Reverse Tumor Multidrug Resistance Research Articles

Abstract 7193: ABCB1-mediated chemotherapeutic drug resistance is reversed by a potent p53-MDM2 inhibitor NVP-HDM201

Abstract The failure of chemotherapy in cancer persists as a result of overexpression of various ATP-binding cassette (ABC) transporters. ABCB1 is one such transporter that actively pumps out chemotherapeutic drugs and it is one of the reasons for multidrug resistance (MDR). In the last few years, activation of p53 has been targeted as a therapeutic strategy in the treatment of cancers. Siremadlin (NVP-HDM201) is a potent and selective inhibitor of p53-MDM2 interaction. The objective of this study was to explore the ability of HDM201 to reverse tumor MDR attributable to overexpression of ABC transporters. According to our findings, HDM201 significantly increased the sensitivity of ABCB1-overexpressing cells to ABCB1 substrates, such as colchicine and doxorubicin. We found that HDM201 reverses ABCB1-mediated MDR by interacting with ABCB1 and blocking its function without affecting the expression and cellular localization of ABCB1. Moreover, HDM201 promoted the accumulation of paclitaxel in cell lines that overexpress ABCB1. At both high and low doses, HDM201 increased the ATPase activity of ABCB1. The computational support for the cross-reactivity of this p53 inhibitor with human ABCB1 comes from docking simulation results that align with the binding conformation of HDM201 within the vast cavity of the transmembrane region of ABCB1. In conclusion, by blocking the transport function of ABCB1, HDM201 can reverse ABCB1-mediated MDR in vitro. Citation Format: Harsh Patel, Chaoyun Cai, Zhuoxun Wu, Qiuxu Teng, Hanli Li, Zhe-Sheng Chen. ABCB1-mediated chemotherapeutic drug resistance is reversed by a potent p53-MDM2 inhibitor NVP-HDM201 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7193.

Natural products reverse cancer multidrug resistance.

Cancer stands as a prominent global cause of death. One of the key reasons why clinical tumor chemotherapy fails is multidrug resistance (MDR). In recent decades, accumulated studies have shown how Natural Product-Derived Compounds can reverse tumor MDR. Discovering novel potential modulators to reduce tumor MDR by Natural Product-Derived Compounds has become a popular research area across the globe. Numerous studies mainly focus on natural products including flavonoids, alkaloids, terpenoids, polyphenols and coumarins for their MDR modulatory activity. Natural products reverse MDR by regulating signaling pathways or the relevant expressed protein or gene. Here we perform a deep review of the previous achievements, recent advances in the development of natural products as a treatment for MDR. This review aims to provide some insights for the study of multidrug resistance of natural products.

A convenient protonated strategy for constructing nanodrugs from hydrophobic drug-inhibitor conjugates to reverse tumor multidrug resistance.

Combination therapy has proven effective in counteracting tumor multidrug resistance (MDR). However, the pharmacokinetic differences among various drugs and inherent water insolubility for most small molecule agents greatly hinder their synergistic effects, which makes the delivery of drugs for combination therapy in vivo a key problem. Herein, we propose a protonated strategy to transform a water-insoluble small molecule drug-inhibitor conjugate into an amphiphilic one, which then self-assembles into nanoparticles for co-delivery in vivo to overcome tumor MDR. Specifically, paclitaxel (PTX) is first coupled with a third-generation P-glycoprotein (P-gp) inhibitor zosuquidar (Zos) through a glutathione (GSH)-responsive disulfide bond to produce a hydrophobic drug-inhibitor conjugate (PTX-ss-Zos). Subsequently treated with hydrochloric acid ethanol solution (HCl/EtOH), PTX-ss-Zos is transformed into the amphiphilic protonated precursor and then forms nanoparticles (PTX-ss-Zos@HCl NPs) in water by molecular self-assembly. PTX-ss-Zos@HCl NPs can be administered intravenously and accumulated specifically at tumor sites. Once internalized by cancer cells, PTX-ss-Zos@HCl NPs can be degraded under the overexpressed GSH to release PTX and Zos simultaneously, which synergistically reverse tumor MDR and inhibit tumor growth. This offers a promising strategy to develop small molecule self-assembled nanoagents to reverse tumor MDR in combination therapy.

