Treatment Of Multidrug-resistant Cancer Research Articles

Synergistic anticancer efficacy of polydatin and sorafenib against the MCF-7 breast cancer cell line via inhibiting of PI3K/AKT/mTOR pathway and reducing resistance to treatment

Polydatin (PD), a glucoside derivative of resveratrol, has been investigated for its potential to mitigate sorafenib (SOF) side effects and combat multidrug resistance in cancer treatment. The study evaluated its mechanism of action for inhibiting the protein kinase B/mTOR pathway in promoting breast cancer proliferation. The combined PD and SOF have synergistic effects with a combination index (CI) < 1 in the liver (HepG2) and breast (MCF-7) cancer cell lines. Molecular docking studies were conducted to analyze interactions of PD& SOF with protein kinases as well as apoptotic and multidrug resistance proteins, including AKT1, PI3K, mTOR, Apaf-1, and ABCB1 in MCF-7 cells. Experimental validation through real-time PCR confirmed. PD has a strong binding affinity, particularly with AKT1 (-56 kcal/mol) and ABCB1 (-27.16 kcal/mol), a gene associated with multidrug resistance. These interactions were linked to anti-proliferative anti-angiogenic effects and reduced resistance to treatment, demonstrating PD has potential therapeutic benefits. Furthermore, PD combined with SOF induced apoptosis, inhibited cell growth, and arrested MCF-7 cells in the sub-G1 phase with increased intracellular ROS. This was accompanied by reduced expression of AKT1 and ABCB1 genes, reinforcing the anticancer efficacy of PD/SOF combination therapy. In conclusion, the findings suggest that PD/SOF could serve as a promising anticancer treatment strategy, warranting further investigation for potential clinical applications and mechanistic studies in vivo.

Activity of protegrin-1 against mouse Ehrlich ascites carcinoma &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt;

BACKGROUND: The problem of multidrug resistance in cancer treatment creates an urgent demand for developing new effective antitumor agents. Due to the unusual mechanism of recognizing and damaging tumor cells, antimicrobial peptides are considered as possible prototypes for designing such therapeutics. AIM: This work was aimed to compare the antitumor potential of the promising membranolytic antimicrobial peptide protegrin-1 in vitro and in vivo in Ehrlich ascites carcinoma mice model. MATERIALS AND METHODS: We used two variants of the model by inducing a tumor in solid or ascites form. In the first case, the mice were injected with the peptide twice a week for three weeks, and in the second injections were provided every other day for six days. The activity of antimicrobial peptides against isolated Ehrlich ascites carcinoma cells in vitro was analyzed using MTT-test. RESULTS: Protegrin-1 demonstrated high activity against Ehrlich ascites carcinoma cells in vitro, but had no significant effect on the lifespan of mice bearing solid or ascites form of Ehrlich tumor at the dosing and administration regimens we used. However, treatment with protegrin-1 caused a decrease in the ascites volume and in the number of cells in the ascites fluid. CONCLUSIONS: Protegrin-1 retains its antitumor properties in vivo, but it may be presumed, that to effectively suppress tumor growth it requires a more frequent and prolonged administration compared with conventional antitumor antibiotics, of which we adopted the administration regimen for protegrin-1 in this study.

Synergistic pH-responsive MUC-1 aptamer-conjugated Ag/MSN Janus nanoparticles for targeted chemotherapy, photothermal therapy, and gene therapy in breast cancer

