ADR Cells Research Articles

A versatile modular preparation strategy for targeted drug delivery systems against multidrug-resistant cancer cells

Nanotechnology is widely used in targeted drug delivery, but different drug delivery systems need to ‘re-determine’ different synthesis schemes, which greatly limits the further expansion of targeted nanomedicine applications. In this study, we propose a facile and versatile modular stacking strategy to fabricate targeted drug delivery systems to enable tailored designs for patient-specific therapeutic responses. The systems were constructed by a pH-sensitive prodrug module and a mitochondrial targeting module via self-assembly. Using this modular strategy, we successfully prepared two targeting nano-drug delivery systems, TPP-DOX and PK-DOX, where the mitochondrial targeting molecules were triphenylphosphonium (TPP) and 1-(2-Chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195), respectively. Confocal laser microscopy and flow cytometry tests revealed that TPP-DOX and PK-DOX exhibited high mitochondria targeting capability and greatly improved the drug retention in drug-resistant cells. The antitumor activity tests showed that the IC50 values of TPP-DOX and PK-DOX in MCF-7/ADR cells were 2.5- and 8.2-fold lower than that of free DOX, respectively. These results indicated that PK was more effective than TPP. The studies on their therapeutic effects on human breast cancer resistant cells verified the feasibility of the modular approach, indicated that the two modular targeted drug delivery systems: (1) retain the drug toxicity and cell-killing effect of the prodrug module, (2) have precise targeting capabilities due to mitochondrial targeting module, (3) enhance drug uptake, reduce drug efflux and reverse the multidrug resistance effect to a certain extent. The results show that modular stacking is a practical, effective and versatile method for preparing targeting drugs with broad application prospects. This study provides an easy approach on preparing customizable targeted drug delivery systems to improve precision therapies.

Microribonucleic Acid-15a-5p Alters Adriamycin Resistance in Breast Cancer Cells by Targeting Cell Division Cycle-Associated Protein 4.

ObjectiveAlthough chemotherapy is one of the first line clinical treatment of tumors, the efficacy of chemotherapy has been severely restricted by the frequent occurrence of drug resistance phenomenon. Multiple studies found that miRNAs can regulate the chemosensitivity of tumor cells. Here, this study aimed to assess the potential role of the miR-15a-5p/cell division cycle-related protein 4 (CDCA4) axis in breast cancer (BC) resistance to Adriamycin.MethodsIn the present study, the relative expression of miRNA-15a-5p in MCF-7/ADR, MCF-7 and Hs578Bst was measured by qRT-PCR. MCF-7/ADR cells underwent transfection with an miR-15a-5p mimic and inhibitor, respectively. Transwell assays, flow cytometry and CCK8 were performed to examine the potential effects of the abnormal expression of miR-15a-5p. The association of aberrant miR-15a-5p expression with Adriamycin resistance in BC was determined in cultured MCF-7/ADR cells. Bioinformatics was employed to predict the genes targeted by miR-15a-5p. Moreover, the correlation between miR-15a-5p and its target gene, CDCA4, was evaluated based on qRT-PCR data.ResultsThe expression of miR-15a-5p was significantly downregulated in MCF/ADR cells compared with MCF-7 and Hs578Bst cell lines. In the presence of Adriamycin, miR-15a-5p overexpression significantly increased cell chemosensitivity, as well as MCF-7/ADR cell proliferation, invasion, and migration, while promoting apoptosis and inducing cell-cycle arrest in the synthesis phase. CDCA4 RNA interference enhanced these effects as shown in our previous study. Bioinformatics identified CDCA4 as an miR-15a-5p target gene. qRT-PCR further demonstrated that CDCA4 and miR-15a-5p expression levels were inversely correlated.ConclusionAdriamycin resistance in BC cells was, at least in part, altered by mRNA-15a-5p via regulation of its target gene, CDCA4, by controlling the cell cycle, which may provide some novel ideas for BC chemotherapy in the future.

Two New Cytotoxic Maytansinoids Targeting Tubulin from Trewia nudiflora.