Chemotherapy/anti-inflammatory drug co-delivery system based on ortho ester-modified pluronic L61 for reversing tumor multidrug resistance

The development of multidrug resistance (MDR) in malignant tumors is one of the major obstacles to chemotherapy. Herein, ortho ester-modified pluronic L61 (L61) was prepared and coupled with sulindac (Su) to obtain a polymeric prodrug (Su-OE-L61). Su-OE-L61 was further loaded with doxorubicin (DOX) to give a pH-sensitive nanoparticles (Su-OE-L61/DOX NPs). Compared with ortho ester-free nanoparticles (Su-L61/DOX NPs), Su-OE-L61/DOX NPs could effectively trigger drug release under tumor acidic conditions. In vitro experiments demonstrated that Su-OE-L61/DOX NPs significantly increased intracellular drug concentration and enhanced the cytotoxicity to DOX-resist cells (MCF-7/ADR) through L61-mediated anti-MDR effect and the anti-inflammatory effect of sulindac. In vivo studies revealed that the tumor inhibition rates of Su-OE-L61/DOX NPs reached 83.70 %, which was attributed to the synergistic anti-tumor effect of L61, sulindac and DOX. Overall, the chemo/anti-inflammatory drugs co-delivery system based on ortho ester-modified pluronic showed unique advantages in reversing tumor multidrug resistance.

Hollow MIL-125 Nanoparticles Loading Doxorubicin Prodrug and 3-Methyladenine for Reversal of Tumor Multidrug Resistance.

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.

Research Progress on Quercetin's Biological Activity and Structural Modification Based on Its Antitumor Effects

AbstractQuercetin is a naturally existing flavonoid with numerous physiological effects, including antitumor activity. It functions as an antitumor agent by inducing apoptosis and inhibiting tumor cell development, preventing tumor cell invasion and metastasis, and reversing tumor multidrug resistance. Quercetin has limited therapeutic usefulness due to its low water solubility, poor oral absorption, and low bioavailability. New quercetin derivatives are being developed and manufactured via a variety of methods to address inadequacies and for utilization in disease prevention and therapy. The synthesis and anticancer effects of quercetin derivatives, as well as the structure‐activity relationship of quercetin derivatives, were explored, and the unique dosage forms of these derivatives were summarized to serve as a reference for future quercetin research and development.

NIR‐II Photothermal Activation of TRPV1 Channels for Intracellular Magnesium Regulation by Porous Pd@Pt Core–Shell Nanostructure to Reverse Tumor Multidrug Resistance

AbstractMultidrug resistance (MDR) caused by overexpressed P‐glycoprotein (P‐gp) in cell membrane is the main barrier for clinical tumor chemotherapy. P‐gp can pump the chemical drugs out of tumor cells depending on ATP‐provided energy. Herein, a photothermal‐driven intracellular magnesium ion (Mg2+) regulation strategy is proposed to reverse drug resistance through constructing Mg2+‐ and doxorubicin (DOX, as model drug)‐loaded bimetallic Pd@Pt nanostructure (DPd@PtM). Although DPd@PtM can deliver Mg2+ into tumor cells through endocytosis, large amount of Mg2+ releases outside cells. To this end, the photothermal effect of Pd@Pt nanostructure in the second near‐infrared region is expected to activate the thermosensitive transient receptor potential cation channel subfamily V member 1 (TRPV1) channel for extracellular released Mg2+ influx. Intercellular Mg2+ accumulation suppresses tricarboxylic acid cycle to block intracellular adenosine triphosphate (ATP) production (cutoff energy supply for P‐gp) and reduce O2 consumption (downregulate P‐gp expression), then inhibiting P‐gp‐mediated tumor MDR. Both in vitro and in vivo results demonstrate that DPd@PtM can open TRPV1 channel to elevate Mg2+ level and then inhibit the P‐gp activity to enhance intracellular DOX concentration for chemotherapy. It is believed that this photothermal‐mediated tumor Mg2+ regulation therapy based on reversing MDR is a promising strategy to kill cancer cells.