Drug resistance in cancer treatment, primarily attributed to the overexpression of the multidrug resistance (MDR) gene, significantly hampers the effectiveness of chemotherapy. This mechanism, driven by the increased production of P-glycoprotein (P-gp) efflux pumps, highlights the urgent need for innovative strategies to combat drug resistance in cancer patients. This study explores the application of antisense technology to suppress MDR gene expression, while addressing the challenges of instability and limited cellular uptake associated with antisense oligonucleotides. We synthesized Janus silver-mesoporous silica nanoparticles (Ag/MSN JNPs) using a sol-gel method, characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS), revealing uniformly sized, dumbbell-shaped nanoparticles with an average size of 285 ± 5.12 nm. Doxorubicin (DOX) was loaded into the porous structure of the mesoporous silica, and JNPs were functionalized with chitosan (CS) to incorporate P-gp antisense and a MUC-1 aptamer, serving as a pH-responsive gatekeeper. Our findings indicate that the Ap-As-DOX-JNPs achieved a remarkable 89 ± 0.59 % cell death in drug-resistant MCF-7/ADR cells after 48 h, alongside an 80 % reduction in P-gp expression. The combination of DOX, antisense technology, and photothermal therapy utilizing these JNPs demonstrates a promising strategy to effectively overcome drug resistance. Notably, normal MCF-7 cells exhibited reduced viability from 39.11 ± 1.12 % to 30.05 ± 1.07 % when treated with DOX-JNPs under near-infrared (NIR) irradiation. These results underscore the potential of utilizing MUC-1 aptamer-conjugated Janus nanoparticles in conjunction with chitosan as a gatekeeper to enhance the efficacy of chemotherapy, photothermal therapy, and gene therapy in overcoming multidrug resistance in cancer treatment.

Mosloflavone from Fissistigma petelotii ameliorates oncogenic multidrug resistance by STAT3 signaling modulation and P-glycoprotein blockade

BackgroundOncogenic multidrug resistance (MDR) is a tough question in cancer therapy. However, no effective medications targeting oncogenic MDR are currently available. Studies have demonstrated that mosloflavone exerts anti-inflammatory effects, yet, its potential to ameliorate MDR remains unclear. PurposeThis study aimed to access the capability and elucidate molecular mechanisms of mosloflavone as a MDR resensitizing candidate. MethodsWe investigated the ability of mosloflavone to reverse oncogenic MDR and investigated its underlying mechanisms through cytotoxicity assay, cell cycle assay, apoptosis assay, and zebrafish xenograft model. The modulatory interplay between mosloflavone and P-gp was investigated through analysis of calcein-AM uptake, substrate efflux, ATPase assays, and molecular docking simulation. ResultsMosloflavone inhibited P-gp efflux function in an uncompetitive manner without altering ABCB1 gene expression. In addition, it stimulated P-gp ATPase activity by binding to an active site distinct from that of verapamil. Regarding MDR reversal potential, mosloflavone resensitized MDR cancer cells to chemotherapies by arresting cell cycle and triggering apoptosis, possibly by enhancing reactive oxygen species accumulation and reducing phospho-STAT3. Moreover, in the zebrafish xenograft model, mosloflavone significantly potentiated the antitumor effect of paclitaxel. ConclusionOur findings underscore the potential of mosloflavone as a novel dual modulator of STAT3 and P-gp, indicating it is a promising candidate for overcoming MDR in cancer treatment.

Cytotoxicity and reversal effect of sertraline, fluoxetine, and citalopram on MRP1- and MRP7-mediated MDR.

Cancer is one of the leading causes of death worldwide, and the development of resistance to chemotherapy drugs is a major challenge in treating malignancies. In recent years, researchers have focused on understanding the mechanisms of multidrug resistance (MDR) in cancer cells and have identified the overexpression of ATP-binding cassette (ABC) transporters, including ABCC1/MRP1 and ABCC10/MRP7, as a key factor in the development of MDR. In this study, we aimed to investigate whether three drugs (sertraline, fluoxetine, and citalopram) from the selective serotonin reuptake inhibitor (SSRI) family, commonly used as antidepressants, could be repurposed as inhibitors of MRP1 and MRP7 transporters and reverse MDR in cancer cells. Using a combination of in silico predictions and in vitro validations, we analyzed the interaction of MRP1 and MRP7 with the drugs and evaluated their ability to hinder cell resistance. We used computational tools to identify and analyze the binding site of these three molecules and determine their binding energy. Subsequently, we conducted experimental assays to assess cell viability when treated with various standard chemotherapies, both with and without the presence of SSRI inhibitors. Our results show that all three SSRI drugs exhibited inhibitory/reversal effects in the presence of chemotherapies on both MRP1-overexpressed cells and MRP7-overexpressed cells, suggesting that these medications have the potential to be repurposed to target MDR in cancer cells. These findings may open the door to using FDA-approved medications in combination therapy protocols to treat highly resistant malignancies and improve the efficacy of chemotherapy treatment. Our research highlights the importance of investigating and repurposing existing drugs to overcome MDR in cancer treatment.