Two new maytansinoids, N-methyltreflorine (1: ) and methyltrewiasine (2: ), were isolated from the dried fruits of Trewia nudiflora, together with three known congeners (3: - 5: ). Their structures were elucidated by spectroscopic methods, and the absolute configuration of 1: and 2: was determined by X-ray crystallographic analysis. Compounds 1: - 5: exhibited strong cytotoxicity against human tumor cell lines, including HeLa, MV-4 - 11, and MCF-7, with IC50 values ranging from 0.12 to 11 nM. Compounds 1: and 4: also showed inhibitory activity against the MCF-7/ADR cell line with IC50 values of 13 and 28 nM, respectively. Compounds 1: and 2: significantly inhibited tubulin polymerization in vitro with IC50 values of 3.6 and 3.2 µM, respectively.

N-Glycoproteomics Study of Putative N-Glycoprotein Biomarkers of Drug Resistance in MCF-7/ADR Cells.

The online version contains supplementary material available at 10.1007/s43657-021-00029-8.

Diterpenoids from Euphorbia glomerulans with potential reversal activities against P-glycoprotein-mediated multidrug resistance

The development of collateral sensitivity agents that are able to modulate P-glycoprotein (P-gp) is the most promising approaches to overcome multidrug resistance (MDR) in cancer. In this study, eight new diterpenoids of jatrophane and ingenane type, 1–8, and three known ones (9–11) were isolated from Euphorbia glomerulans. Their structures were elucidated by spectroscopic analysis and electronic circular dichroism (ECD) calculations. The MDR reversal activity evaluation of these isolates on breast cancer MCF-7/ADR cells demonstrated the four potent MDR modulators (3, 4, 5, and 9) with great chemoreversal ability and low cytotoxicity. The structure-activity relationship (SAR) analysis indicated that the presence of isobutanoyloxy group at C-8 significantly enhance reversal efficiency. Compound 5 exhibited high efficacy (EC50 = 159.5 nM) in reversing MDR resistance, being stronger than verapamil (EC50 = 302.9 nM). The MDR reversal mechanism assays revealed that 5 could promote the accumulation of Rh123 and DOX in drug-resistant cells in a certain dose-dependent manner, and inhibit P-gp transport function. In addition, the possible recognition mechanism of compound 5 and verapamil (VRP) with P-gp was predicted by molecular docking.

Ultrasound‐Augmented Nanocatalytic Ferroptosis Reverses Chemotherapeutic Resistance and Induces Synergistic Tumor Nanotherapy

AbstractInducing ferroptosis has been acknowledged as an emerging strategy to kill drug‐resistant tumor cells, but how to efficiently induce ferroptosis at the tumor site and enhance its therapeutic efficacy are still highly challenging. In this work, an ultrasound (US)‐augmented nanocatalytic ferroptosis strategy is implemented by a GA‐Fe(II)‐based liposomal nanosystem, which simultaneously encapsulates doxorubicin hydrochloride (DOX), for reversing chemotherapeutic resistance and inducing synergistic ferroptosis/apoptosis‐based nanotherapy. GA‐Fe(II), as an iron‐containing Fenton catalyst that catalyzes the persistent conversion of H2O2 to hydroxyl radicals, is utilized to deplete glutathione and deliver excess iron into cells for accumulating lipid peroxidation and inducing ferroptosis in DOX‐resistant MCF‐7/ADR cancer cells. US irradiation is capable of promoting cell phagocytosis of nano‐agents, enhancing Fenton reaction, and controlling drug release at tumor sites to strengthen nanocatalytic therapy. Transcriptomics analysis reveals that the US‐augmented Fenton reaction enables the down‐regulation of PGC‐1α and Bcl‐2 expression, rendering MCF‐7/ADR cells susceptible to DOX‐induced apoptosis. The distinct US‐responsive Fenton reaction collaborating with chemotherapy substantially reverses tumor drug resistance and achieves high tumor‐killing efficacy in MCF‐7/ADR cells and MCF‐7/ADR tumor‐bearing mice, suggesting that such a synergistic ferroptosis/apoptosis‐targeting strategy is instructive to the future design of therapeutic regimens against drug‐resistant tumors.