Design, synthesis, and biological evaluation of ocotillol derivatives fused with 2-aminothiazole via A-ring as modulators of P-glycoprotein-mediated multidrug resistance

Overexpression of P-glycoprotein (P-gp) plays a key role in the development of multidrug resistance (MDR), the major reason for the failure of chemotherapy in clinics. Ocotillol and its derivatives had been reported with good P-gp-mediated tumor MDR reversal activity in vitro. Herein, a series of ocotillol derivatives fused with 2-aminothiazole (2-AT) via A-ring were designed and synthesized to further improve the tumor MDR reversal potency. These compounds were evaluated for their MDR reversal activity against the KBV cells by MTT assay. Among them, the most promising derivative against P-gp-mediated MDR was compound 12 with 2-AT and glycine in the A-ring. Rhodamine123 (Rh123) accumulation assay, Western blot assay, and P-gp-Glo™ assay showed that compound 12 efficiently inhibited the efflux function of P-gp by stimulating P-gp ATPase rather than downregulating its expression. Moreover, compound 12 sensitized KBV cells to paclitaxel arrested cells in the G2/M phase and induced cell apoptosis. Importantly, compound 12 significantly inhibited the growth of KBV cell-derived xenograft tumors in nude mice by increasing the sensitivity of paclitaxel in vivo. Finally, the structure-activity relationships (SARs) of ocotillol derivatives were further investigated. In summary, compound 12 has the potential to overcome MDR in cancer caused by P-gp.

An ester derivative of tenacigenin B from Marsdenia tenacissima (Roxb.) Wight et Arn reversed paclitaxel-induced MDR in vitro and in vivo by inhibiting both P-gp and MRP2

Ethnopharmacological relevanceMarsdenia tenacissima is a medicinal plant, used as a raw material for cancer treatment in China. In our previous studies, 11α-O-2-methylbutanoyl-12β-O-tigloyl-tenacigenin B (MT2), the main steroid aglycone isolated from M. tenacissima, was found to significantly enhance the antitumor activity of paclitaxel (PTX) in vivo. However, it is unclear whether MT2 reverses multidrug resistance (MDR) in tumors. Aim of the studyTo determine the role and mechanism of MT2 in reversing tumor MDR. Materials and methodsMDR cell line HeLa/Tax was established from the human cervical carcinoma cell line HeLa by long-term exposure to subtoxic concentrations of PTX and was used to evaluate the ability of MT2 to restore chemosensitivity of cells both in vitro and in a nude mouse model. The expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) was determined using western blotting and immunohistochemistry. The substrate transport function was assessed using an MDR function assay kit. The binding modes of MT2 and P-gp were determined using the conformation-sensitive anti-P-gp antibodies. The permeability and transport properties of MT2 were analyzed in Caco-2 cell monolayers. ResultsCompared to parental cells, HeLa/Tax cells overexpress P-gp and MRP2 and are approximately 100–360 fold more resistant to the anticancer drugs PTX, docetaxel, and vinblastine. MT2 at 5 or 10 μmol/L significantly increased the sensitivity of HeLa/Tax to these three anticancer drugs (18–56-fold decrease in IC50 value) and suppressed the expression of P-gp and MRP2. Knockdown of P-gp with small interfering RNA partially reversed MT2-induced sensitivity to PTX in HeLa/Tax cells. Moreover, MT2 directly inhibited P-gp-mediated substrate transport while interacting with membrane P-gp in non-substrate ways. MT2 was highly permeable and could not be transported in the Caco-2 cell monolayers. In nude mice bearing HeLa/Tax xenografts, the combination treatment with MT2 and PTX exerted a synergistic inhibitory effect on the growth of tumors and the expression of P-gp and MRP2 without increasing toxicity. ConclusionMT2 is a potential agent for reversing MDR. It impedes membrane drug efflux pumps by suppressing P-gp and MRP2 expression, and directly inhibiting the transport function of P-gp.

Two-Pronged Anti-Tumor Therapy by a New Polymer-Paclitaxel Conjugate Micelle with an Anti-Multidrug Resistance Effect.

IntroductionCancerous tumors are still a major disease that threatens human life, with tumor multidrug resistance (MDR) being one of the main reasons for the failure of chemotherapy. Thus, reversing tumor MDR has become a research focus of medical scientists.MethodsHere, a reduction-sensitive polymer prodrug micelle, mPEG-DCA-SS-PTX (PDSP), was manufactured with a new polymer inhibitor of drug resistance as a carrier to overcome MDR and improve the anti-tumor effect of PTX.ResultsThe PDSP micelles display good stability, double-responsive drug release, and excellent biocompatibility. The PDSP micelles reduced the cytotoxicity of PTX to normal HL-7702 cells and enhanced that to SMMC-7721 and MCF-7 cells in vitro. Improved sensitivity of A549/ADR to PDSP was also observed in vitro. Furthermore, in vivo experiments show reduced systemic toxicity and enhanced therapeutic efficacy of PTX to H22 subcutaneous tumor-bearing mice.ConclusionThis work proves that the reduction-sensitive polymer prodrug micelles carried by the new polymer inhibitor can be used as an alternative delivery system to target tumors and reverse MDR for paclitaxel and other tumor-resistant drugs.