Furmonertinib, a Third-Generation EGFR Tyrosine Kinase Inhibitor, Overcomes Multidrug Resistance through Inhibiting ABCB1 and ABCG2 in Cancer Cells.

ATP-binding cassette transporters, including ABCB1 (P-glycoprotein) and ABCG2 (BCRP/MXR/ABCP), are pivotal in multidrug resistance (MDR) development in cancer patients undergoing conventional chemotherapy. The absence of approved therapeutic agents for multidrug-resistant cancers presents a significant challenge in effectively treating cancer. Researchers propose repurposing existing drugs to sensitize multidrug-resistant cancer cells, which overexpress ABCB1 or ABCG2, to conventional anticancer drugs. The goal of this study is to assess whether furmonertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor overcomes drug resistance mediated by ABCB1 and ABCG2 transporters. Furmonertinib stands out due to its ability to inhibit drug transport without affecting protein expression. The discovery of this characteristic was validated through ATPase assays, which revealed interactions between furmonertinib and ABCB1/ABCG2. Additionally, in silico docking of furmonertinib offered insights into potential interaction sites within the drug-binding pockets of ABCB1 and ABCG2, providing a better understanding of the underlying mechanisms responsible for the reversal of MDR by this repurposed drug. Given the encouraging results, we propose that furmonertinib should be explored as a potential candidate for combination therapy in patients with tumors that have high levels of ABCB1 and/or ABCG2. This combination therapy holds the potential to enhance the effectiveness of conventional anticancer drugs and presents a promising strategy for overcoming MDR in cancer treatment.

Redefine the role of d-α-Tocopheryl polyethylene glycol 1000 succinate on P-glycoprotein, multidrug resistance protein 1, and breast cancer resistance protein mediated cancer multidrug resistance

Cancer drug resistance is an ever-changing problem that most patients need to face in their later stages of treatment, especially the multidrug resistant (MDR) type. The drug efflux transporters, including P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), and breast cancer resistance protein (BCRP), play the crucial roles in this sophisticated battle. In recent decades, researchers try to find potential inhibitors to impede the drug efflux function of above transporters. d-α-Tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) is a prevalently used excipient in the formulation design. In the present study, the modulatory effects and mechanisms of vitamin E TPGS on the efflux transporters were investigated. And the cancer MDR reversing ability of vitamin E TPGS was evaluated as well. Stable-cloned transporter over-expressed cell lines were used for mechanisms study, while several types of MDR cancer cell lines were adopted as reversing evaluation models. The results exhibited that vitamin E TPGS significantly inhibited the efflux function of P-gp, MRP1, and BCRP under non-cytotoxic concentrations, but not influencing the protein expression levels. Through efflux assay and molecular docking, vitamin E TPGS was found to be an uncompetitive, non-competitive, and competitive inhibitor on chemotherapeutic drug doxorubicin efflux in P-gp, MRP1, and BCRP over-expressing cell lines, respectively. Furthermore, the basal ATPase activity of three transporters were significantly inhibited by vitamin E TPGS at 10 μM. And the cell membrane fluidity of P-gp over-expressing cell line was enhanced by 22.58% with 5 μM vitamin E TPGS treatment, compared to the parental Flp-In™-293 cell line (without P-gp). The resistance reversing ability of vitamin E TPGS was prominent in MCF-7/DOX MDR breast cancer cell line, which over-expressed P-gp, MRP1, and BCRP. These significant results suggested that vitamin E TPGS is a promising modulator on transporters mediated cancer MDR. Vitamin E TPGS is not an inert excipient, but possesses MDR-reversing pharmacological effects, and deserves a re-purposing application on the future combinatorial regimen design for MDR cancer treatment.