Curcumin attenuates Adriamycin-resistance of acute myeloid leukemia by inhibiting the lncRNA HOTAIR/miR-20a-5p/WT1 axis

Acute myeloid leukemia (AML) is a common subtype of leukemia, and a large proportion of patients with AML eventually develop drug resistance. Curcumin exerts cancer suppressive effects and increases sensitivity to chemotherapy in several diseases. This study aimed to investigate the mechanism by which curcumin affects the resistance of AML to Adriamycin by regulating HOX transcript antisense RNA (HOTAIR) expression. Cell viability, colony-formation, flow cytometry, and Transwell assays were used to assess cell proliferation, apoptosis, and migration. A dual-luciferase reporter assay was used to verify the interaction between microRNA (miR)-20a-5p and HOTAIR or Wilms' tumor 1 (WT1). RT-qPCR and Western blotting assays were performed to detect gene and protein expression. The results showed that curcumin suppressed the resistance to Adriamycin, inhibited the expression of HOTAIR and WT1, and promoted the expression of miR-20a-5p in human acute leukemia cells (HL-60) or Adriamycin-resistant HL-60 cells (HL-60/ADR). Furthermore, curcumin suppressed proliferation and promoted apoptosis of HL-60/ADR cells. Overexpression of HOTAIR reversed the regulatory effect of curcumin on apoptosis and migration and restored the effect of curcumin on inducing the expression of cleaved caspase3, Bax, and P27. In addition, HOTAIR upregulated WT1 expression by targeting miR-20a-5p, and inhibition of miR-20a-5p reversed the regulation of Adriamycin resistance by curcumin in AML cells. Finally, curcumin inhibited Adriamycin resistance by suppressing the HOTAIR/miR-20a-5p/WT1 pathway in vivo. In short, curcumin suppressed the proliferation and migration, blocked the cell cycle progression of AML cells, and sensitized AML cells to Adriamycin by regulating the HOTAIR/miR-20a-5p/WT1 axis. These findings suggest a potential role of curcumin and HOTAIR in AML treatment.The authors show that curcumin suppresses the proliferation and migration of acute myeloid leukemia (AML) cells. Curcumin also blocks cell cycle progression and sensitizes AML cells to Adriamycin by regulating the HOTAIR/miR-20a-5p/WT1 axis. These findings suggest a potential role of curcumin and HOTAIR in AML treatment.

Endogenous NO-releasing Carbon Nanodots for Tumor-specific Gas Therapy

Carbon nanodots based on L-arginine (L-Arg) were developed for enhanced nitric oxide (NO) gas therapy for cancer. The L-Arg-based carbon nanodots (Arg-dots) produced high levels of NO in the tumor environment rich in endogenous H2O2. In vitro cell experiments revealed that the Arg-dots could kill tumor cells (including human breast cancer cell line MCF-7, female gastric cancer cell line BGC-823, male lung cancer cell line A549, and female leukemic cell line K562) but did not affect the activity of normal cells (human normal lung epithelial cell line BEAS-2B). The Arg-dots produced twice the amount of NO for an equivalent amount of L-Arg. Theoretical calculations showed that the carbonization structure of the Arg-dots promoted significantly more electrons toward the guanidinium groups of L-Arg and boosted the adsorption of H2O2 molecules. In vitro and in vivo investigations confirmed that the Arg-dots reduced the multidrug resistance (MDR) effect of the tumor cells (MCF-7/ADR cells) and produced a combined antitumor efficacy with traditional chemotherapeutic drugs (adriamycin [ADR]). The fluorescence property (quantum yield, 6.88%) allows the Arg-dots to be used as a suitable fluorescent probe for fluorescence imaging of tumor cells. The ultra-small size of the Arg-dots (diameter: ca. 2.5 nm) enables them not only to penetrate deep tumors and provide enhanced antitumor activity but also to be removed through kidney filtration and have a renal clearance property. Statement of significanceNitric oxide (NO), which serves as a biological messenger, can be used in gas therapy for cancer. The development of a safe and efficient NO cancer therapy is, however, challenging because of the low NO release amount and poor tumor specificity of most NO donors. Many efforts have been made to overcome these drawbacks, but solving both these limitations through a single approach has been seldom achieved. In the present work, carbon nanodots (Arg-dots) from L-arginine were used for gas therapy of cancer. The Arg-dots produced NO in the H2O2-rich tumor environment. Theoretical calculations were consistent with the mechanism of enhanced NO release amount. The Arg-dots also reduced the multidrug resistance effect in cancer chemotherapy. In vivo and in vitro toxicity assessments confirmed that the Arg-dots have excellent biosafety.

