in cancer-related women deaths, chemotherapy drug resistance is a major factor that contributes to their mortality and presents a clinical obstacle. Although the exact mechanisms behind the chemoresistance in these cancers has not been revealed, accumulating evidence points to the dysregulation of non-coding RNAs (ncRNAs), particularly long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as key contributors. These ncRNAs perform the roles of regulators of signaling pathways linked to tumor formation and chemoresistance. Strong data from various recent studies have uncovered that the main mechanism of these ncRNAs in the induction of chemoresistance of CC and OC is done through a dysregulated miRNA sponge activity as competing endogenous RNA (ceRNA) in the competing endogenous RNA networks (ceRNETs), where a miRNA regulating a messenger RNA (mRNA) is trapped, thereby removing its inhibitory effect on the desired mRNA. Understanding these mechanisms is essential to enhancing treatment outcomes and managing the problem of drug resistance. This review provides a comprehensive overview of lncRNA- and circRNA-mediated ceRNETs as the core process of chemoresistance against the commonly used chemotherapeutics, including cisplatin, paclitaxel, oxaliplatin, carboplatin, and docetaxel in CC and OC. Furthermore, we highlight the clinical potential of these ncRNAs serving as diagnostic indicators of chemotherapy responses and therapeutic targets.

Thyroid cancer (TC) is a significant global health issue that exhibits notable heterogeneity in incidence and outcomes. In low-resource settings such as Africa, delayed diagnosis and limited healthcare access exacerbate mortality rates. Among follicular cell-derived thyroid cancers-including papillary (PTC), follicular (FTC), anaplastic (ATC), and poorly differentiated (PDTC) subtypes-the role of CD44 variants has emerged as a critical factor influencing tumor progression and multidrug resistance (MDR). CD44, a transmembrane glycoprotein, and its splice variants (CD44v) mediate cell adhesion, migration, and survival, contributing to cancer stem cell (CSC) maintenance and therapy resistance. Differential expression patterns of CD44 isoforms across TC subtypes have shown diagnostic, prognostic, and therapeutic implications. Specifically, CD44v6 expression in PTC has been correlated with metastasis and aggressive tumor behavior, while in FTC, its expression aids in distinguishing malignant from benign lesions. Furthermore, CD44 contributes to MDR through enhanced drug efflux via ABC transporters, apoptosis evasion, and CSC maintenance via the Wnt/β-catenin and PI3K/Akt pathways. Targeted therapies against CD44 such as monoclonal antibodies, hyaluronic acid-based nanocarriers, and gene-editing technologies hold promise in overcoming MDR. However, despite the mounting evidence supporting CD44-targeted strategies in various cancers, research on this therapeutic potential in TC remains limited. This review synthesizes existing knowledge on CD44 variant expression in follicular cell-derived thyroid cancers and highlights potential therapeutic strategies to mitigate MDR, particularly in high-burden regions, thereby improving patient outcomes and survival.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects more than 50 million people worldwide. One of the hallmark features of AD is the accumulation of amyloid β-peptide (Aβ) protein in the brain. P-glycoprotein (P-gp) is a membrane-bound protein expressed in various tissues, including the cerebrovascular endothelium. It plays a crucial role in the efflux of toxic substances, including Aβ, from the brain. Aberrations in P-gp levels or activity have been implicated in the pathogenesis of AD by promoting the accumulation of Aβ in the brain. Therefore, modulating the P-gp function represents a promising therapeutic strategy for treating AD. P-gp has multiple substrate binding sites, creating the potential for substrates to fall into complementation groups based on these sites; two substrates in the same complementation group may compete with one other, but two substrates in different groups may exhibit cooperativity. Thus, a given P-gp substrate may interfere with Aβ efflux whereas another may promote clearance. These threats and opportunities, as well as other aspects of P-gp relevance to AD, are discussed here.

The scarcity of ATP-binding cassette subfamily B member 1 (ABCB1, also known as P-glycoprotein, P-gp) inhibitors suitable for clinical application in improving multidrug resistance (MDR) promotes the development of drugs aimed at reversing MDR. In this work, we reported a comprehensive study for the first time about the reversal activity of β-carboline derivatives on ABCB1-mediated MDR. Among 48 synthesized derivatives, compound K27 significantly increased the sensitivity of ABCB1-mediated MDR SW620/AD300 cells to paclitaxel (PTX) (IC50 = 15.33 ± 5.4 nM, RF = 171.2) and hardly showed toxicity even at a high concentration of 20 μM when used alone. The in vitro studies indicated that compound K27 distinctly enhanced the arresting effect of PTX on the SW620/AD300 cell cycle, thereby inhibiting their proliferation. Mechanistically, compound K27 was confirmed to directly bind to ABCB1 to inhibit efflux function, reducing cellular efflux and ensuring stable intracellular concentration of PTX without affecting ABCB1's normal expression. Importantly, the combination of compound K27 and PTX exhibited potent tumor suppression in vivo without generating toxicity. These results demonstrated that β-carboline compounds represented by compound K27 may be potent ABCB1 inhibitors with considerable potential in effectively reversing ABCB1-mediated MDR, showing promising prospects.

Multidrug resistance (MDR) in triple-negative breast cancer (TNBC) leads to treatment failure and tumor recurrence. Dysregulation of the MYC oncogene is associated with the pathogenesis of TNBC and the development of chemoresistance via overexpression of ATP-binding cassette (ABC) transporters. Therefore, in the present study, we aimed to identify molecules from a natural product origin that prevent the development of MDR in TNBC by targeting the MYC signaling.

The cell viability of TNBC was evaluated using sulforhodamine assay. Protein levels were detected by western blots or enzyme-linked immunosorbent assays. Intracellular calcein and hoechst33342 accumulation assay aimed to evaluate the inhibitory ability of phytocompounds on drug-efflux functions of ABCB1 and ABCG2 transporters. The Cancer Genome Atlas (TCGA) database was used to explore clinical genomic data. Furthermore, the zebrafish xenotransplantation model bearing Dil-labeled TNBC cells was applied to testify the in vivo effects of phyto-sesquiterpene lactones.