Use of Enzymatically Activated Carbon Monoxide Donors for Sensitizing Drug-Resistant Tumor Cells.

The application of gaseous signaling molecules like NO, H2S or CO to overcome the multidrug resistance in cancer treatment has proven to be a viable therapeutic strategy. The development of CO-releasing molecules (CORMs) in a controlled manner and in targeted tissues remains a challenge in medicinal chemistry. In this paper, we describe the design, synthesis and chemical and enzymatic stability of a novel non-metal CORM (1) able to release intracellularly CO and, simultaneously, facilitate fluorescent degradation of products under the action of esterase. The toxicity of 1 against different human cancer cell lines and their drug-resistant counterparts, as well as the putative mechanism of toxicity were investigated. The drug-resistant cancer cell lines efficiently absorbed 1 and 1 was able to restore their sensitivity vs. chemotherapeutic drugs by causing a CO-dependent mitochondrial oxidative stress that culminated in mitochondrial-dependent apoptosis. These results demonstrate the importance of CORMs in cases where conventional chemotherapy fails and thus open the horizons towards new combinatorial strategies to overcome multidrug resistance.

Abstract 1997: 2C5 antibody modified dendrimer-based mixed micelles for the treatment of multidrug resistant cancers

Abstract Purpose: A major hurdle in chemotherapy is multidrug resistance (MDR) observed in tumors. Downregulation of efflux proteins such as P-glycoprotein (P-gp) using small interfering RNA (siRNA) can be an effective way to treat resistant tumors. In this study, monoclonal antibody 2C5 (mAb 2C5) - PEG7k-DOPE conjugates were post-inserted into the mixed dendrimer micelles containing generation 4 (G4) polyamidoamine (PAMAM)-PEG2k-DOPE and PEG5k-DOPE. The inherent amphiphilic nature of DOPE conjugates causes the copolymers to self-assemble to form a micelle and encapsulate hydrophobic chemotherapeutic drug in its core. The siRNA electrostatically binds to the cationic charges on the G4 PAMAM dendrimer. The tumor-specific mAb 2C5 on the surface of these nano-preparations resulted in improved tumor targeting. Methods: G4 PAMAM-PEG2k-DOPE was prepared by conjugating G4 PAMAM with para-nitrophenol (pNP)-PEG2k-DOPE. To prepare 2C5-PEG7k-DOPE, mAb 2C5 was mixed with micelles containing pNP-PEG7k-DOPE and PEG5k-DOPE in sodium citrate buffer at pH 5.0 and later adjusted the pH to 8.0. In vitro evaluation of the targeted and non-targeted micelles were performed in both MDA-MB-231 and SKOV-3TR resistant cell lines. Further a xenograft MDA-MB-231 in vivo mice tumor models were performed. Results: The 2C5-conjugated mixed dendrimer micelles have a uniform size distribution with a slightly positive zeta potential. They show a stable size and zeta potential for 20 days. The morphology of the 2C5 modified micelles was confirmed using TEM imaging. A higher cellular association was observed in the micelles with the 2C5 antibody targeting using fluorescence imaging (DOPE-FITC tagged micelle) in both the cell lines. At 30 minutes the 2C5 targeted mixed dendrimer micelles showed high cellular uptake and was analyzed using flow cytometry. We further evaluated the P-gp downregulation using western blot and observed a significant downregulation of P-gp levels in the targeted formulation versus the non-targeted formulation. The in vivo tumor growth inhibition study in nude NCG 572 MDA-MB-231 tumor bearing mice showed that the immuno-micelles loaded with siMDR-1 and chemotherapeutics resulted in significantly increased therapeutic efficacy compared to non-modified mixed dendrimer micelles. Conclusions: We have evaluated the 2C5 antibody-modified mixed dendrimer micelles in different cell models, in addition to the models tested in our previous studies. We have successfully established the stability of the formulation in this study and established a 20-day shelf-life. Cellular association, internalization and P-gp downregulation studies show the superiority of the 2C5 modified dendrimer micelles upon non-targeted preparations or free actives. Citation Format: Satya Siva Kishan Yalamarty, Nina Filipczak, Xiang Li, Tanvi Vinod Pathrikar, Colin Cotter, Vladimir P. Torchilin. 2C5 antibody modified dendrimer-based mixed micelles for the treatment of multidrug resistant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1997.