Antitumor Activity of α-Linolenic Acid-Paclitaxel Conjugate Nanoparticles: In vitro and in vivo.

PurposeSmall molecule modified antitumor drug conjugate nanoparticles have the advantages of high drug loading, simple synthesis and preparation, and better biocompatibility. Due to the large demand for exogenous α-linolenic acid (ALA) by tumor cells, we synthesized α-linolenic acid-paclitaxel conjugate (ALA-PTX) and prepared α-linolenic acid-paclitaxel conjugate nanoparticles (ALA-PTX NPs), in order to obtain better tumor cellular uptake and antitumor activity in vitro and in vivo.MethodsWe synthesized and characterized ALA-PTX, and then prepared and characterized ALA-PTX NPs. The cellular uptake, uptake pathways, intracellular behavior, in vitro and in vivo antitumor activity of ALA-PTX NPs were evaluated.ResultsThe size of ALA-PTX NPs was approximately 110.7±1.7 nm. The drug loading was approximately 90% (w/w) with CrEL-free and organic solvent-free characteristics. The cellular uptake of ALA-PTX NPs was significantly higher than that of PTX injection by MCF-7, MCF-7/ADR and HepG2 cells. In these three cell lines, the cellular uptake of ALA-PTX NPs at 6h was approximately 1.5–2.6 times higher than that of PTX injection. ALA-PTX NPs were ingested through clathrin-mediated endocytosis, then transferred to lysosomes, and could dissolve in cells to play an antitumor activity. The in vitro and in vivo antitumor activity of ALA-PTX NPs was confirmed in MCF-7/ADR and HepG2 cell models and tumor-bearing nude mouse models.ConclusionALA-PTX NPs developed in our study could provide a new method for the preparation of nano-delivery systems suitable for antitumor therapy that could increase tumor cellular uptake and enhance antitumor activity.

Cetuximab-Modified Human Serum Albumin Nanoparticles Co-Loaded with Doxorubicin and MDR1 siRNA for the Treatment of Drug-Resistant Breast Tumors.

BackgroundBreast cancer is the most prevalent cancer among women. Doxorubicin (DOX) is a common chemotherapeutic drug used to treat many different cancers. However, multidrug resistance limits the treatment of breast cancer. MDR1 siRNA (siMDR1) combinatorial therapy has attracted significant attention as a breakthrough therapy for multidrug resistance in tumors. However, naked siRNA is easily degraded by enzymatic hydrolysis requiring an siRNA carrier for its protection. Human serum albumin (HSA) was selected as the carrier due to its excellent biocompatibility, non-toxicity, and non-immunogenicity. Cetuximab was used to modify the HSA nanoparticles in order to target the tumor tissues.MethodsThis study used a central composite design response surface methodology (CCD-RSM) to investigate the optimal formula for HSA NPs preparation. Cex-HSA/DOX/MDR1 siRNA (C-H/D/M) was characterized by dynamic light scattering and transmission electron microscopy. The efficacy of C-H/D/M tumor growth inhibitory activity was investigated in vitro and in vivo using confocal imaging, MTT assay, and an MCF-7/ADR tumor-bearing mice model. RT–qPCR, ELISA analysis, and flow cytometry were used to investigate the in vitro antitumor mechanisms of C-H/D/M.ResultsThe diameter and PDI of the C-H/D/M were 173.57 ± 1.30 nm and 0.027 ± 0.004, respectively. C-H/D/M promoted and maintained the sustained release and the uptake of DOX significantly. After transfection, the MDR1 mRNA and P-gp expression levels were down-regulated by 44.31 ± 3.6% (P < 0.01) and 38.08 ± 2.4% (P < 0.01) in an MCF-7/ADR cell line. The fluorescent images of the treated BALB/c nude mice revealed that C-H/D/M achieved targeted delivery of siMDR1 and DOX into the tumor tissue. The in vivo tumor inhibition results demonstrated that the tumor inhibition rate of the C-H/D/M treated group was 54.05% ± 1.25%. The biosafety results indicated that C-H/D/M did not induce significant damages to the main organs in vivo.ConclusionC-H/D/M can be used as an ideal non-viral tumor-targeting vector to overcome MDR and enhance the antitumor effect.