The results of the present study demonstrated that the phyto-sesquiterpene lactones exhibited an MDR prevention effect by repressing efflux activities of ABCB1 and ABCG2 transporters. Mechanistic studies showed that phyto-sesquiterpene lactones inducted TNBC cell apoptosis and cell cycle G2/M arrested by blocking the STAT3/MYC pathway. Clinical genomic data demonstrated that the percentages of MYC amplification and mRNA were upregulated approximately two-fold higher in the TNBC patients than the non-TNBC breast cancer patients. The survival of patients with an alteration in MYC was significantly lower in TNBC as compared to other subtypes. Moreover, the results of the zebrafish xenograft model confirmed that phyto-sesquiterpene lactones exerted stronger inhibitory effects on TNBC tumor growth in vivo.

In conclusion, these three phyto-sesquiterpene lactones were promising candidates for TNBC treatment and shed light on the prevention of developing MDR TNBC.

The human ABCG2 transporter plays roles in physiological detoxification across barriers and in anticancer multidrug resistance. The translocation pathway for drug extrusion and its gating mechanism remains elusive. Here, we demonstrate that the ABCG2 multidrug transporter holds two cavities that are delineated by three regulatory gates, indicating a substrate translocation channel. Drugs are trapped in the central cavity after entering through the pivotal intracellular entry gate. This flexible cavity is surrounded by a cluster of three highly conserved phenylalanines. Their aromatic side chains enact a "clamp-push-seal" motion to ensure unidirectional substrate movement. The unique residues T435 and N436 act as critical selectors for ligands, determining the broad substrate specificity. The upper cavity is covered by the lid architecture, constituting the final gate before multidrug extrusion. This work unravels deep mechanistic details on how the translocation channel utilizes pivotal gating steps, including the sequence of events that drive ABCG2-mediated multidrug efflux.

Despite advances in malaria chemotherapy, the disease continues to claim thousands of lives annually. Addressing this issue requires the discovery of new compounds to counteract resistance threatening the current therapeutic arsenal. In this context, bi-triazoles are substances with diverse biological activities, showing promise as lead compound to fight malaria. Triazoles are heterocyclic structures composed of five members, including three nitrogen atoms and two double bonds. Bi-triazoles, the focus of this study, are derivatives of triazoles consisting of two triazole rings (nitrogen heterocyclic) with isolated nuclei lacking a spacer and two substituents at each end. The goal of the present study was to assess the in vitro and in silico, antimalarial activity of bi-triazole compounds 14c, 14d, 13c, and 13d against asexual and sexual forms of Plasmodium falciparum.

For in silico predictions, the software OSIRIS, Molinspiration, and ADMETlab were employed. To determine the 50% inhibitory concentration (IC50) on the asexual forms, the W2 clone was used, while the strain NF54 was used to assess inhibition of sexual forms. Cytotoxicity was evaluated using the HepG2 cell line, and haemolysis tests were conducted. Additionally, the selectivity index (SI) of each compound was calculated.

In silico analyses of physicochemical properties revealed that all compounds have favorable potential for drug development. Pharmacokinetics predictions also provided important, novel insights into this chemical class. Antimalarial activity tests showed that compounds 14d and 13d exhibited promising activity, with IC50 values of 3.1 and 4.4 µM, respectively. Antimalarial activity of compounds 14d and 13d may be related to the presence of methyl acetate in substituent R2 conjugated to the bi-triazole. None of the compounds demonstrated cytotoxic or haemolytic activity, with SI values above 51 for the three most active compounds, highlighting their selectivity. For the sexual forms, compounds 14c and 14d were classified as having a high potential to block malaria transmission.

Overall, the in vitro and in silico results showed that bi-triazole compounds may guide new biological investigation for malaria, enabling the identification and development of more active and selective antimalarial agents.

Chemotherapy resistance is a significant barrier to effective cancer treatment. A key mechanism of resistance at the single-cell level is the overexpression of drug transporters in the ABC family, particularly P-glycoprotein (P-gp), which leads to multidrug resistance (MDR). Inhibitors of these transporters can help re-sensitize cancer cells to chemotherapeutics. This study evaluated elacridar (GG918 and GF120918), a potent third-generation P-gp inhibitor, for its ability to reverse MDR in paclitaxel (PAC)-resistant ovarian cancer cell lines. Sensitive and PAC-resistant cells were cultured in two-dimensional (2D) and three-dimensional (3D) models. MDR1 gene expression was analyzed using Q-PCR, and P-gp protein expression was examined via Western blot and immunofluorescence. Drug sensitivity was evaluated with MTT assays, and P-gp activity was analyzed by flow cytometry and fluorescence microscopy. Elacridar effectively inhibited P-gp activity and increased sensitivity to PAC and doxorubicin (DOX) in 2D cultures but not cisplatin (CIS). In 3D spheroids, P-gp activity inhibition was observed via Calcein-AM staining. However, no re-sensitization to PAC occurred and limited improvement was observed for DOX. These findings suggest that elacridar effectively inhibits P-gp in both 2D and 3D conditions. However, its ability to overcome drug resistance in 3D models is limited, highlighting the complexity of tissue-specific resistance mechanisms.

Tetrabromobisphenol A bis (2-hydroxyethyl) ether (TBBPA-DHEE), a derivative of TBBPA, has been frequently detected in the environment. In this study, the median lethal concentration (LC50) of TBBPA-DHEE at 96 h post-fertilization (hpf) was 1.573 mg/L. Based on the reported environmental concentrations, we investigated the effects of TBBPA-DHEE on the nervous system of zebrafish embryos following exposure to varying concentrations (0, 20, 100, and 500 μg/L) for 4 to 144 hpf. Our results indicated that exposure to 100 μg/L at 144 hpf led to behavioral abnormalities in zebrafish. Furthermore, exposure to TBBPA-DHEE inhibited the development of the central nervous system and motor neurons in zebrafish. Real-time polymerase chain reaction (PCR) analysis revealed that exposure to TBBPA-DHEE significantly downregulated the expression levels of neurodevelopmental genes (shha, syn2a, elavl3, gfap, and gap43). Additionally, TBBPA-DHEE increased oxidative stress in zebrafish. Transcriptomic analysis demonstrated that exposure to TBBPA-DHEE affected the signaling pathways involved in neurodevelopment. Overall, this study demonstrated that TBBPA-DHEE may disrupt the early development of the nervous system, leading to abnormal motor behavior in zebrafish larvae, and provided novel insights into the potential mechanisms of TBBPA-DHEE neurotoxicity.