Nanocracker capable of simultaneously reversing both P-glycoprotein and tumor microenvironment.

Here, we describe a multidrug-resistant nanocracker (MDRC) that can treat multi-drug resistant (MDR) cancer by recognizing the acidic microenvironment and inhibiting two mechanisms of MDR such as P-glycoprotein (P-gp) and vacuolar-type ATPase (V-ATPase). MDRC is a liposome formulation co-loading pantoprazole (PZ) and paclitaxel (PTX). PZ acts as a chemosensitizer that enhances the MDR cancer treatment effect of PTX by disrupting the pH gradient and inhibiting P-gp. MDRC-encapsulated PZ and PTX have different release rates, with PZ released within 12h and PTX sustained release for 48h in the plasma. MDRC could increase cell uptake by inhibiting the P-gp overexpressed MCF-7/mdr cells and UV-2237M cells, which are human breast MDR cancer cells and murine fibrosarcoma cells, respectively. MDRC can also increase the cytotoxic efficacy of PTX by increasing intracellular pH. MDRC has a 10.5-fold reduced IC50 value in the P-gp overexpressed human breast adenocarcinoma and a 6.3- to 9.5-fold reduced IC50 value in the P-gp non-expressed human breast adenocarcinoma compared to the mixture of PZ and PTX, respectively. Intravenous injection of MDRC did not cause weight loss, liver dysfunction, or major organ toxicity. MDRC exhibited 80% complete remission of murine fibrosarcoma. The excellent therapeutic effect of MDRC on MDR tumors was accompanied by an increase in dendritic cell maturation and cytotoxic T cells. In other words, MDRC has the potential to terminate MDR therapy through the complete remission of MDR tumors.

Metal-organic framework for biomimetic nitric oxide generation and anticancer drug delivery

The potential therapeutic implications of nitric oxide (NO) have drawn a great deal of interest for reversing multidrug resistance (MDR) in cancer; however, previous strategies utilized unstable or toxic NO donors often oxidized by the excessive addition of reactive oxygen species, leading to unexpected side effects. Therefore, this study proposed a metal-organic framework (MOF), Porous coordination network (PCN)-223-Fe, to be loaded with a biocompatible NO donor, L-arginine (L-arg; i.e., PCN-223-Fe/L-arg). This specific MOF possesses a ligand of Fe-porphyrin, a biomimetic catalyst. Thus, with PCN-223-Fe/L-arg, L-arg was released in a sustained manner, which generated NO by a catalytic reaction between L-arg and Fe-porphyrin in PCN-223-Fe. Through this biomimetic process, PCN-223-Fe/L-arg could generate sufficient NO to reverse MDR at the expense of hydrogen peroxide already present and highly expressed in cancer environments. For treatment of MDR cancer, this study also proposed PCN-223-Fe loaded with an anticancer drug, irinotecan (CPT-11; i.e., PCN-223-Fe/CPT-11), to be formulated together with PCN-223-Fe/L-arg. Owing to the synergistic effect of reversed MDR by NO generation and sustained release of CPT-11, this combined formulation exhibited a higher anticancer effect on MDR cancer cells (MCF-7/ADR). When intratumorally injected in vivo, coadministration of PCN-223-Fe/L-arg and PCN-223-Fe/CPT-11 greatly suppressed tumor growth in nude mice bearing MDR tumors.