Long-circulating doxorubicin and schizandrin A liposome with drug-resistant liver cancer activity: preparation, characterization, and pharmacokinetic

The selectivity of chemotherapeutic agents for liver cancer is poor. When they kill tumour cells, they produce serious adverse reactions in the whole body and multidrug resistance (MDR) is also a major hurdle in liver cancer chemotherapy. Combination therapy is a useful method for overcoming MDR and reducing toxic and side effects. In this study, we developed a long-circulating codelivery system, in which doxorubicin (DOX) and schizandrin A (SchA) are combined against MCF-7/ADR cells. The DOX-SchA long-circulating liposome (DOX-SchA-Lip) was prepared using ammonium sulphate gradient method. The two drugs were co-encapsulated into the distearoyl phosphatidylethanolamine-polyethylene glycol (DSPE-mPEG2000) liposome and the liposome had an average particle size of (100 ± 3.5) nm and zeta electrical potential of (–31.3 ± 0.5) mV. The average encapsulation rate of DOX was 97.98% and that of SchA was 86.94%. DOX in liposome had good sustained-release effect. The results showed that DOX-SchA-Lip could significantly prolong the half-life (t 1/2z) of the DOX and SchA, increase their circulation time in vivo, improve its bioavailability and reduce their side effects. Liposome can effectively induce early apoptosis of HepG2/ADR cells and the cell cycle was blocked in S-phase by DOX-SchA-Lip in a dose-dependent manner. The IC50 of compound liposome to HepG2 and HepG2/ADR were 0.55 μmol/L and 1.38 μmol/L, respectively, which could significantly reverse the resistance of HepG2/ADR and the reversion multiple was 30.28. It was verified that DOX-SchA-Lip can effectively kill tumour cells and reverse MDR.

Grape seed proanthocyanidin extract induces apoptosis of HL-60/ADR cells via the Bax/Bcl-2 caspase-3/9 signaling pathway.

BackgroundOur previous study detailed the direct induction of apoptosis by grape seed proanthocyanidin extract (GSPE) in a multidrug resistant human acute myeloid leukemia (AML) HL-60/adriamycin (HL-60/ADR) cell line, although the mechanism of this effect was not detailed. This study aims to elucidate the mechanism underlying GSPE-induced cell apoptosis in HL-60/ADR cells.MethodsHL-60/ADR cells were studied to evaluate effects of GSPE (0–100 µg/mL); a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was employed to identify the cytotoxic effect of varying GSPE concentrations. Trypan blue staining was used to observe changes in cell viability; flow cytometry assays were used to verify apoptosis. Expression of Bax and Bcl-2 mRNA was analyzed using real-time polymerase chain reaction (PCR). Activity of caspase-3 and caspase-9 was also detected.ResultsHere, GSPE was found to inhibit HL-60/ADR cell growth and induce cell apoptosis in a dose-dependent manner. Real-time PCR findings revealed that GSPE concentrations above 75 µg/mL significantly increase expression of Bax mRNA (P<0.001). GSPE concentrations above 25 µg/mL were found to significantly decrease expression of Bcl-2 mRNA (P<0.01), while concentrations above 50 µg/mL were found to significantly increase caspase-3 activity after 6, 12 and 24 h (P<0.01). However, only 100 µg/mL GSPE was found to significantly increase caspase-9 activity (P<0.001 at 6 and 12 h; P<0.05 at 24 h).ConclusionsGSPE inhibits the proliferation of HL-60/ADR cells by the induction of apoptosis in a dose-dependent manner via the Bax/Bcl-2 caspase-3/9 signaling pathway.

