Search Results (42)

Effective management of multidrug-resistant cancers depends on effective, localized drug release and accumulation within the tumor microenvironment. In our work, Pluronic P105 and F127 mixed nanogels (PM) were fabricated through self-assembly to combat multidrug-resistant cancer. The approximate diameter of our prepared PM is 115.7 nm, an optimal size for tumor accumulation through the enhanced permeability and retention (EPR) effect. An in vitro drug release assay indicated that ultrasound could accelerate the drug release rate in doxorubicin-loaded Pluronic nanogels (PM/D). Additionally, the resistance reversion index (RRI) in the ultrasound-treated PM/D group was 4.55 and was two times higher than that in the free PM/D group, which represented better MDR reverse performance. Cell experiments demonstrated that, after 3 min of ultrasound, a greater amount of chemo-drug was released and absorbed by the MDR human breast cell line (MCF-7/ADR), resulting in significant cytotoxicity. Such enhanced therapeutic efficiency could be attributed to the combined effects of the two independent mechanisms: (i) ultrasound-controllable drug release realized effective release within resistant tumors with spatial and temporal precision and (ii) the contained Pluronic in the PM/D inhibited P-gp-mediated efflux activity to overcome MDR in tumors. Collectively, our findings support the feasibility of ultrasound-responsive PM as a drug-delivery platform for resistant cancers. Full article

In this study, twenty-four new furoxan and seco-coumarin hybrids were synthesized, and their antiproliferative activities against four breast cancer cells (MCF-7/ADR, MCF-7, MDA-MB-231, and MDA-MB-468) were evaluated. Among them, compound 9e exhibited significant toxicity against MCF-7/ADR cells compared to MCF-7 cells, with a 1401-fold increase, indicating its high collateral sensitivity. Meanwhile, 9e exhibited relatively lower toxicity to normal cell lines and improved solubility compared to the previous active compound, 4A93, which features a coumarin integrity core. Preliminary pharmacological studies revealed that 9e might be a potential P-glycoprotein substrate, which enters the lysosomes of MCF-7/ADR to release effective concentrations of nitric oxide, producing reactive oxygen species and inducing apoptosis. Moreover, laser confocal microscopy and Western Blot experiments showed that 9e could induce autophagy in MCF-7/ADR cells. Additionally, the anti-tumor activity of compound 9e could be inhibited by the ferroptosis inhibitor Fer-1. These results suggest that the remarkable antiproliferative potency of these hybrids in MCF-7/ADR may be related to multiple anticancer mechanisms. As a novel nitric oxide donor, compound 9e was used to explore the potential development of an anti-tumor candidate with special pharmacological mechanisms to overcome multidrug resistance in breast cancer. Full article

Targeting and multidrug resistance are the significant problems of current antitumor drugs, and these problems become the key factors in the design of nanomedicine. Herein, Au NRs and OPC-Au NPs were prepared via the hydroquinone seedless growth method and proanthocyanidin (OPC) one-pot method, and then pH-GSH-near-infrared ΙΙ (NIR-ΙΙ)-responsive nano-prodrugs Au/DOX-ss LNRs and OPC-Au/DOX-ss LNPs were designed by the encapsulation of doxorubicin prodrug DOX-ss with Au-S affinity and thermal-sensitive liposomes. Interestingly, OPC endowed OPC-Au NPs with reducibility and excellent performance in terms of particle size, zeta potential, encapsulation rate, and drug loading rate. In particular, the photothermal efficiencies of OPC-Au/DOX-ss LNPs increased to 59.22% under the 1064 nm NIR-ΙΙ irradiation. Compared with free DOX-ss and Lipid DOX-ss, the IC50 of OPC-Au/DOX-ss LNPs was decreased by 91.68% and 97.60%, respectively. Furthermore, the expression of P-gp in MCF-7/ADR was significantly inhibited (decreased by 65%). The potential of proanthocyanidin remodels the pH-GSH-NIR-ΙΙ responsiveness and drug resistance of OPC-Au/DOX-ss LNPs for breast cancer treatment in NIR-ΙΙ photodynamic/photothermal therapy. Full article