Olaparib Conjugates with Selenopheno[3,2-c]quinolinone Inhibit PARP1 and Reverse ABCB1-Related Multidrug Resistance.

The restoration of the efficacy of antitumor medicines is a cornerstone in the combat with multidrug resistant (MDR) cancers. The overexpression of the ABCB1 transporter is a major obstacle to conventional doxorubicin therapy. The synergy of ABCB1 suppression and PARP1 activity inhibition that hampers malignant cell DNA repair could be a powerful tool in anticancer therapy. Herein, we report the design and synthesis of three novel olaparib conjugates with selenophenoquinolinones, their ability to reverse doxorubicin resistance in uterus sarcoma cells as well as their mechanism of action. It was found that the most potent chemosensitizer among studied compounds preserves PARP1 inhibitory activity and attenuates cells' resistance to doxorubicin by inhibiting ABCB1 transporter activity. These results demonstrate that the conjugation of PARP inhibitors with selenophenoquinolinones is a prospective direction for the development of agents for the treatment of MDR cancers.

Paclitaxel-loaded ginsenoside Rg3 liposomes for drug-resistant cancer therapy by dual targeting of the tumor microenvironment and cancer cells

IntroductionInherent or acquired resistance to paclitaxel (PTX) is a pivotal challenge for chemotherapy treatment of multidrug-resistant (MDR) breast cancer. Although various targeted drug-delivery systems, including nanoparticles and liposomes, are effective for MDR cancer treatment, their efficacy is restricted by immunosuppressive tumor microenvironment (TME). MethodsGinsenosides Rg3 was used to formulate unique Rg3-based liposomes loaded with PTX to establish Rg3-PTX-LPs, which were prepared by the thin-film hydration method. The stability of the Rg3-PTX-LPs was evaluated by particle size analysis through dynamic light scattering. The active targeting effect of Rg3-based liposomes was examined in an MCF-7/T xenograft model by an in a vivo imaging system. To evaluate the antitumor activity and mechanism of Rg3-PTX-LP, MTT, apoptosis assays, TAM regulation, and TME remodeling were performed in MCF-7/T cells in vitro and in vivo. ResultsRg3-PTX-LPs could specifically distribute to MCF7/T cancer cells and TME simultaneously, mainly through the recognition of GLUT-1. The drug resistance reversing capability and in vivo antitumor effect of Rg3-PTX-LPs were significantly improved compared with conventional cholesterol liposomes. The TME remodeling mechanisms of Rg3-PTX-LPs included inhibiting IL-6/STAT3/p-STAT3 pathway activation to repolarize protumor M2 macrophages to antitumor M1 phenotype, suppressing myeloid-derived suppressor cells (MDSCs), decreasing tumor-associated fibroblasts (TAFs) and collagen fibers in TME, and promoting apoptosis of tumor cells. Hence, through the dual effects of targeting tumor cells and TME remodeling, Rg3-PTX-LPs achieved a high tumor inhibition rate of 90.3%. ConclusionOur multifunctional Rg3-based liposome developed in the present study offered a promising strategy for rescuing the drug resistance tumor treatment.

Screening potential P-glycoprotein inhibitors by combination of a detergent-free membrane protein extraction with surface plasmon resonance biosensor