Emodin-loaded polymer-lipid hybrid nanoparticles enhance the sensitivity of breast cancer to doxorubicin by inhibiting epithelial\u2013mesenchymal transition

BackgroundThe role of epithelial–mesenchymal transition (EMT) involved in breast cancer metastasis and chemoresistance has been increasingly recognized. However, it is necessary to search for more effective strategies to inhibit EMT thereby increase the sensitivity of breast cancer cells to chemotherapy drugs. Emodin has a potential in overcoming tumor drug resistance and restraining the development of EMT, but the poor internalization into breast cancer cells limited the application.ResultsMCF-7/ADR cells have more EMT characteristics than MCF-7 cell. EMT in MCF-7/ADR cells promotes the development of drug resistance via apoptosis resistance and facilitating the expression of P-gp. The anti-cancer effect of DOX enhanced by the decreasing of drug resistance protein P-gp and apoptosis-related proteins after EMT inhibited in MCF-7/ADR cells. E-PLNs increase the cellular uptake of EMO and restore DOX sensitivity in MCF-7/ADR cells by inhibiting EMT.ConclusionE-PLNs inhibit EMT to enhance the sensitivity of breast cancer to DOX. The combination of E-PLNs and DOX can improve the efficacy of DOX in the treatment of breast cancer, which provides a new method to prevent or delay clinical drug resistance.

Synergistic Therapy of Doxorubicin with Cationic Anticancer Peptide L-K6 Reverses Multidrug Resistance in MCF-7/ADR Cancer Cells In Vitro via P-glycoprotein Inhibition

Multidrug resistance (MDR) is one of the major obstacles to efficient chemotherapy against cancers, resulting from the overexpression of drug efflux transporters such as P-glycoprotein (P-gP). In the present study, we aimed to evaluate the MDR reversal activity and synergistic therapeutic potential of cationic anticancer peptide L-K6 with doxorubicin (DOX) on P-gP-overexpressing and DOX-resistant MCF-7/ADR human breast cancer cells. Flow cytometry and confocal laser scanning microscopy were used to determine the intracellular accumulation of DOX and another P-gP substrate, Rho123. P-gP-Glo assay, Western blot and Biacore analysis were further performed to evaluate the P-gP function and expression. The cytotoxicity in MCF-7 or MCF-7/ADR cells was measured by MTT assay. Flow cytometry assay and confocal laser scanning microscopy observation clearly revealed an increased intracellular accumulation of DOX and Rho123 in MCF-7/ADR cells treated with L-K6, suggesting a P-gP inhibiting potential. Biacore analysis, P-gP-Glo assay and Western blot further confirmed that L-K6 could directly interact with P-gP, inhibit P-gP function and decrease P-gP expression in MCF-7/ADR cells. In addition, as expected, the data from MTT assay indicated that L-K6 restored the sensitivity of MCF-7/ADR cells to DOX, indicating a MDR reversal potential and a promising synergistic anticancer activity. All these findings may provide experimental evidence to support the promising applications and synergistic therapeutic potential of peptidic P-gP inhibitors against MDR cancer.