Design, synthesis, and tumor drug resistance reversal activity of novel hederagenin derivatives modified by nitrogen-containing heterocycles

The emergence of multidrug resistance (MDR) in tumors leads to reduced chemotherapeutic efficacy, and P-glycoprotein (P-gp) overexpression is one of the main causes of MDR. In previous reports, we demonstrated that a variety of hederagenin (HD) derivatives could reverse MDR in tumors in vivo and in vitro. To further enrich the structure types, enhance the activity, and improve the structure–activity relationships (SARs), three series of HD derivatives were designed and synthesized in this study via A-ring fusion and innovative utilization of the structural advantages of nitrogen-containing heterocycles and benzyl group substitution. We evaluated the MDR reversal activity of 21 HD derivatives in KBV (multidrug-resistant oral epidermoid carcinoma) cells and refined their SARs. The results of cell experiments illustrated that more than half of the compounds had MDR reversal activity. Among them, compound 16 displayed relatively stronger MDR reversal ability, as it improved the sensitivity of KBV cells to paclitaxel, vincristine, mitoxantrone and cisplatin with IC50 values of 3.19, 0.65, 125.30, and 4.54 nM, respectively. The results of mechanistic analysis demonstrated that compound 16 inhibited the efflux function of P-gp by activating P-gp ATPase and increased the accumulation of rhodamine 123 in KBV cells. Importantly, the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors in nude mice was enhanced by compound 16 based on the growth suppression rate of 56.24%. These results indicated that introducing nitrogen-containing heterocycles could effectively improve the MDR reversal activity of HD derivatives, which appear to be promising lead compounds for tumor MDR reversal agent development.

Combating multidrug resistance and metastasis of breast cancer by endoplasmic reticulum stress and cell-nucleus penetration enhanced immunochemotherapy.

Rationale: Multidrug resistance (MDR) and metastasis of breast cancer remain major hurdles in clinical anticancer therapy. The unsatisfactory outcome is largely due to insufficient cytotoxicity of chemotherapeutic agents and limited immunogenic cell death (ICD). On the other hand, efflux proteins, especially P-glycoprotein (P-gp), can recognize and promote the efflux of drugs from tumor cells.Methods: In this study, silver nanoparticles (Ag NPs) and peptide- functionalized doxorubicin (PDOX) were used to prepare a theranostic nanocomposite (Ag-TF@PDOX), which induced organelle-mediated immunochemotherapy and drug efflux protein inhibition in drug-resistant breast cancer cells (MCF-7/ADR) via a strategy based on endoplasmic reticulum (ER) stress and cell-nucleus penetration.Results: The silver nanoparticle-triggered persistent activation of ER stress synergizes with chemotherapy to enhance cytotoxicity and stimulate the ICD effect. It has the potential to enhance chemosensitivity by downregulating of P-gp expression due to the increased production of ATP-consuming chaperones. In addition, the novel peptide (CB5005), which not only penetrates the cell membrane but also has a nuclear localization sequence, is conjugated to DOX to improve both cellular internalization and intranuclear accumulation. Moreover, surface TA-Fe3+ engineering endows the nanocomposite with ATP-responsive disassembly and ATP depletion properties to improve biocompatibility and decrease ATP-dependent drug efflux. Ag-TF@PDOX has potential as a dual-mode (PAI/MRI) contrast-enhanced agent for realizing theranostic guidance.Conclusion: This theranostic nanocomposite greatly restricts the growth of drug-resistant breast tumors and activates a strong immune response as well, providing an opportunity for the development of therapeutics that reverse tumor MDR and metastasis at the subcellular level.