P-glycoprotein (P-gp) highly expressed in cancer cells can lead to multidrug resistance (MDR) and the combination of anti-cancer drugs with P-gp inhibitor has been a promising strategy to reverse MDR in cancer treatment. In this study, we established a label-free and detergent-free system combining surface plasmon resonance (SPR) biosensor with styrene maleic acid (SMA) polymer membrane proteins (MPs) stabilization technology to screen potential P-gp inhibitors. First, P-gp was extracted from MCF-7/ADR cells using SMA polymer to form SMA liposomes (SMALPs). Following that, SMALPs were immobilized on an SPR biosensor chip to establish a P-gp inhibitor screening system, and the affinity between P-gp and small molecule ligand was determined. The methodological investigation proved that the screening system had good specificity and stability. Nine P-gp ligands were screened out from 50 natural products, and their affinity constants with P-gp were also determined. The in vitro cell verification experiments demonstrated that tetrandrine, fangchinoline, praeruptorin B, neobaicalein, and icariin could significantly increase the sensitivity of MCF-7/ADR cells to Adriamycin (Adr). Moreover, tetrandrine, praeruptorin B, and neobaicalein could reverse MDR in MCF-7/ADR cells by inhibiting the function of P-gp. This is the first time that SMALPs-based stabilization strategy was applied to SPR analysis system. SMA polymer can retain P-gp in the environment of natural lipid bilayer and thus maintain the correct conformation and physiological functions of P-gp. The developed system can quickly and accurately screen small molecule ligands of complex MPs and obtain affinity between complex MPs and small molecule ligands without protein purification.

Subcellular-Targeted Near-Infrared-Responsive Nanomedicine with Synergistic Chemo-photothermal Therapy against Multidrug Resistant Cancer.

Multidrug resistance (MDR) is a major obstacle to effective cancer treatment. Therefore, developing effective approaches for overcoming the limitation of MDR in cancer therapy is very essential. Chemotherapy combined with photothermal therapy (PTT) is a potential therapeutic option against MDR. Herein, we developed a subcellular-targeted near-infrared (NIR)-responsive nanomedicine (Fe3O4@PDA-TPP/S2-PEG-hyd-DOX, abbreviated as Fe3O4-ATSPD) as a new photothermal agent with improved photothermal stability and efficiency. This system demonstrates high stability in blood circulation and can be accumulated at the tumor site by magnetic targeting enhanced permeability and retention effect (EPR). Near-infrared (NIR) irradiation at the tumor site generates a photothermal effect from the photosensitizer Fe3O4@PDA, leading to a dramatic decrease in mitochondrial membrane potential. Simultaneously, the conjugated drugs released under low pH condition in endosomes or lysosomes cause nucleus DNA damage and cell apoptosis. This subcellular-targeted NIR-responsive nanomedicine with efficient integration of diagnosis and therapy could significantly enhance MDR cancer treatment by combination of chemotherapy and PTT.

The relationship between autophagy and multidrug resistance in cancer stem cells

Cancer stem cells (CSCs) are considered the origin of tumors and cancer. Recently, CSCs have been described as the cause of multidrug resistance (MDR) in almost all cancers. The MDR phenotype of CSCs manifests as the upregulation of ATP-binding cassette subfamily G, isoform 2 protein (ABCG2) in the cell membranes of CSCs. However, recent studies have demonstrated a relationship between MDR and the autophagy process of CSCs. Based on publications indexed in PubMed, Google Scholar, and Scopus, this review summarizes the relationship between autophagy and MDR in CSCs and the approaches to targeting autophagy to reduce MDR in CSCs. Autophagy can be considered a new target to overcome MDR in cancer treatment.

A Literature Curated Profile of miRNA IN Modulating Multi-Drug Resistance for Cancer Therapy

Abstract: At present, cancer is one of the major causes of death, affecting millions of people each year. Multi Drug Resistance (MDR) remains the major clinical obstacle in cancer treatment. Till date various mechanisms of MDR has been elucidated which includes- over expression of drug transporter, defect in cell cycle and apoptotic machinery, induction of autophagy, alteration in drug metabolism and drug target. microRNAs (miRNAs) are an extensive class of 22 nucleotide long non coding RNAs which are involved in gene regulation. Recent work has underlined the involvement of miRNA in cancer development with several studies regarding their involvement in drug resistance, thereby holding much promise for developing novel and more effective therapy for cancer treatment. This review presents the mechanisms of MDR and focuses on the profile of miRNA in regulating MDR in cancer treatment. Keywords: miRNA, Cancer, Multi-drug resistance, Drug target, Drug transporter, Apoptotic machinery.