Background/Objectives: The ineffective delivery of drugs into tumors and the existence of multidrug resistance (MDR) are the primary causes of chemotherapy failure. Downregulation of the Sonic Hedgehog (Shh) pathway has been shown to reduce P-glycoprotein (P-gp) expression on cell membranes and to resist MDR. Methods: In this study, we combine cyclopamine (CYP, a potent Shh antagonist) with paclitaxel (PTX, an antitumor drug that can produce MDR) in a nano-drug delivery system (CYP NP and PTX NP) for the treatment of drug-resistant breast cancer. Nanoparticles were characterized for size, zeta potential, and encapsulation efficiency. P-gp expression, nanoparticle accumulation, cytotoxicity, and apoptosis were evaluated in MCF-7 and MCF-7/Adr cells. Penetration ability was assessed using 3D multicellular tumor spheroids. Antitumor efficacy and nanoparticle biodistribution were validated in MCF-7/Adr-bearing nude mice models. Results: Our engineered CYP nanoparticles (~200 nm) demonstrated prolonged intratumoral retention, enabling sustained Shh pathway inhibition and P-gp functional suppression. This size-optimized formulation created a favorable tumor microenvironment for the smaller PTX nanoparticles (~30 nm), facilitating deeper tumor penetration and enhanced cellular uptake. Meanwhile, by down-regulating P-gp expression, CYP NPs could convert drug-resistant cells to PTX-sensitive cells in both cytotoxicity and apoptosis induction through the Shh pathway. The combination of CYP NP and PTX NP augmented the antitumor effects in MCF-7/Adr-bearing nude mice models. Conclusions: The CYP NP and PTX NP combination offers a new therapeutic strategy in cancer treatment. Full article

Background: Doxorubicin (DOX) is a very powerful chemotherapy drug. However, its severe toxicity and potential for resistance development limit its application. Withania somnifera L. Dunal (WIT) has therapeutic capacities, including anti-inflammatory, antioxidant, and anticancer activities. This study investigates the preventative benefits of a standardized WIT extract against DOX-induced renal damage in vivo. We also investigate the synergistic effects of combining WIT and DOX to improve therapeutic efficacy in breast cancer cells (MCF7-ADR). Methods: This study employed an animal model where rats were administered 300 mg/kg/day of WIT orally for a duration of 14 days. Rats received DOX injections at a dose of 5 mg/kg, for a total of 15 mg, on the 6th, 8th, and 10th days. Results: Present results revealed that WIT reduced DOX-induced increase levels of blood urea and creatinine and the activity of kidney injury molecule-1. WIT also reduced renal tissue damage, oxidative stress, and levels of pro-inflammatory markers. WIT alleviated the effects of DOX on nuclear factor erythroid 2-related factor 2, heme oxygenase-1, and sirtuin 1 in the renal tissues. WIT modulated nuclear factor-κB activity and decreased apoptotic indicators. Furthermore, WIT improves DOX’s capacity to kill drug-resistant MCF7-ADR cells by arresting the cell cycle and promoting apoptosis. Chemical analysis of WIT root extract revealed 34 distinct compounds, including alkaloids, withanolides, flavanones, and fatty acids. Conclusions: These constituents synergistically contribute to WIT’s antioxidant, anti-inflammatory, and anti-apoptotic properties. In addition, they confirm its ability to reduce systemic toxicity while improving treatment efficacy. Full article

Acquired resistance to chemotherapeutic drugs is the primary cause of treatment failure in the clinic. While multiple factors contribute to this resistance, increased expression of ABC transporters—such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance proteins—play significant roles in the development of resistance to various chemotherapeutics. We found that Erastin, a ferroptosis inducer, was significantly cytotoxic to NCI/ADR-RES, a P-gp-expressing human ovarian cancer cell line. Here, we examined the effects of both Erastin and RSL3 (Ras-Selected Ligand 3) on reversing Adriamycin resistance in these cell lines. Our results show that Erastin significantly enhanced Adriamycin uptake in NCI/ADR-RES cells without affecting sensitive cells. Furthermore, we observed that Erastin enhanced Adriamycin cytotoxicity in a time-dependent manner. The selective iNOS inhibitor, 1400W, reduced both uptake and cytotoxicity of Adriamycin in P-gp-expressing NCI/ADR-RES cells only. These findings were also confirmed in a BCRP-expressing human breast cancer cell line (MCF-7/MXR), which was selected for resistance to Mitoxantrone. Both Erastin and RSL3 were found to be cytotoxic to MCF-7/MXR cells. Erastin significantly enhanced the uptake of Hoechst dye, a well-characterized BCRP substrate, sensitizing MCF-7/MXR cells to Topotecan. The effect of Erastin was inhibited by 1400W, indicating that iNOS is involved in Erastin-mediated enhancement of Topotecan cytotoxicity. RSL3 also significantly increased Topotecan cytotoxicity. Our findings—demonstrating increased cytotoxicity of Adriamycin and Topotecan in P-gp- and BCRP-expressing cells—suggest that ferroptosis inducers may be highly valuable in combination with other chemotherapeutics to manage patients’ cancer burden in the clinical setting. Full article