Aripiprazole (ARI) is an atypical antipsychotic which is a substrate of P-glycoprotein (P-gp), a transmembrane glycoprotein that plays a crucial role in eliminating potentially harmful compounds from the organism. ARI once-monthly (AOM) is a long-acting injectable form which improves treatment compliance. Genetic polymorphisms in ABCB1 may lead to changes in P-gp function, leading to individual differences in drug disposition. The present study aims to determine how the different variants of the three most prevalent SNPs of the ABCB1 gene affect plasma concentrations of ARI, of its active metabolite dehydroaripiprazole (DHA) and ARI/DHA ratio in patients under AOM treatment. The metabolizing state of the two main aripiprazole metabolizing enzymes (CYP2D6 and CYP3A4) were considered to specifically study the effect of P-gp on plasma concentrations of the parent compound and its active metabolite. The study found a clear relationship between the genotypes found for the different ABCB1 SNPs and the ARI/DHA ratio. Specifically, patients with GG genotype in G2677T have almost twice the ratio compared to TT genotype. Similarly, this increase is also found in C3435T with 1.4-fold and in C1236T with 1.6-fold for the same genotypes. Regarding haplotypes, significant differences were obtained between CC-GG-CC and TT-TT-TT patients, with an 87.9% higher ratio in patients with the CC-GG-CC haplotype. There was a clear trend towards lower ARI concentrations and higher DHA concentrations when the presence of mutated T alleles increases. The ABCB1 gene could be a good partner along with CYP2D6 and CYP3A4 genotyping in conjunction with monitoring ARI plasma concentrations.

P-glycoprotein (P-gp, ABCB1) is a well-researched ATP-binding cassette (ABC) drug efflux transporter linked to the development of cancer multidrug resistance (MDR). Despite extensive studies, approved therapies to safely inhibit P-gp in clinical settings are lacking, necessitating innovative strategies beyond conventional inhibitors or antibodies to reverse MDR. Photodynamic therapy is a globally approved cancer treatment that uses targeted, harmless red light to activate non-toxic photosensitizers, confining its cytotoxic photochemical effects to disease sites while sparing healthy tissues. This study demonstrates that photodynamic priming (PDP), a sub-cytotoxic photodynamic therapy process, can inhibit P-gp function by modulating cellular respiration and ATP levels in light accessible regions. Using chemoresistant (VBL-MDA-MB-231) and chemosensitive (MDA-MB-231) triple-negative breast cancer cell lines, we showed that PDP decreases mitochondrial membrane potential by 54.4% ± 30.4 and reduces mitochondrial ATP production rates by 94.9% ± 3.46. Flow cytometry studies showed PDP can effectively improve the retention of P-gp substrates (calcein) by up to 228.4% ± 156.3 in chemoresistant VBL-MDA-MB-231 cells, but not in chemosensitive MDA-MB-231 cells. Further analysis revealed that PDP did not alter the cell surface expression level of P-gp in VBL-MDA-MB-231 cells. These findings indicate that PDP can reduce cellular ATP below the levels that is required for the function of P-gp and improve intracellular substrate retention. We propose that PDP in combination with chemotherapy drugs, might improve the efficacy of chemotherapy and overcome cancer MDR.

Omacetaxine, a semisynthetic form of Homoharringtonine (HHT), was approved for the treatment of Chronic Myeloid Leukemia (CML). Previously, we have published the synthesis of this natural alkaloid and three of its derivatives: Deoxyharringtonine (DHT), Deoxyhomoharringtonine (DHHT), and Bis(demethyl)-deoxyharringtonine (BDHT), and reported its refractory activity against the HL-60/RV+ cells over-expressing P-glycoprotein 1 (MDR1).

In this study, we have explored the extent of this resistance by first expanding the panel of established cell lines and using a panel of 21 leukemia patient-derived primary cells.

Herein, we have reported consistent resistance to HTT of K562-derived cells and to mitoxantrone of MES-SA/MX2-derived cells; all of them have been found to overexpress MDR1, while we have found U87MG-ABCG2 and H69AR cells to be very sensitive to HTT. In contrast, DHT, DHHT, and BDHT seemingly overcame this resistance due to the changes made to the acyl chain of HTT, rendering the derivatives less susceptible to efflux. Surprisingly, the leukemia primary cells were very sensitive to HHT and its derivatives with low nanomolar potencies, followed by a new class of CDC7 kinase inhibitors, the anthracycline class of topoisomerase inhibitors, the DNA intercalator actinomycin-D, and the vinca alkaloid class of microtubule inhibitors. The mechanism of cell death induced by HTT and DHHT was found to be mediated via caspase 3 cleavage, leading to apoptosis.

Taken together, our results confirm that HHT is a substrate for MDR1. It opens the door to a new opportunity to clinically evaluate HHT and its derivatives for the treatment of AML and other cancers.

Drug safety is a paramount concern in the field of drug development, with researchers increasingly focusing on the bidirectional regulation of gut microbiota in this context. The gut microbiota plays a crucial role in maintaining drug safety. It can influence drug transport processes in the body through various mechanisms, thereby modulating their efficacy and toxicity. The main mechanisms include: (1) The gut microbiota directly interacts with drugs, altering their chemical structure to reduce toxicity and enhance efficacy, thereby impacting drug transport mechanisms, drugs can also change the structure and abundance of gut bacteria; (2) bidirectional regulation of intestinal barrier permeability by gut microbiota, promoting the absorption of nontoxic drugs and inhibiting the absorption of toxic components; (3) bidirectional regulation of the expression and activity of transport proteins by gut microbiota, selectively promoting the absorption of effective components or inhibiting the absorption of toxic components. This bidirectional regulatory role enables the gut microbiota to play a key role in maintaining drug balance in the body and reducing adverse reactions. Understanding these regulatory mechanisms sheds light on novel approaches to minimize toxic side effects, enhance drug efficacy, and ultimately improve drug safety. This review systematically examines the bidirectional regulation of gut microbiota in drug transportation from the aforementioned aspects, emphasizing their significance in ensuring drug safety. Furthermore, it offers a prospective outlook from the standpoint of enhancing therapeutic efficacy and reducing drug toxicity, underscoring the importance of further exploration in this research domain. It aims to provide more effective strategies for drug development and treatment.