DNAzyme-Based nanoflowers for reversing P-glycoprotein-mediated multidrug resistance in breast cancer

Multidrug resistance (MDR) of tumors has been recognized as an important cause of chemotherapy failure, which is responsible for about 90% of cancer deaths. Therefore, it is desirable to develop a highly effective strategy to reverse tumor MDR for rebuilding the sensitivity of tumor cells towards chemodrugs. Here, self-assembled DNAzyme nanoflowers (NFs) constructed by rolling circle amplification (RCA) strategy were applied in doxorubicin (Dox) delivery for efficiently ablating Dox-resistant breast cancer. The encoded multiple DNAzymes could catalytically cleave P-glycoprotein (P-gp) mRNA which assists the efflux of chemodrugs, for reversing the MDR. The in vitro and in vivo results showed that the P-gp DNAzymes NFs not only had a high drug-loading capacity (69.21%) and acid-triggered biodegrade ability, but also effectively suppressed the expression of P-gp for reversing MDR of the tumor. Therefore, the DNAzyme-based drug delivery nanoplatform would be a promisingstrategyfor reversing MDR in cancer therapy.

Bioactivities and Structure-Activity Relationships of Fusidic Acid Derivatives: A Review.

Fusidic acid (FA) is a natural tetracyclic triterpene isolated from fungi, which is clinically used for systemic and local staphylococcal infections, including methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci infections. FA and its derivatives have been shown to possess a wide range of pharmacological activities, including antibacterial, antimalarial, antituberculosis, anticancer, tumor multidrug resistance reversal, anti-inflammation, antifungal, and antiviral activity in vivo and in vitro. The semisynthesis, structural modification and biological activities of FA derivatives have been extensively studied in recent years. This review summarized the biological activities and structure–activity relationship (SAR) of FA in the last two decades. This summary can prove useful information for drug exploration of FA derivatives.

Reversing tumor multidrug resistance with a catalytically active covalent organic framework.

We report here a catalytically active nano covalent organic framework [COF(Fe)] with high drug loading capacity for reversing tumor multidrug resistance (MDR). The Fe catalytic sites in COF(Fe) could convert intracellular overexpressed H2O2 into highly reactive ˙OH to induce oxidation stress and down-regulate MDR protein. Therefore, COF(Fe) could enhance the intracellular drug accumulation to overcome MDR, which was demonstrated both in vitro and in vivo.

Design, synthesis, and biological evaluation of hederagenin derivatives with improved aqueous solubility and tumor resistance reversal activity.

Multidrug resistance (MDR) has become a major obstacle to malignancies treatment by chemotherapeutic drugs, therefore, it is important to develop MDR reversal agents with high activity. We have previously found that the hederagenin (HD) derivative HBQ showed good tumor MDR reversal activity invitro and invivo but had poor solubility. In this study, to enhance the aqueous solubility and tumor MDR reversal activity of HBQ, three series of HD derivatives were designed and synthesized. Nitrogen-containing heterocyclic-substituted, PEGylated, and ring-A substituted derivatives significantly reversed the MDR phenotype of KBV (multidrug-resistant oral epidermoid carcinoma) cells toward paclitaxel at a concentration of 10μM in MTT assays. The PEGylated derivatives 10c-10e had increased aqueous solubility compared with HBQ by 18-657 fold, while maintaining tumor MDR reversal activity. The most invitro active compound 10c possessed good chemical stability to an esterase over 24h and enhanced the sensitivity of KBV cells to paclitaxel and vincristine with IC50 values of 4.58 and 0.79nM, respectively. Mechanism studies indicated that compound 10c increased the accumulation of P-glycoprotein (P-gp) substrates rhodamine 123 and Flutax1 in KBV cells and MCF-7T (paclitaxel-resistant breast carcinoma) cells, that is to say, compound 10c exerted the reversal effect of tumor MDR by inhibiting the efflux function of P-gp. Finally, the structure-activity relationships were further investigated by analyzing the relationship between structure and tumor MDR reversal activity of HD derivatives. This study highlights the potential of PEGylated HD derivatives such as compound 10c for the development of tumor MDR reversal agents and provides information for the further improvement of the aqueous solubility and tumor MDR reversal activity of HD derivatives in the future.