Euphorbia uralensis belongs to the family Euphorbiaceae and is widely distributed in northern Xinjiang, making it a characteristic plant of the region in Xinjiang, China. The chemical composition and biological activity of Euphorbia uralensis have not yet been reported, although certain compounds isolated from Euphorbia plants in Xinjiang, China, have demonstrated exceptional multidrug resistance (MDR) reversal. This study aims to investigate the chemical components present in Euphorbia uralensis with the potential to reverse MDR. The aerial parts of Euphorbia uralensis were extracted using organic solvents of varying polarities, resulting in dichloromethane (Fr-E) and petroleum ether (Fr-S) fractions, which exhibited greater MDR reversal activity than the other fractions. The chemical constituents of the Fr-S fraction were analyzed using GC-MS. The chemical components of the Fr-E fraction were isolated and purified using column chromatography. The most effective compounds with MDR reversal activity were screened out, and the mechanism was investigated using molecular docking, molecular dynamics simulations, Western blotting, and rhodamine 123 staining. GC-MS analysis showed that the Fr-S fraction was rich in triterpenes, fatty acids, phenols, and long-chain alkanes, all of which were identified for the first time in Euphorbia uralensis. Among these, palmitic acid was present at a content level of 15.86%. This study notably unveils the discovery of a new compound and 16 previously recorded compounds for the first time in this plant, with the main types identified as steroids, sesquiterpenes, and flavonoids. The isolated compounds were tested for cytotoxicity and MDR reversal activity. The new compounds Euphouralosides A, pubinernoid A, naringenin, and punigratine showed good MDR reversal activity against MCF-7 and MCF-7/ADR cell lines. Punigratine was the most active compound. Moreover, punigratine could stably bind to the ABCB1 protein. Western blot analysis revealed that punigratine did not affect the expression of the ABCB1 protein in cells (p > 0.05). However, following treatment with punigratine (0.16 μM), there was a significant increase the intracellular accumulation of Rh123 in MCF-7/ADR cells (p < 0.05). These findings suggest that punigratine can inhibit the efflux of the ABCB1 protein, thereby overcoming MDR in tumors. This study provides a foundation for further research on the biological activity and medicinal potential of Euphorbia uralensis. Full article

Multidrug resistance (MDR) is frequently induced after long-term exposure to reduce the therapeutic effect of chemotherapeutic drugs, which is always associated with the overexpression of efflux proteins, such as P-glycoprotein (P-gp). Nano-delivery technology can be used as an efficient strategy to overcome tumor MDR. In this study, mesoporous silica nanoparticles (MSNs) were synthesized and linked with a disulfide bond and then coated with lipid bilayers. The functionalized shell/core delivery systems (HT-LMSNs-SS@DOX) were developed by loading drugs inside the pores of MSNs and conjugating with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and hyaluronic acid (HA) on the outer lipid surface. HT-LMSNs-SS and other carriers were characterized and assessed in terms of various characteristics. HT-LMSNs-SS@DOX exhibited a dual pH/reduction responsive drug release. The results also showed that modified LMSNs had good dispersity, biocompatibility, and drug-loading capacity. In vitro experiment results demonstrated that HT-LMSNs-SS were internalized by cells and mainly by clathrin-mediated endocytosis, with higher uptake efficiency than other carriers. Furthermore, HT-LMSNs-SS@DOX could effectively inhibit the expression of P-gp, increase the apoptosis ratios of MCF-7/ADR cells, and arrest cell cycle at the G0/G1 phase, with enhanced ability to induce excessive reactive oxygen species (ROS) production in cells. In tumor-bearing model mice, HT-LMSNs-SS@DOX similarly exhibited the highest inhibition activity against tumor growth, with good biosafety, among all of the treatment groups. Therefore, the nano-delivery systems developed herein achieve enhanced efficacy towards resistant tumors through targeted delivery and redox-responsive drug release, with broad application prospects. Full article