Collagen is a crucial protein in the extracellular matrix (ECM) essential for preserving tissue architecture and supporting crucial cellular functions like proliferation and differentiation. There are twenty-eight identified types of collagen, which are further divided into different subgroups. This protein plays a critical role in regulating tissue homeostasis. However, in solid tumors, the balance can be disrupted, due to an abundance of collagen in the tumor microenvironment, which significantly affects tumor growth, cell invasion, and metastasis. It is important to investigate the specific types of collagens in cancer ECM and their distinct roles in tumor progression to comprehend their unique contribution to tumor behavior. The diverse pathophysiological functions of different collagen types in cancers illustrate collagen's dual roles, offering potential therapeutic options and serving as prognostic markers.

P-glycoprotein (P-gp) plays a crucial role in cellular detoxification and drug efflux processes, transitioning between inward-facing (IF) open, occluded, and outward-facing (OF) states to facilitate substrate transport. Its role is critical in cancer therapy, where P-gp contributes to the multidrug resistance phenotype. In our study, classical and enhanced molecular dynamics (MD) simulations were conducted to dissect the structural and functional features of the P-gp conformational states. Our advanced MD simulations, including kinetically excited targeted MD (ketMD) and adiabatic biasing MD (ABMD), provided deeper insights into state transition and translocation mechanisms. Our findings suggest that the unkinking of TM4 and TM10 helices is a prerequisite for correctly achieving the outward conformation. Simulations of the IF-occluded conformations, characterized by kinked TM4 and TM10 helices, consistently demonstrated altered communication between the transmembrane domains (TMDs) and nucleotide binding domain 2 (NBD2), suggesting the implication of this interface in inhibiting P-gp's efflux function. A particular emphasis was placed on the unstructured linker segment connecting the NBD1 to TMD2 and its role in the transporter's dynamics. With the linker present, we specifically noticed a potential entrance of cholesterol (CHOL) through the TM4-TM6 portal, shedding light on crucial residues involved in accommodating CHOL. We therefore suggest that this entry mechanism could be employed for some P-gp substrates or inhibitors. Our results provide critical data for understanding P-gp functioning and developing new P-gp inhibitors for establishing more effective strategies against multidrug resistance.

Ovarian cancer (OC) accounts for the highest mortality rates among all gynecologic malignancies. The high mortality of OC is often associated with delayed detection, prolonged latency, enhanced metastatic potential, acquired drug resistance, and frequent recurrence. This review comprehensively explores key aspects of OC, including cancer diagnosis, mechanisms of disease resistance, and the pivotal role of epigenetic regulation, particularly by microRNAs (miRs) in cancer progression. We highlight the intricate regulatory mechanisms governing miR expression within the context of OC and the current status of epigenetic advancement in the therapeutic development and clinical trial progression. Through network analysis we elucidate the regulatory interactions between dysregulated miRs in OC and their targets which are involved in different signaling pathways. By exploring these interconnected facets and critical analysis, we endeavor to provide a nuanced understanding of the molecular dynamics underlying OC, its detection and shedding light on potential avenues for miRs and epigenetics-based therapeutic intervention and management strategies.

Triple-negative breast cancer (TNBC) is associated with a generally poor prognosis due to its highly aggressive and metastatic nature, lack of targetable receptors, as well as the frequent development of resistance to chemotherapy. We previously reported that AU1, a small molecule developed as an inhibitor of BPTF (bromodomain PHD finger-containing transcription factor), was capable of sensitizing preclinical models of TNBC to chemotherapy in part via the promotion of autophagy. In studies reported here, we identify an additional property of this compound, specifically that sensitization is associated with the inhibition of the P-glycoprotein (P-gp) efflux pump. In silico molecular docking studies indicate that AU1 binds to active regions of the efflux pump in a manner consistent with the inhibition of the pump function. This work identifies a novel chemical structure that can influence multidrug efflux, an established mechanism of drug resistance in TNBC, that has not yet been successfully addressed by clinical efforts.

The incidence of pancreatic cancer (PC), a highly fatal malignancy, is increasing every year. Chemotherapy is an important treatment for it in addition to surgery, yet most patients become resistant to chemotherapeutic agents within a few weeks of treatment initiation.​ MUC1 is a highly glycosylated transmembrane protein, and studies have shown that aberrantly glycosylated overexpression of MUC1 is involved in regulating the biology of chemoresistance in cancer cells. This article summarizes the mechanism of MUC1 in PC chemoresistance and reviews MUC1-based targeted therapies.

A growing number of deep learning (DL) methodologies have recently been developed to design novel compounds and expand the chemical space within virtual libraries. Most of these neural network approaches design molecules to specifically bind a target based on its structural information and/or knowledge of previously identified binders. Fewer attempts have been made to develop approaches for de novo design of virtual libraries, as synthesizability of generated molecules remains a challenge. In this work, we developed a new Monte Carlo Search (MCS) algorithm, DrugSynthMC (Drug Synthesis using Monte Carlo), in conjunction with DL and statistical-based priors to generate thousands of interpretable chemical structures and novel drug-like molecules per second. DrugSynthMC produces drug-like compounds using an atom-based search model that builds molecules as SMILES, character by character. Designed molecules follow Lipinski's "rule of 5″, show a high proportion of highly water-soluble nontoxic predicted-to-be synthesizable compounds, and efficiently expand the chemical space within the libraries, without reliance on training data sets, synthesizability metrics, or enforcing during SMILES generation. Our approach can function with or without an underlying neural network and is thus easily explainable and versatile. This ease in drug-like molecule generation allows for future integration of score functions aimed at different target- or job-oriented goals. Thus, DrugSynthMC is expected to enable the functional assessment of large compound libraries covering an extensive novel chemical space, overcoming the limitations of existing drug collections. The software is available at https://github.com/RoucairolMilo/DrugSynthMC.

