Multidrug Resistance Reversal Agents Research Articles

Synthesis of novel D-seco-taxoids derived from 1-deoxybaccatin VI

New D-seco-taxoids were synthesized from 1-deoxybaccatin VI and their structures were confirmed by 1H NMR, 13C NMR, ESIMS and X-ray crystallography. The key step of the synthesis involved the opening of the oxetane ring under acid and basic conditions in order to obtain new multidrug resistance (MDR) reversal agents and new synthetic precursors of paclitaxel analogues.

Inhibition of P‐Glycoprotein‐Induced Multidrug Resistance by a Clerodane‐Type Diterpenoid from Sindora sumatrana

The aim of the present study was to investigate the effects of di- and sesquiterpenoids isolated from the pods of Sindora sumatrana Miq. (Leguminosae) on P-glycoprotein (P-gp) function in an adriamycin-resistant human breast cancer cell line, MCF-7/ADR. Over-expression of P-gp is known to be one of the mechanisms involved in multidrug resistance (MDR), which is a major obstacle in clinical cancer treatment. Among six di- and sesquiterpenoids extracted from S. sumatrana, (+)-7beta-acetoxy-15,16-epoxycleroda-3,13(16),14-trien-18-oic acid (1) showed a strong P-gp inhibitory effect, as great as that of verapamil, a representative P-gp inhibitor. Compound 1 enhanced daunomycin accumulation more than fourfold and significantly decreased daunomycin efflux compared with control, resulting in a decrease in the IC(50) value for daunomycin. These results suggest that compound 1 inhibits the functioning of P-gp and, therefore, can be developed as an MDR-reversing agent.

Synthesis and structure–activity relationships of sinenxan A derivatives as multidrug resistance reversal agents

Two types of sinenxan A derivatives with different side chains at C-5 were synthesized and evaluated for their in vitro multidrug resistant reversal activities. Several derivatives exhibited better activities than the positive control verapamil. The structure–activity relationships of these derivatives suggested that a carbonyl group at C-13 and the length of side chain at C-5 are important for the activity.

8-Prenylnaringenin is an inhibitor of multidrug resistance-associated transporters, P-glycoprotein and MRP1

Flavonoids with hydrophobic e.g. prenyl substituents might constitute the promising candidates for multidrug resistance (MDR) reversal agents. The interaction of 8-prenylnaringenin (8-isopentenylnaringenin), a potent phytoestrogen isolated from common hop (Humulus lupulus), with two multidrug resistance-associated ABC transporters of cancer cells, P-glycoprotein and MRP1, has been studied for the first time. Functional test based on the transport of fluorescent substrate BCECF revealed that the flavonoid strongly inhibited MRP1 transport activity in human erythrocytes (IC50=5.76±1.80μM). Expression of MDR-related transporters in drug-sensitive (LoVo) and doxorubicin-resistant (LoVo/Dx) human colon adenocarcinoma cell lines was characterized by RT-PCR and immunochemical methods and elevated expression of P-glycoprotein in resistant cells was found to be the main difference between these two cell lines. By means of flow cytometry it was shown that 8-prenylnaringenin significantly increased the accumulation of rhodamine 123 in LoVo/Dx cells. Doxorubicin accumulation in both LoVo and LoVo/Dx cells observed by confocal microscopy was also altered in the presence of 8-prenylnaringenin. However, the presence of the studied compound did not increase doxorubicin cytotoxicity to LoVo/Dx cells. It was concluded that 8-prenylnaringenin was not able to modulate MDR in human adenocarcinoma cell line in spite of the ability to inhibit both P-glycoprotein and MRP1 activities. To our best knowledge, this is the first report of 8-prenylnaringenin interaction with clinically important ABC transporters.

ChemInform Abstract: Total Synthesis of 5-N-Acetylardeemin and Amauromine: Practical Routes to Potential MDR Reversal Agents.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Papyriferic acid derivatives as reversal agents of multidrug resistance in cancer cells

Forty-one derivatives of papyriferic acid were prepared based on our previous finding that methyl papyriferate ( 3) showed potent reversing effect on cytotoxicity of colchicine against multidrug resistance (MDR) human cancer cells (KB-C2), and evaluated for their cytotoxicity and effect on reversing P-gp-mediated MDR against KB-C2 cells. 3- O-(Morpholino-β-oxopropanoyl)-12β-acetoxy-3α,25-dihydroxy-(20 S,24 R)-epoxydammarane ( 37) significantly increased the sensitivity of colchicine against KB-C2 cells by 185-fold at 5 μg/mL (7.4 μM), and the cytotoxicity of colchicine was recovered to nearly that of sensitive (KB) cells. The other several new amide derivatives also exhibited potent reversal activity comparable to or more potent than methyl papyriferate and verapamil.