Multidrug resistance (MDR) is a key factor in chemotherapy failure and tumor recurrence. The inhibition of drug efflux and autophagy play important roles in MDR therapy. Herein, a multifunctional delivery system (HA-MIL-125@DVMA) was prepared for synergistically reverse tumor MDR. Tumor-targeted hollow MIL-125-Ti nanoparticles were used to load the doxorubicin–vitamin E succinate (DV) prodrug and 3-methyladenine (3-MA) to enhance reverse MDR effects. The pH-sensitive DV can kill tumor cells and inhibit P-gp-mediated drug efflux, and 3-MA can inhibit autophagy. HA-MIL-125@DVMA had uniformly distributed particle size and high drug-load content. The nanoparticles could effectively release the drugs into tumor microenvironment due to the rapid hydrazone bond-breaking under low pH conditions, resulting in a high cumulative release rate. In in vitro cellular experiments, the accumulation of HA-MIL-125@DVMA and HA-MIL-125@DV in MCF-7/ADR cells was significantly higher than that in the control groups. Moreover, the nanoparticles significantly inhibited drug efflux in the cells, ensuring the accumulation of the drugs in cell cytoplasm and causing drug-resistant cells’ death. Importantly, HA-MIL-125@DVMA effectively inhibited tumor growth without changes in body weight in tumor-bearing mice. In summary, the combination of the acid-sensitive prodrug DV and autophagy inhibitor 3-MA in a HA-MIL-125 nanocarrier can enhance the antitumor effect and reverse tumor MDR. Full article

Multidrug resistance (MDR) caused by ATP-Binding Cassette Subfamily B Member 1 (ABCB1, P-glycoprotein, P-gp) is a major barrier for the success of chemotherapy in clinics. In this study, we designed and synthesized a total of 19 Lissodendrins B analogues and tested their ABCB1-mediated MDR reversal activity in doxorubicin (DOX)-resistant K562/ADR and MCF-7/ADR cells. Among all derivatives, compounds D₁, D₂, and D₄ with a dimethoxy-substituted tetrahydroisoquinoline fragment possessed potent synergistic effects with DOX and reversed ABCB1-mediated drug resistance. Notably, the most potent compound D₁ merits multiple activities, including low cytotoxicity, the strongest synergistic effect, and effectively reversing ABCB1-mediated drug resistance of K562/ADR (RF = 1845.76) and MCF-7/ADR cells (RF = 207.86) to DOX. As a reference substance, compound D₁ allows for additional mechanistic studies on ABCB1 inhibition. The synergistic mechanisms were mainly related to the increased intracellular accumulation of DOX via inhibiting the efflux function of ABCB1 rather than from affecting the expression level of ABCB1. These studies suggest that compound D₁ and its derivatives might be potential MDR reversal agents acting as ABCB1 inhibitors in clinical therapeutics and provide insight into a design strategy for the development of ABCB1 inhibitors. Full article

Multidrug resistance (MDR) is the major complex mechanism that causes the failure of chemotherapy, especially with drugs of natural origin such as doxorubicin (DOX). Intracellular drug accumulation and detoxification are also involved in cancer resistance by reducing the susceptibility of cancer cells to death. This research aims to identify the volatile composition of Cymbopogon citratus (lemon grass; LG) essential oil and compare the ability of LG and its major compound, citral, to modulate MDR in resistant cell lines. The composition of LG essential oil was identified using gas chromatography mass spectrometry (GC-MS). In addition, a comparison of the modulatory effects of LG and citral, performed on breast (MCF-7/ADR), hepatic (HepG-2/ADR), and ovarian (SKOV-3/ADR) MDR cell lines, were compared to their parent sensitive cells using the MTT assay, ABC transporter function assays, and RT-PCR. Oxygenated monoterpenes (53.69%), sesquiterpene hydrocarbons (19.19%), and oxygenated sesquiterpenes (13.79%) made up the yield of LG essential oil. α-citral (18.50%), β-citral (10.15%), geranyl acetate (9.65%), ylangene (5.70), δ-elemene (5.38%), and eugenol (4.77) represent the major constituents of LG oil. LG and citral (20 μg/mL) synergistically increased DOX cytotoxicity and lowered DOX dosage by >3-fold and >1.5-fold, respectively. These combinations showed synergism in the isobologram and CI < 1. DOX accumulation or reversal experiment confirmed that LG and citral modulated the efflux pump function. Both substances significantly increased DOX accumulation in resistant cells compared to untreated cells and verapamil (the positive control). RT-PCR confirmed that LG and citral targeted metabolic molecules in resistant cells and significantly downregulated PXR, CYP3A4, GST, MDR1, MRP1, and PCRP genes. Our results suggest a novel dietary and therapeutic strategy combining LG and citral with DOX to overcome multidrug resistance in cancer cells. However, these results should be confirmed by additional animal experiments before being used in human clinical trials. Full article