Overexpression of the polyspecific efflux transporter, P-glycoprotein (P-gp, MDR1, ABCB1 ), is a major mechanism by which cancer cells acquire multidrug resistance (MDR), the resistance to diverse chemotherapeutic drugs. Inhibiting drug transport by P-gp can resensitize cancer cells to chemotherapy, but there are no P-gp inhibitors available to patients. Clinically unsuccessful P-gp inhibitors tend to bind at the pump's transmembrane drug binding domains and are often P-gp transport substrates, resulting in lowered intracellular concentration of the drug and altered pharmacokinetics. In prior work, we used computationally accelerated drug discovery to identify novel P-gp inhibitors that target the pump's cytoplasmic nucleotide binding domains. Our first-draft study provided conclusive evidence that the nucleotide binding domains of P-gp are viable targets for drug discovery. Here we develop an enhanced, computationally accelerated drug discovery pipeline that expands upon our prior work by iteratively screening compounds against multiple conformations of P-gp with molecular docking. Targeted molecular dynamics simulations with our homology model of human P-gp were used to generate docking receptors in conformations mimicking a putative drug transport cycle. We offset the increased computational complexity using custom Tanimoto chemical datasets, which maximize the chemical diversity of ligands screened by docking. Using our expanded, virtual-assisted pipeline, we identified nine novel P-gp inhibitors that reverse MDR in two types of P-gp overexpressing human cancer cell lines, reflecting a 13.4% hit rate. Of these inhibitors, all were non-toxic to non-cancerous human cells, and six were not likely to be transport substrates of P-gp. Our novel P-gp inhibitors are chemically diverse and are good candidates for lead optimization. Our results demonstrate that the nucleotide binding domains of P-gp are an underappreciated target in the effort to reverse P-gp-mediated multidrug resistance in cancer.

We developed first-in-class antimitotic prodrugs phenyl 4-(2-oxo-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) bioactivated by cytochrome P450 (CYP) 1A1 that are highly selective toward several breast cancer cells. However, they show sparingly water solubility. Therefore, we replaced their phenyl ring B with a substituted pyridinyl group preparing novel pyridinyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PYRAIB-SOs) and their hydrochloride salts. Our results evidence that PYRAIB-SO hydrochloride salts show higher water solubility compared to their neutral and PAIB-SO counterparts by up to 625-fold. PYRAIB-SOs with a nitrogen atom at position 3 of the pyridinyl ring exhibited strong antiproliferative activity (IC50: 0.03-3.3 μM) and high selectivity (8->1250) toward sensitive CYP1A1-positive breast cancer cells and cells stably transfected with CYP1A1. They induce cell cycle arrest in the G2/M phase and disrupt microtubule dynamic assembly. Enzymatic assays confirmed that CYP1A1 metabolizes PYRAIB-SOs into their active form with in vitro hepatic half-lives (55-120 min) in rodent and human liver microsomes. Overall, this will allow to increase drug concentration for in vivo studies.

As a precursor of protoporphyrin IX (PpIX), an endogenous pro-apoptotic and fluorescent molecule, 5-Aminolevulinic acid (5-ALA) has gained substantial attention for its potential in fluorescence-guided surgery as well as photodynamic therapy (PDT). Moreover, 5-ALA-PDT has been suggested as a promising chemo-radio sensitization therapy for various cancers. However, insufficient 5-ALA-induced PpIX fluorescence and the induction of multiple resistance mechanisms may hinder the 5-ALA-PDT clinical outcome. Reduced efficacy and resistance to 5-ALA-PDT can result from genomic alterations, tumor heterogeneity, hypoxia, activation of pathways related to cell surveillance, production of nitric oxide, and most importantly, deregulated 5-ALA transporter proteins and heme biosynthesis enzymes. Understanding the resistance regulatory mechanisms of 5-ALA-PDT may allow the development of effective personalized cancer therapy. Here, we described the mechanisms underlying resistance to 5-ALA-PTD across various tumor types and explored potential strategies to overcome this resistance. Furthermore, we discussed future approaches that may enhance the efficacy of treatments using 5-ALA-PDT.

Multi-drug resistance (MDR) is a major cause of cancer therapy failure. Photodynamic therapy (PDT) is a promising modality that can circumvent MDR and synergize with chemotherapies, based on the generation of reactive oxygen species (ROS) by photosensitizers. However, overproduction of glutathione (GSH) by cancer cells scavenges ROS and restricts the efficacy of PDT. Additionally, side effects on normal tissues are unavoidable after PDT treatment. Here, to develop organic systems that deliver effective anticancer PDT and chemotherapy simultaneously with very little side effects, three GSH-sensitive photosensitizer-drug conjugates (CyR-SS-L) are designed and synthesized. CyR-SS-L localized in the mitochondria then is cleaved into CyR-SG and SG-L parts by reacting with and consuming high levels of intracellular GSH. Notably, CyR-SG generates high levels of ROS in tumor cells instead of normal cells and be exploited for PDT and the SG-L part is used for chemotherapy. CyR-SS-L inhibits better MDR cancer tumor inhibitory activity than indocyanine green, a photosensitizer (PS) used for PDT in clinical applications. The results appear to be the first to show that CyR-SS-L may be used as an alternative PDT agent to be more effective against MDR cancers without obvious damaging normal cells by the combination of PDT, GSH depletion, and chemotherapy.

Outcomes for women with breast cancer have improved dramatically in recent decades. However, many patients present with intrinsic drug resistance and others are initially sensitive to anti-cancer drugs but acquire resistance during the course of their treatment, leading to recurrence and/or metastasis. Drug therapy-induced senescence (TIS) is a form of drug resistance characterised by the induction of cell cycle arrest and the emergence of a senescence-associated secretory phenotype (SASP) that can develop in response to chemo- and targeted- therapies. A wide range of anticancer interventions can lead to cell cycle arrest and SASP induction, by inducing genotoxic stress, hyperactivation of signalling pathways or oxidative stress. TIS can be anti-tumorigenic in the short-term, but pro-tumorigenic in the long-term by creating a pro-inflammatory and immunosuppressive microenvironment. Moreover, the SASP can promote angiogenesis and epithelial-mesenchymal transition in neighbouring cells. In this review, we will describe the characteristics of TIS in breast cancer and detail the changes in phenotype that accompany its induction. We also discuss strategies for targeting senescent cancer cells in order to prevent or delay tumour recurrence.