Homotypic biomimetic coating synergizes chemo-photothermal combination therapy to treat breast cancer overcoming drug resistance

Breast cancer (BC) is a leading cause of death in women worldwide and multidrug resistance (MDR) severely limits its treatment since chemotherapy is the standard approach for treating BCs. In this work, high biocompatibility resulted from biomimetic coating, magnetic and homotypic targeting plus triggered release properties were integrated in one smart drug delivery system (DDS) to overcome drug resistance and to achieve combination cancer therapy. MCF-7 cancer cell membrane coating was applied to chitosan-PLGA based DDS entrapping photothermal iron oxide nanoparticles (PIO NPs), Doxorubicin (Dox) and Mcl-1-siRNA. Such coating facilitated homotypic targeting of MCF-7/ADR cells, whereas PIO NPs facilitated magnetic targeting by the external magnetic field, thereby resulting in high in vitro cellular uptake and in vivo accumulation at the tumor site. Upon NIR (near-infrared) laser irradiation and at acidic pH, the DDS exhibited triggered release. The cytotoxicity of Dox on MCF-7 and MCF-7/ADR cells significantly improved by the developed DDS due to increased intracellular Dox accumulation. Application of NIR laser and external magnetic field resulted in maximum therapeutic outcome utilizing chemo-photothermal combination and the DDS was able to inhibit almost 80% tumor growth in MCF-7/ADR tumor model. This new nanoplatform holds strong promise in BC therapy and can be exploited to treat other cancers.

Astragalus IV Undermines Multi-Drug Resistance and Glycolysis of MDA-MB-231/ADR Cell Line by Depressing hsa_circ_0001982-miR-206/miR-613 Axis

BackgroundAllowing for the power of astragalus in improving cancer patients’ response to chemotherapy, we endeavored to clarify if hsa_circ_0001982-centered miRNA axes participated in the impact of astragaloside IV on multi-drug resistance (MDR) of triple-negative breast cancer (TNBC).MethodsTNBC patients were recruited into an Astragalus detoxification decoction (ADD) treatment group (N=62) and a non-ADD treatment group (N=78), according to whether they consumed ADD after chemotherapy or not. Furthermore, drug resistance of the MDA-MB-231/ADR cell line in response to gemcitabine (GEM), adriamycin (ADM), oxaliplatin (OXA), and cisplatin (DDP) was evaluated, and glycolytic potential of MDA-MB-231/ADR cells was determined after astragaloside IV treatment or si-hsa_circ_0001982/miR-206 inhibitor/miR-613 inhibitor transfection.ResultsTNBC patients receiving ADD adjuvant therapy after chemotherapy, with decreased serum level of hsa_circ_0001982 and increased serum level of miR-206/miR-613 as relative to non-ADD treatment group (P<0.05), were less likely to relapse than TNBC population not undergoing ADD treatment (P<0.05). In addition, GEM/ADM/OXA/DDP-resistance and glycolysis of MDA-MB-231/ADR cell line were debilitated after exposure to astragaloside IV or transfection by si-hsa_circ_0001982 (P<0.05). Nonetheless, miR-206/miR-613 inhibitor transfection reversed inhibitory effects of si-hsa_circ_0001982 and astragaloside IV on glycolysis and MDR of MDA-MB-231/ADR cell line (P<0.05).ConclusionAstragaloside IV undermined MDR and glycolysis of MDA-MB-231/ADR cell line by blocking hsa_circ_0001982-miR-206/miR-613 axis.

Dual-Functional Prodrug Equipped With Hyaluronic Acid Micelles for Stimuli-Release and Overcoming Doxorubicin Resistance

Multidrug resistance (MDR) is the main challenge faced by cancer chemotherapy. Drug-conjugate offers a promising strategy for breast cancer therapy. In this regard, we developed a DNVM multifunctional drug delivery system by crosslinking doxorubicin (DOX) and vitamin E succinate (VES) with a pH-sensitive hydrazone bond and then encapsulated the DOX-NN-VES prodrug into pH-sensitive hyaluronic acid-2-(octadecyloxy)-1,3-dioxan-5-amine (HOD) micelles. DOX resistant MCF-7/ADR cell were adopted as a model to study the capability and mechanism of MDR reversal. DNVM exhibited much higher cytotoxicity and cell uptake efficiency compared with that of acid-insensitive DOX-VES loaded HOD micelles (DVSM) and DOX loaded HOD micelles (DOXM), indicating the better capacity of DNVM for the reversal of MDR. Moreover, DNVM prevented drug efflux more effectively, inhibited the expression of P-gp, induced excessive production of reactive oxygen species and affected the expression of apoptosis-related proteins. In vivo experiments showed that DNVM significantly inhibited the tumor growth with no obvious changes in the body weight of MCF-7/ADR cells-bearing nude mice. The results suggested that the “double gain” DNVM can synergistically enhance the efficacy of chemotherapeutics for DOX resistant tumor cells and has the potential to overcome tumor MDR.