Multidrug Resistance Reversal Agent, NSC77037, Identified with a Cell-Based Screening Assay

The development of multidrug resistance (MDR) remains a significant obstacle in treating cancer patients with chemotherapy. To identify small-molecule compounds that can reverse MDR, the authors used a cell-based screening assay with an MDR ovarian cancer cell line. Incubating MDR cells with a sublethal concentration of paclitaxel in combination with each of 2000 small-molecule compounds from the National Cancer Institute Diversity Set Library, they identified NSC77037. The cytotoxic activity of NSC77037 and the duration of its effect were evaluated in vitro using a panel of cancer cell lines expressing permeability glycoprotein (Pgp), multiple drug resistance protein 1 (MRP 1), and breast cancer resistance protein (BCRP). The mechanism of its effects was further analyzed by assessing the retention of calcein and Pgp-ATPase activity. The relative potency of MDR reversal by NSC77037 was significantly higher than that of frequently used MDR reversal agents such as verapamil and cyclosporine A. NSC77037 reversed Pgp without reversing MRP or BCRP-mediated MDR. NSC77037, at a concentration of >10 microM, moderately inhibited the proliferation of both sensitive and resistant cell lines, but the inhibitory effect of NSC77037 was not altered by coincubation with the Pgp inhibitor verapamil, suggesting that NSC77037 itself is not a substrate of Pgp. NSC77037 directly inhibited the function of Pgp in a dose-dependent manner, but it did not alter the protein expression level of Pgp. The use of NSC77037 to restore sensitivity to chemotherapy or to prevent resistance could be a potential treatment strategy for cancer patients.

Modulation of P-glycoprotein activity by the substituted quinoxalinone compound QA3 in adriamycin-resistant K562/A02 cells

QA3 is a derivative of the substituted 1,3-dimethyl-1H-quinoxalin-2-ones, which are compounds that may selectively antagonize P-glycoprotein (P-gp) in multidrug resistance (MDR) cancer cells. Our previous work identified QA3 as a candidate compound for reversing MDR in cancer cells. In the present study, we found that QA3 significantly decreases the intracellular level of ATP, stimulates ATPase activity in membrane microsomes and decreases protein kinase C (PKC) activity. These results indicated that QA3 inhibits P-gp activity by blocking ATP hydrolysis and ATP regeneration. Furthermore, QA3 triggered and increased adriamycin-induced K562/A02 cell apoptosis as evidenced by Annexin V-FITC plus PI staining. Western blot analysis showed that the levels of cleaved caspase-9 and cleaved caspase-3 proteins increased, and similarly, the levels of procaspase-9 and procaspase-3 decreased after QA3 treatment. Consequently, poly ADP-ribose polymerase (PARP) activity increased as evidenced by the presence of the PARP cleavage product in K562/A02 cells. QA3 also enhanced the potency of adriamycin against K562/A02 cells as demonstrated by increased apoptosis and activation of caspase-9,-3 and PARP. These data support the observation that P-gp activity is inhibited after QA3 treatment. Moreover, these results indicate that QA3 is a novel MDR reversal agent with potent inhibitory action against P-gp MDR cancer cells.

Substituted tetrahydroisoquinoline compound B3 inhibited P-glycoprotein-mediated multidrug resistance in-vitro and in-vivo

P-glycoprotein (P-gp) mediated multidrug resistance (MDR) is one of the main obstacles in tumour chemotherapy. A promising approach to reverse MDR is the combined use of nontoxic and potent P-gp inhibitor with conventional anticancer drugs. We have examined the potential of a newly synthesized tetrahydroisoquinoline derivative B3 as a MDR-reversing agent. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to examine the effect of B3 on the cytotoxicity in K562/A02 and MCF-7/ADM cells caused by doxorubicin (adriamycin). Accumulation and efflux of P-gp substrate rhodamine123 in K562/A02 and primary cultured rat brain microvessel endothelial cells (RBMECs) were measured to evaluate the inhibitory effect of B3 on P-gp. The K562/A02 xenograft model in nude mice was established to examine MDR-reversing efficacy of B3 in-vivo. The results indicated that co-administration of B3 resulted in an increase on chemosensitivity of K562/A02 and MCF-7/ADM cells to doxorubicin in a dose-dependent manner. Rhodamine123 accumulation in K562/A02 cells and RBMECs were significantly enhanced after the incubation with various concentrations of B3. Furthermore, B3 inhibited the efflux of rhodamine123 from RBMECs. Co-administration of B3 with doxorubicin significantly decreased weight and volume of tumour in nude mice. In conclusion, B3 is a novel and potent MDR reversal agent with the potential to be an adjunctive agent for tumour chemotherapy.