This review explores the hallmarks of cancer resistance, including drug efflux mediated by ATP-binding cassette (ABC) transporters, metabolic reprogramming characterized by the Warburg effect, and the dynamic interplay between cancer cells and mitochondria. The role of cancer stem cells (CSCs) in treatment resistance and the regulatory influence of non-coding RNAs, such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are studied. The chapter emphasizes future directions, encompassing advancements in immunotherapy, strategies to counter adaptive resistance, integration of artificial intelligence for predictive modeling, and the identification of biomarkers for personalized treatment. The comprehensive exploration of these hallmarks provides a foundation for innovative therapeutic approaches, aiming to navigate the complex landscape of cancer resistance and enhance patient outcomes.

A series of novel coumarin-thiazoles was designed and synthesized as a possible CDK2 inhibitor with anticancer activity with low toxicity. The design relied on having hydrazine thiazole or its open-form thioamide to form H-bonds with the ATP binding site while coumarin maintained the crucial hydrophobic interactions for proper fitting. The biological evaluation revealed that the hydroxycoumarin-thiazole derivative 6c demonstrated the best inhibition with HepG2 and HCT116 IC50 2.6 and 3.5 μM, respectively. Similarly, its open thioamide chain congener 5c exhibited potent inhibition on MCF-7 and HepG2 with IC50 of 4.5 and 5.4 μM, respectively. Molecular docking simulations supported the assumption of inhibiting CDK2 by preserving the crucial interaction pattern with the hinge ATP site and the surrounding hydrophobic (HPO) side chains. Furthermore, molecular dynamics simulations of 5c and 6c established satisfactory stability and affinity within the CDK2 active site.

Altered glycosylation plays a role in carcinogenesis. GALNT14 promotes cancer stem-like properties and drug resistance. GDF-15 is known to induces drug resistance and stemness markers for maintenance of breast cancer (BC) stem-like cell state. Currently there is lack of data on association of GDF-15 and GALNTs. In this study, the expression and interaction of GALNT14 and GDF-15 with stemness (OCT4 and SOX2) and drug resistance (ABCC5) markers were evaluated in BC.

We investigated tumour tissue from 30 BC patients and adjacent non-tumour tissues. Expression of serum GALNT14 from BC patients and matched healthy controls was evaluated. Expression of GALNT14, GDF-15, OCT4, SOX2, ABCC5, and β-catenin in BC tissue was determined by RT-PCR. Knockdown of GALNT14 and GDF-15 in the MCF-7 cell line was done through siRNA, gene expression and protein expression of β-catenin by western blot were determined.

A significant increase in the expression of GALNT14, GDF-15, OCT4, SOX2, ABCC5, and β-catenin was observed in BC tumour tissues compared to adjacent non-tumour tissues. The serum level of GALNT14 was significantly high in BC patients (80.7 ± 65.3 pg/ml) compared to healthy controls (12.2 ± 9.12 pg/ml) (p < 0.000). To further analyse the signalling pathway involved in BC stemness and drug resistance, GALNT14 and GDF-15 were knocked down in the MCF-7 cell line, and it was observed that after knockdown, the expression level of OCT4, SOX2, ABCC5, and β-catenin was decreased, and co-knockdown with GALNT14 and GDF-15 further decreased the expression of genes.

It can be concluded that GALNT14, in association with GDF-15, promotes stemness and intrinsic drug resistance in BC, possibly through the β-catenin signalling pathway.

P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) multidrug resistance (MDR) transporters are localized at the luminal surface of the blood-brain barrier (BBB). They confer fetal brain protection against harmful compounds that may be circulating in the peripheral blood. The fetus develops in low oxygen levels; however, some obstetric pathologies such as pre-eclampsia, placenta accreta/previa may result in even greater fetal hypoxic states. We investigated how hypoxia impacts MDR transporters in human fetal brain endothelial cells (hfBECs) derived from early and mid-stages of pregnancy. Hypoxia decreased BCRP protein and activity in hfBECs derived in early pregnancy. In contrast, in hfBECs derived in mid-pregnancy there was an increase in P-gp and BCRP activity following hypoxia. Results suggest a hypoxia-induced reduction in fetal brain protection in early pregnancy, but a potential increase in transporter-mediated protection at the BBB during mid-gestation. This would modify accumulation of various key physiological and pharmacological substrates of P-gp and BCRP in the developing fetal brain and potentially contribute to the pathogenesis of neurodevelopmental disorders commonly associated with in utero hypoxia.

Triptans are anti-migraine drugs with a potential central site of action. However, it is not known to what extent triptans cross the blood-brain barrier (BBB). The aim of this study was therefore to determine if triptans pass the brain capillary endothelium and investigate the possible underlying mechanisms with focus on the involvement of the putative proton-coupled organic cation (H+/OC) antiporter. Additionally, we evaluated whether triptans interacted with the efflux transporter, P-glycoprotein (P-gp).

We investigated the cellular uptake characteristics of the prototypical H+/OC antiporter substrates, pyrilamine and oxycodone, and seven different triptans in the human brain microvascular endothelial cell line, hCMEC/D3. Triptan interactions with P-gp were studied using the IPEC-J2 MDR1 cell line. Lastly, in vivo neuropharmacokinetic assessment of the unbound brain-to-plasma disposition of eletriptan was conducted in wild type and mdr1a/1b knockout mice.

We demonstrated that most triptans were able to inhibit uptake of the H+/OC antiporter substrate, pyrilamine, with eletriptan emerging as the strongest inhibitor. Eletriptan, almotriptan, and sumatriptan exhibited a pH-dependent uptake into hCMEC/D3 cells. Eletriptan demonstrated saturable uptake kinetics with an apparent Km of 89 ± 38 µM and a Jmax of 2.2 ± 0.7 nmol·min-1·mg protein-1 (n = 3). Bidirectional transport experiments across IPEC-J2 MDR1 monolayers showed that eletriptan is transported by P-gp, thus indicating that eletriptan is both a substrate of the H+/OC antiporter and P-gp. This was further confirmed in vivo, where the unbound brain-to-unbound plasma concentration ratio (Kp,uu) was 0.04 in wild type mice while the ratio rose to 1.32 in mdr1a/1b knockout mice.