Cancer is considered one of the most burdensome diseases affecting lives and, hence, the economy. Breast cancer is one of the most common types of cancer. Patients with breast cancer are divided into two groups: one group responds to the chemotherapy, and the other group resists the chemotherapy. Unfortunately, the group which resists the chemotherapy is still suffering the pain associated with the severe side effects of the chemotherapy. Therefore, there is a critical need for a method to differentiate between both groups before the administration of the chemotherapy. Exosomes, the recently discovered nano-vesicles, are often used as cancer diagnostic biomarkers as their unique composition allows them to represent their parental cells, which makes them promising indicators for tumor prognosis. Exosomes contain proteins, lipids, and RNA that exist in most body fluids and are expelled by multiple cell types, including cancer cells. Furthermore, exosomal RNA has been significantly used as a promising biomarker for tumor prognosis. Herein, we have developed an electrochemical system that could successfully differentiate between MCF7 and MCF7/ADR depending on the exosomal RNA. The high sensitivity of the proposed electrochemical assay opens the door for further investigation that will address the other type of cancer cells. Full article

The simultaneous drug delivery efficiency of a co-loaded single-carrier system of docetaxel (DTX)- and tariquidar (TRQ)-loaded nanostructured lipid carrier (NLC) functionalized with PEG and RIPL peptide (PRN) (D^T-PRN) was compared with that of a physically mixed dual-carrier system of DTX-loaded PRN (D-PRN) and TRQ-loaded PRN (T-PRN) to overcome DTX mono-administration-induced multidrug resistance. NLC samples were prepared using the solvent emulsification evaporation technique and showed homogeneous spherical morphology, with nano-sized dispersion (<220 nm) and zeta potential values of −15 to −7 mV. DTX and/or TRQ was successfully encapsulated in NLC samples (>95% encapsulation efficiency and 73–78 µg/mg drug loading). In vitro cytotoxicity was concentration-dependent; D^T-PRN exhibited the highest MDR reversal efficiency, with the lowest combination index value, and increased the cytotoxicity and apoptosis in MCF7/ADR cells by inducing cell-cycle arrest in the G2/M phase. A competitive cellular uptake assay using fluorescent probes showed that, compared to the dual nanocarrier system, the single nanocarrier system exhibited better intracellular delivery efficiency of multiple probes to target cells. In the MCF7/ADR-xenografted mouse models, simultaneous DTX and TRQ delivery using D^T-PRN significantly suppressed tumor growth as compared to other treatments. A single co-loaded system for PRN-based co-delivery of DTX/TRQ (1:1, w/w) constitutes a promising therapeutic strategy for drug-resistant breast cancer cells. Full article

In this work, we used microwave irradiation conditions to synthesize β-enaminonitrile (4), which was affirmed using single crystal X-ray diffraction and the different spectral data. Two tumor cell lines, MCF-7 and MCF-7/ADR, as well as two normal cell lines, HFL-1 and WI-38, were used to assess the anticancer activity of compound 4. The studied molecule exhibited potent efficacy against the MCF-7 and MCF-7/ADR cell lines compared with the reference drugs. Furthermore, target compound 4 had feeble activity against HFL-1 and WI-38. The chemical reactivity was discussed using DFT and QTAIM analysis to study the intrinsic electronic properties of compound 4. A molecular docking study was also conducted to examine their binding affinity to the EGFR. Compound 4 revealed a stable binding mode at the enzyme active pocket more than the reference inhibitor. The docking analysis was performed for molecule (4). Full article

β-Enaminonitriles bearing 9-hydroxy-1H-benzo[f]chromene moiety was synthesized. The targeted compounds were evaluated for their anti-proliferative activity against three human tumor cell lines, PC-3, SKOV-3 and HeLa, and the active cytotoxic compounds were further evaluated against cancer cells, MCF-7/ADR, and two normal cell lines, HFL-1 and WI-38. Few compounds were assigned to be the most potent derivatives against PC-3, SKOV-3 and HeLa cell lines in comparison with Vinblastine and Doxorubicin. Several compounds possessed a relatively good potency against MCF-7/ADR cells as compared with Doxorubicin and were tested as a P-gp inhibitor. Moreover, the halogenated substituents, 2,4-F₂, 2,3-Cl₂, 2,5-Cl₂ and 3,4-Cl_2; have good potency against P-gp-mediated MDR in MCF-7/ADR as compared with Doxorubicin. Meanwhile, Rho123 accumulation assays revealed that few compounds effectively inhibited P-pg and efflux function. In addition, certain derivatives induced apoptosis and an accumulation of the treated MCF-7/ADR cells in the G1, S and G1/S phases. Full article