ChemInform Abstract: A Novel Class of Highly Potent Multidrug Resistance Reversal Agents: Disubstituted Adamantyl Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A novel class of highly potent multidrug resistance reversal agents: Disubstituted adamantyl derivatives

Novel disubstituted adamantyl derivatives were synthesized and evaluated in a P-glycoprotein dependent multidrug resistance cancer cell line. The hit to lead optimization provided potent MDR reversal agents. Some potent adamantyl derivatives were more than 10-fold more potent than verapamil without considerable intrinsic cytotoxicity. The 3-trifluorophenyl derivative 14f did not affect the metabolism of CYP450 3A4, whereas most of MDR revertants had a weak inhibitory effect.

Synthesis and multidrug resistance reversal activity of dihydroptychantol A and its novel derivatives

The macrocyclic bisbibenzyl dihydroptychantol A (DHA), previously isolated from Asterella angusta, was synthesized and showed significant multidrug resistance (MDR) reverting activity in chemoresistant cancer cells. In an attempt to discover more potent MDR reversal agents for efficient cancer chemotherapy, DHA derivatives with thiazole rings ( 19– 22) were synthesized, and their cytotoxicities and MDR reversal activities were evaluated in adriamycin-resistant K562/A02, vincristine-resistant KB/VCR and in their parental cells by MTT assays. In response to treatment with each compound, the K562 cell line was the most sensitive, and the vincristine-resistant KB/VCR cell line was the most resistant. Marked decreases in K562 and K562/A02 cell viability were detectable after treatment with the synthesized derivatives of DHA, while less inhibitory effects on cell growth were observed in chemical-resistant KB/VCR and KB cells. Moreover, among the tested compounds, the intermediate 17 and the analogues 19, 20, and 21 showed potent MDR reversal activities and increased vincristine cytotoxicity in KB/VCR cells, with the reversal fold ranges from 10.54 to 13.81 (10 μM), which is 3.2–4.3-fold stronger than the natural product DHA.

Modulation of Anticancer Drug-Induced P-Glycoprotein Expression by Naringin

Multidrug resistance (MDR) is a phenomenon that is often associated with decreased intracellular drug accumulation in the tumour cells of a patient, resulting from enhanced drug efflux. It is often related to the overexpression of P-glycoprotein (P-gp) on the surface of tumour cells, thereby reducing drug cytotoxicity. In the present study, naringin (the predominant flavonone found in grapefruit and other related citrus species) was tested for its potential ability to modulate the expression of P-gp in a short-term animal bioassay, in comparison with verapamil (a calcium channel blocker and positive MDR reversal agent). Western blot analysis showed that pre-treatment by i.p. administration of 5 mg naringin/kg body weight for 3 consecutive days prior to doxorubicin (the most common used anticancer drug which induces MDR) administration was able to significantly lower the P-gp expression reaching nearly the level of animals treated with verapamil. Moreover, pre-treatment with naringin prior to doxorubicin increased the sensitivity to the drug. Naringin inhibited the doxorubicin-stimulated ATPase activity demonstrating that naringin may interact directly with the transporter. In addition, the results demonstrated that induction of both glutathione (GSH) and glutathione-S-transferase (GST) by doxorubicin is consistent with an increased ATP-dependent doxorubicin transport. Thus, naringin seems to modulate the in vivo expression of P-gp. In summary, the present study describes the dual modulation of P-gp expression and function by the flavonoid naringin, which may be an attractive new agent for the chemosensitization of cancer cells.