We have demonstrated that the triptan family of compounds possesses affinity for the H+/OC antiporter proposing that the putative H+/OC antiporter plays a role in the BBB transport of triptans, particularly eletriptan. Our in vivo studies indicate that eletriptan is subjected to simultaneous brain uptake and efflux, possibly facilitated by the putative H+/OC antiporter and P-gp, respectively. Our findings offer novel insights into the potential central site of action involved in migraine treatment with triptans and highlight the significance of potential transporter related drug-drug interactions.

The escalating prevalence of membrane drug transporters and drug efflux pumps in pathogenic yeast like Candida albicans necessitates a comprehensive understanding of their roles in MDR. The overexpression of drug transporter families, ABC and MFS, implicated in MDR through drug efflux and poses a significant challenge in the diagnosis and treatment of fungal infection. Various mechanisms have been proposed for MDR; however, the upregulation of ABC and MFS superfamily transporters is most noticeable in MDR. The direct inhibition of these transporters seems an efficient strategy to overcome this problem. The goal of the article is to present an overview of the prospect of utilizing these modulators of C. albicans drug transports as effective antifungal molecules against MDR addressing a critical gap in the field. The review tries to address to prevent drug extrusion by modulating the expression of drug transporters of C. albicans. The review discussed the progress in identifying potent, selective, and non-toxic modulators of these transporters to develop some effective antifungals and overcome MDR. We reviewed major studies in this area and found that recent work has shifted toward the exploration of natural compounds as potential modulators to restore drug sensitivity in MDR fungal cells. The focus of this review is to survey and interpret current research information on modulators of C. albicans drug transporters from natural sources emphasizing those compounds that are potent antifungal agents.

In the current study, a series of benzimidazole-oxindole conjugates 8a-t were designed and synthesized as type II multi-kinase inhibitors. They exhibited moderate to potent inhibitory activity against BRAFWT up to 99.61 % at 10 µM. Notably, compounds 8e, 8k, 8n and 8s demonstrated the most promising activity, with 99.44 to 99.61 % inhibition. Further evaluation revealed that 8e, 8k, 8n and 8s exhibit moderate to potent inhibitory effects on the kinases BRAFV600E, VEGFR-2, and FGFR-1. Additionally, compounds 8a-t were screened for their cytotoxicity by the NCI, and several compounds showed significant growth inhibition in diverse cancer cell lines. Compound 8e stood out with a GI50 range of 1.23 - 3.38 µM on melanoma cell lines. Encouraged by its efficacy, it was further investigated for its antitumor activity and mechanism of action, using sorafenib as a reference standard. The hybrid compound 8e exhibited potent cellular-level suppression of BRAFWT, VEGFR-2, and FGFR-1 in A375 cell line, surpassing the effects of sorafenib. In vivo studies demonstrate that 8e significantly inhibits the growth of B16F10 tumors in mice, leading to increased survival rates and histopathological tumor regression. Furthermore, 8e reduces angiogenesis markers, mRNA expression levels of VEGFR-2 and FGFR-1, and production of growth factors. It also downregulated Notch1 protein expression and decreased TGF-β1 production. Molecular docking simulations suggest that 8e binds as a promising type II kinase inhibitor in the target kinases interacting with the key regions in their kinase domain.

Trastuzumab emtansine (T-DM1) has been approved worldwide for treating metastatic breast cancer (mBC) in patients who have received first-line therapy, shown disease progression, and are human epidermal growth factor receptor 2 (HER2)-positive. T-DM1 received approval in China to treat early-stage breast cancer (BC) in 2020 and for mBC in 2021. In March 2023, T-DM1 was included in medical insurance coverage, significantly expanding the eligible population.

This post-marketing observational study aimed to assess the safety and effectiveness of T-DM1 in real-world clinical practice in China. This study enrolled 31 individuals with HER2-positive early-stage BC and 70 individuals with HER2-positive advanced BC from 8 study centers in Shandong Province, China. The T-DM1 dosage was 3.6 mg/kg injected intravenously every 3 weeks until the disease advanced or the drug toxicity became uncontrollable, whichever occurred earlier. Additionally, efficacy and safety information on T-DM1 were collected.

During the 7-month follow-up period, no recurrence or metastases were observed in patients who had early-stage BC. The disease control rate was 31.43% (22/70) in patients with advanced BC. The most common adverse effect of T-DM1 was thrombocytopenia, with an incidence of 69.31% (70/101), and the probability of Grade ≥ 3 thrombocytopenia was 11.88% (12/101).

This real-world study demonstrated that T-DM1 had good efficacy and was well tolerated by both HER2-positive early-stage BC and mBC patients.

Cryptococcus neoformans has been designated as critical fungal pathogens by the World Health Organization, mainly due to limited treatment options and the prevalence of antifungal resistance. Consequently, the utilization of novel antifungal agents is crucial for the effective treatment of C. neoformans infections. This study exposed that the minimum inhibitory concentration (MIC) of isobavachalcone (IBC) against C. neoformans H99 was 8 µg/mL, and IBC dispersed 48-h mature biofilms by affecting cell viability at 16 µg/mL. The antifungal efficacy of IBC was further validated through microscopic observations using specific dyes and in vitro assays, which confirmed the disruption of cell wall/membrane integrity. RNA-Seq analysis was employed to decipher the effect of IBC on the C. neoformans H99 transcriptomic profiles. Real-time quantitative reverse transcription PCR (RT-qPCR) analysis was performed to validate the transcriptomic data and identify the differentially expressed genes. The results showed that IBC exhibited various mechanisms to impede the growth, biofilm formation, and virulence of C. neoformans H99 by modulating multiple dysregulated pathways related to cell wall/membrane, drug resistance, apoptosis, and mitochondrial homeostasis. The transcriptomic findings were corroborated by the antioxidant analyses, antifungal drug sensitivity, molecular docking, capsule, and melanin assays. In vivo antifungal activity analysis demonstrated that IBC extended the lifespan of C. neoformans-infected Caenorhabditis elegans. Overall, the current study unveiled that IBC targeted multiple pathways simultaneously to inhibit growth significantly, biofilm formation, and virulence, as well as to disperse mature biofilms of C. neoformans H99 and induce cell death.