Overcoming multidrug resistance by intracellular drug release and inhibiting p-glycoprotein efflux in breast cancer

Doxorubicin (DOX) is limited to use in clinical practice because of poor targeting, serious side effects and multidrug resistance (MDR). Vitamin E and its derivatives are currently considered as hydrophobic material that can reverse tumor MDR by suppressing the action of p-glycoprotein (p-gp). Therefore, reduction-sensitive amphiphilic heparosan polysaccharide-cystamine-vitamin E succinate (KSV) copolymers were designed to reverse breast cancer MDR cells. The spherical micelles (DOX/KSV) micelles which had suitable particle size presented redox-sensitive release character. Simultaneously, DOX-loaded reduction insensitive heparosan-adipic dihydrazide-vitamin E succinate (KV) micellar system was designed as a control. DOX/KSV and DOX/KV micelles had the higher capability to overcome tumor MDR than that free DOX. However, DOX/KSV had the highest amount of cellular uptake which might be caused by the synergistic intracellular drug release and inhibition of p-gp expression. The mechanism experiments revealed that DOX/KSV could be fast disassembled to release DOX after internalization into tumor cells. Moreover, DOX/KSV produced more ROS than free DOX and DOX/KV resulting in enhanced anticancer effect. In vivo tumor-bearing mice study suggested that DOX/KSV micelles could efficiently enhance antitumor effect by overcoming tumor MDR and reduce toxicity of DOX. The DOX/KSV micelles could synergistically increase the therapeutic effect of chemotherapeutic drug on tumor MDR cells.

Application of curcumin and its derivatives in tumor multidrug resistance.

Malignant tumor endangers seriously the health of all mankind. Multidrug resistance (MDR) is one of the main causes of clinical tumor chemotherapy failure. Curcumin (CUR) has not only antitumor activity but also reversing tumor MDR effect. CUR reverses tumor MDR via regulating related signal pathways or corresponding expressed proteins or gene. When combined with chemotherapeutic agents, CUR can be a chemotherapeutic sensitive agent to enhance chemotherapy efficacy and weaken tumor MDR. On the other hand, to improve the MDR reversal effect of CUR, its derivatives have been extensively studied. Therefore, this article mainly focuses on reviewing the application of CUR and its derivatives in MDR and its mechanism of reversing MDR.

Indomethacin-grafted and pH-sensitive dextran micelles for overcoming inflammation-mediated multidrug resistance in breast cancer

We first synthesized indomethacin (IND)-grafted dextran copolymer by acetal or ester linkage, which self-assembled with doxorubicin (DOX) into prodrug micelles (IDAC/DOX or IDES/DOX) with the size of ∼200 nm. In vitro drug release test verified IDAC/DOX could trigger more DOX and IND release by the hydrolysis of acetal than that of ester linkage. A series cells experiments demonstrated pH-sensitive IDAC/DOX could greatly improve cellular uptake and intracellular drug accumulation, thus enhancing DOX toxicity in drug-resistant tumor cells. IDAC/DOX was capable of reversing tumor multidrug resistance (MDR) through reducing multidrug resistance-associated protein 1 (MRP1) level (0.23-fold vs control group) and regulating bcl-2/bax pathway, eventually induced more apoptosis in MCF-7/ADR cells. These nanoparticles possessed long-term blood-circulation and high tumor accumulation, thereby reducing side effect and increasing bioavailability. Anti-tumor evaluation showed that IDAC/DOX possessed the highest tumor growth inhibition (TGI, 92.5 %), which might provide a promising way to overcome malignant tumor resistance.

Voacamine: Alkaloid with its essential dimeric units to reverse tumor multidrug resistance

Search for natural substances in association with conventional chemotherapeutic drugs with a chemiosensitizing action easily accessible to the tumor mass has encouraged our studies on voacamine (VOA) and its monomeric units, voacangine and vobasine. Our previous results showed that VOA sensitized multidrug resistant (MDR) osteosarcoma cells (U-2 OS/DX) to doxorubicin (DOX) cytotoxicity. VOA, extracted by Peschiera fuchsiaefolia plant, is a bisindole alkaloid consisting of an Iboga skeleton (voacangine) directly linked to a 2-acyl indole unit (vobasine). High-performance thin-layer chromatography densitometry demonstrated the purity of VOA, voacangine and vobasine samples. Flow cytometry analysis showed that VOA, voacangine and vobasine enhanced DOX accumulation of U-2 OS/DX cells, in equally way, whereas VOA reduced more efficiently DOX efflux. Optical microscopy and clonogenic assay confirmed that VOA was more effective than voacangine and vobasine in enhancing DOX cytotoxic effect. These results showed that monomers linked together are necessary to modulate resistant phenotype of osteosarcoma cells. To complete the study, we evaluated the effect of three compounds on microtubules by confocal microscopy, suggesting that only the whole molecule depolymerizes the microtubules blocking so DOX efflux-mediated by vesicles.