Autophagy Modulation and Synergistic Therapy to Combat Multidrug Resistance Breast Cancer Using Hybrid Cell Membrane Nanoparticles.

The development of multidrug resistance (MDR) is a commonly observed phenomenon in many cancer types. It contributed significantly to the poor outcome of many currently available chemotherapies. Considering autophagy as one of the most important physiological process in cancer progression, we thereby proposed an anti-autophagy siRNA and doxorubicin (Dox) co-delivery system (MC/D-siR) to combat MDR breast cancer using sequential construction. Our results demonstrated the potential of MC/D-siR to effectively transfect the loaded siRNA to result in significant downregulation of intracellular autophagy level in MCF-7/Adr (Dox resistance MCF-7 cell line) cells, which in turn cut off the ATP supply and to reverse the MDR and potentiated accumulated drug retention in cells. As a result, MC/D-siR showed much elevated anticancer benefits than single loaded platforms (MC/Dox or MC/siRNA), indicating the ability for effective MDR cancer treatment through the combination of autophagy regulation and chemotherapy.

TPGS and chondroitin sulfate dual-modified lipid-albumin nanosystem for targeted delivery of chemotherapeutic agent against multidrug-resistant cancer

Multidrug resistance (MDR) remains the primary issue leading to the failure of chemotherapy. In this study, a d-α-tocopherol polyethylene 1000 glycol succinate (TPGS) and chondroitin sulfate (CS) dual-modified lipid-albumin nanosystem was constructed for targeted delivery of paclitaxel (PTX) in treating MDR cancer. The obtained nanosystem (TLA/PTX@CS) had an average size of around 176 nm and a negative zeta potential of around −18 mV. TPGS was confirmed to improve the intracellular accumulation of PTX and facilitate the mitochondrial-targeting of lipid-albumin nanosystem. Functionalized with the outer CS shell, TLA/PTX@CS entered MDR breast cancer (MCF-7/MDR) cells via CD44 receptor-mediated endocytosis. CS shell was degraded by concentrated hyaluronidase in the lysosomes, thereby releasing PTX into cytoplasm and inhibiting cell proliferation. In vivo studies revealed that TLA/PTX@CS possessed prolonged blood circulation, resulting in elevated tumor accumulation, excellent antitumor efficacy with a tumor inhibition ratio of 75.3%, and significant survival benefit in MCF-7/MDR tumor-bearing mice. Hence, this TPGS and CS dual-modified lipid-albumin nanosystem provides a promising strategy for targeted delivery of chemotherapeutic drug and reversal of MDR in cancer treatment.

Reversal of Multidrug Resistance by Apolipoprotein A1-Modified Doxorubicin Liposome for Breast Cancer Treatment

Multidrug resistance (MDR) remains a major problem in cancer therapy and is characterized by the overexpression of p-glycoprotein (P-gp) efflux pump, upregulation of anti-apoptotic proteins or downregulation of pro-apoptotic proteins. In this study, an Apolipoprotein A1 (ApoA1)-modified cationic liposome containing a synthetic cationic lipid and cholesterol was developed for the delivery of a small-molecule chemotherapeutic drug, doxorubicin (Dox) to treat MDR tumor. The liposome-modified by ApoA1 was found to promote drug uptake and elicit better therapeutic effects than free Dox and liposome in MCF-7/ADR cells. Further, loading Dox into the present ApoA1-liposome systems enabled a burst release at the tumor location, resulting in enhanced anti-tumor effects and reduced off-target effects. More importantly, ApoA1-lip/Dox caused fewer adverse effects on cardiac function and other organs in 4T1 subcutaneous xenograft models. These features indicate that the designed liposomes represent a promising strategy for the reversal of MDR in cancer treatment.