The bee gut microbiota plays an important role in the services the bees pay to the environment, humans and animals. Alongside, gut-associated microorganisms are vehiculated between apparently remote habitats, promoting microbial heterogeneity of the visited microcosms and the transfer of the microbial genetic elements. To date, no metaproteomics studies dealing with the functional bee microbiota are available. Here, we employ a metaproteomics approach to explore a fraction of the bacterial, fungal, and unicellular parasites inhabiting the bee gut. The bacterial community portrays a dynamic composition, accounting for specimens of human and animal concern. Their functional features highlight the vehiculation of virulence and antimicrobial resistance traits. The fungal and unicellular parasite fractions include environment- and animal-related specimens, whose metabolic activities support the spatial spreading of functional features. Host proteome depicts the major bee physiological activities, supporting the metaproteomics strategy for the simultaneous study of multiple microbial specimens and their host-crosstalks. Altogether, the present study provides a better definition of the structure and function of the bee gut microbiota, highlighting its impact in a variety of strategies aimed at improving/overcoming several current hot topic issues such as antimicrobial resistance, environmental pollution and the promotion of environmental health.

Fungal non-ribosomal peptide synthetase (NRPS)-encoding products play a paramount role in new drug discovery. Fusarium, one of the most common filamentous fungi, is well-known for its biosynthetic potential of NRPS-type compounds with diverse structural motifs and various biological properties. With the continuous improvement and extensive application of bioinformatic tools (e.g., anti-SMASH, NCBI, UniProt), more and more biosynthetic gene clusters (BGCs) of secondary metabolites (SMs) have been identified in Fusarium strains. However, the biosynthetic logics of these SMs have not yet been well investigated till now. With the aim to increase our knowledge of the biosynthetic logics of NPRS-encoding products in Fusarium, this review firstly provides an overview of research advances in elucidating their biosynthetic pathways.

Breast cancer is significantly influenced by endoplasmic reticulum (ER) stress, impacting both its initiation and progression. When cells experience an accumulation of misfolded or unfolded proteins, they activate the unfolded protein response (UPR) to restore cellular balance. In breast cancer, the UPR is frequently triggered due to challenging conditions within tumors. The UPR has a dual impact on breast cancer. On one hand, it can contribute to tumor growth by enhancing cell survival and resistance to programmed cell death in unfavorable environments. On the other hand, prolonged and severe ER stress can trigger cell death mechanisms, limiting tumor progression. Furthermore, ER stress has been linked to the regulation of non-coding RNAs (ncRNAs) in breast cancer cells. These ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play essential roles in cancer development by influencing gene expression and cellular processes. An improved understanding of how ER stress and ncRNAs interact in breast cancer can potentially lead to new treatment approaches. Modifying specific ncRNAs involved in the ER stress response might interfere with cancer cell survival and induce cell death. Additionally, focusing on UPR-associated proteins that interact with ncRNAs could offer novel therapeutic possibilities. Therefore, this review provides a concise overview of the interconnection between ER stress and ncRNAs in breast cancer, elucidating the nuanced effects of the UPR on cell fate and emphasizing the regulatory roles of ncRNAs in breast cancer progression.

Multidrug resistance protein 7 (MRP7), also known as ATP-binding cassette (ABC) transporter subfamily C10 (ABCC10), is an ABC transporter that was first identified in 2001. ABCC10/MRP7 is a 171 kDa protein located on the basolateral membrane of cells. ABCC10/MRP7 consists of three transmembrane domains and two nucleotide binding domains. It mediates multidrug resistance of tumor cells to a variety of anticancer drugs by increasing drug efflux and results in reducing intracellular drug accumulation. The transport substrates of ABCC10/MRP7 include antineoplastic drugs such as taxanes, vinca alkaloids, and epothilone B, as well as endobiotics such as leukotriene C4 (LTC4) and estradiol 17 β-D-glucuronide. A variety of ABCC10/MRP7 inhibitors, including cepharanthine, imatinib, erlotinib, tariquidar, and sildenafil, can reverse ABCC10/MRP7-mediated MDR. Additionally, the presence or absence of ABCC10/MRP7 is also closely related to renal tubular dysfunction, obesity, and other diseases. In this review, we discuss: 1) Structure and functions of ABCC10/MRP7; 2) Known substrates and inhibitors of ABCC10/MRP7 and their potential therapeutic applications in cancer; and 3) Role of ABCC10/MRP7 in non-cancerous diseases.

In this study, for the first time, we analyzed the chemical composition of essential oils (EOs) steam-distilled from the flowers and leaves of Perralderia coronopifolia by GC-FID/MS. The objective was to explore new anticancer and antioxidant bioactive substances and understand their mechanisms of action through the use of plant-derived natural products. The major chemical components characterizing the EOs were cis-chrysanthenyl acetate 1, 6-oxocyclonerolidol 2, cis-8-acetoxychrysanthenyl acetate 3, and 6α-hydroxycyclonerolidol 4, respectively. Furthermore, the EOs inhibited cell proliferation in HeLa (human cervix carcinoma) and PC3 (human prostate cancer) cells and protected plasmid DNA from oxidative damage caused by UV-photolyzed H2 O2 . Employing a molecular docking study, we elucidated the main compounds' inhibition mechanisms. Consequently, the antitumor activity could be related to the inhibitory property of compound 3 against CDC25B phosphatase. The evaluation of ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties and the density functional theory (DFT) calculations of the major compounds, especially compound 3, offer potential insights for designing and developing new cancer drug candidates. In conclusion, our study provides a framework for future research and development in the field by establishing a scientific foundation for the use of Perralderia coronopifolia essential oils as a prospective source of antioxidant and anticancer agents.