Berberine Acts As a Putative Epigenetic Modulator By Affecting Histone Code in Acute Myelocytic Leukemia Cells

Berberine (BBR) has a wide range of biochemical and pharmacological effects. However, the exact mechanism of these bio-activities remains poorly understood. Based on the bioinformatics analyses, our study firstly discovered the possibility of berberine being an epigenetic modulator in U266 cells. We demonstrated significant similarity between berberine and two epigenetic modulators (CG-1521 and TSA). We conducted this study to explore how these molecular events are regulated by berberine in (Acute Myelocytic Leukemia) AML cells. The analysis found that enzymes involved in histone acetylation and methylation have been impacted predominantly. In addition to this, the results showed that berberine also inhibited the expression of EZH2 and DNMT1 in HL-60/ADR and KG1-α cells, both in protein and mRNA. In DNA methylation, BBR induced decrease methylation level in the SFRPs, then depressed the wnt/β-catenin pathway.The results of this study suggest that berberine might modulate expression of epigenetic regulators importent for some downstream pathways, thereby manifests its various bio-activities in AML cells. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Reversing Chemotherapy Resistance by a Synergy between Lysosomal pH-Activated Mitochondrial Drug Delivery and Erlotinib-Mediated Drug Efflux Inhibition.

Mitochondrial drug delivery has attracted increasing attention in various mitochondrial dysfunction-associated disorders such as cancer owing to the important role of energy production. Herein, we report a lysosomal pH-activated mitochondrial-targeting polymer nanoparticle to overcome drug resistance by a synergy between mitochondrial delivery of doxorubicin (DOX, an anticancer drug) and erlotinib-mediated inhibition of drug efflux. The obtained nanoparticles, DE-NPs could maintain negative charge and have long blood circulation while undergoing charge reversal at lysosomal pH after internalization by cancer cells. Thereafter, the acidity-activated polycationic and hydrophobic polypeptide domains boost lysosomal escape and mitochondrial-targeting drug delivery, leading to mitochondrial dysfunction, ATP suppression, and cell apoptosis. Moreover, the suppressed ATP supply and erlotinib enabled dual inhibition of drug efflux by DOX-resistant MCF-7/ADR cells, leading to significantly augmented intracellular DOX accumulation and a synergistic anticancer effect with a 17-fold decrease of IC50 relative to DOX. In vivo antitumor study demonstrates that DE-NPs efficiently suppressed the tumor burden in MCF-7/ADR tumor-bearing mice and led to negligible toxicity. This work establishes that a combination of mitochondrial drug delivery and drug efflux inhibition could be a promising strategy for combating multidrug resistance.

Rational design of phenyl thiophene (pyridine) derivatives that overcome P-glycoprotein mediated MDR in MCF-7/ADR cell

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) has become an important hindrance in the clinical treatment of malignant tumors. In this paper, based on our lead compound 5m and strategies of bioisosteric replacement and alkoxy effect, phenylthiophene and phenylpyridine derivatives were designed as chemosensitizers for front-line antineoplastic agents and overcomes P-gp mediated MDR in MCF-7/ADR cell. Generally, 4-phenylthiophene-2-carboxamide derivative 60 has been screened and obtained with optimal activity against P-gp mediated MDR in MCF-7/ADR (IC50 (doxorubicin) = 1.02 μM, RF = 49.9 with 5 μM 60 treated). The results of western blot and Rh123 accumulation assays showed that 60 effectively inhibited P-gp efflux function but not its expression. It is noted that compound 60 is a potentially broad-spectrum chemosensitizer in combination with commonly used anti-tumor drugs, such as doxorubicin, paclitaxel, daunorubicin and vincristine with RF value of 20–80.