Mechanism of Drug Sensitivity and Resistance in Melanoma

Melanoma is the most aggressive form of skin cancer and advanced stages are inevitably resistant to conventional therapeutic agents. In particular, the inability of undergo apoptosis in response to chemotherapy and other external stimuli poses a selective advantage for tumor progression, metastasis formation as well as resistance to therapy in melanoma. Herein, we will review the molecular mechanisms of sensitivity and/or resistance of the most important drugs used in the treatment of melanoma. Furthermore, the novel strategies to overcome tumor chemoresistance will also be discussed. In particular, we will review the cancer stem cell hypothesis and how the failure of MDR reversal agents might increase the therapeutic index of substrate antineoplastic agents.

Perspectives of inhibition of multidrug resistance during cancer chemotherapy, in vitro and in vivo experiments

The development of pharmacological agents able to counteract the mechanisms of multidrug resistance in oncology has remained a major goal for the past ten years. Our purpose was to find multidrug resistance reversal agents less toxic than verapamil among various synthetic compounds: cinnamylidene ketones; 1,4-dihydropyridines; phenothiazines; heat shock 90 inhibitor peptides; betti base derivative of tylosin and among some naturally occurring plant derived jatrophane and lathyrane-type diterpenes. The first part of this thesis presents the inhibition of multidrug resistance through inhibition of the P-glycoprotein efflux pump in various cell lines. In general, the newly identified multidrug resistance modifiers were able to enhance the antiproliferative activity of selected anticancer drugs in a synergistic or additive way in in vitro experiments. The in vitro activity of betti base derivative of tylosin was confirmed by further in vivo efficacy studies in DBA/2 mice. As an alternative way of antitumor effect, apoptosis inductions of resistance modifiers were studied. The substituted dihydropyridine 13 was the most promising apoptosis inducer on mouse lymphoma cells. Human cytomegalovirus was used in a modified in vitro model for characterizing lathyrane compounds with antipromotion effect on human lung cancer cells. All the six macrocyclic lathyrane-type diterpenoids reduced the promotion in vitro , except latilagascene D, decreased IE-antigen expression of cytomegalovirus to prevent progression of tumor malignancy.

Novel dihydro-β-agarofuran sesquiterpenes as potent modulators of human P-glycoprotein dependent multidrug resistance

P-Glycoprotein (Pgp) overexpression is one factor contributing to multidrug resistance (MDR) in cancer cells and represents one drawback in the treatment of cancer. In an attempt to find more specific and less toxic anticancer MDR-reversal agents, we report herein the isolation, structure elucidation and biological activity of nine new (, and ) and seven known (, and ) dihydro-beta-agarofuran sesquiterpenes from the leaves of Celastrus vulcanicola. Their stereostructures were elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR techniques, CD studies and biogenetic means. All the compounds were assayed on human MDR1-transfected NIH-3T3 cells, in order to determine their ability to reverse the MDR phenotype due to Pgp overexpression. Six compounds from these series (, , , , and ) showed an effectiveness that was similar to (or higher than) the classical Pgp reversal agent verapamil for the reversal of resistance to daunomycin and vinblastine. The structure-activity relationships are discussed.

Bis-pyranobenzoquinones as a New Family of Reversal Agents of the Multidrug Resistance Phenotype Mediated by P-Glycoprotein in Mammalian Cells and the Protozoan Parasite Leishmania

We have synthesized a set of bis-pyranobenzoquinones through a direct and highly efficient approach based on a double intramolecular domino Knoevenagel hetero Diels-Alder reaction. These bis-pyranobenzoquinone derivatives are compounds whose skeletons have similarities to those of some anticancerous and leishmanicidal drugs. Considering that these drugs are substrates for some members of the ATP-binding cassette (ABC) family of proteins that confers a multidrug resistance (MDR) phenotype, we have carried out the biological evaluation of 20 bis-pyranobenzoquinones as modulators of the MDR phenotype in mammalian cell lines overexpressing P-glycoprotein, MRP1, or BCRP. Moreover, we also tested some of these compounds as potential MDR modulators in a Leishmania tropica line overexpressing a P-glycoprotein-like transporter. Compounds 9 and 10 are, in this work, the most promising reversal agents of MDR in human cancer cell lines, while compounds 4 and 20 showed potent reversal activity of MDR phenotype in the protozoan parasite Leishmania.

ChemInform Abstract: Design and Synthesis of Tetrahydroisoquinoline Derivatives as Potential Multidrug Resistance Reversal Agents in Cancer.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis and Biochemical Characterization of New Phenothiazines and Related Drugs as MDR Reversal Agents

Chemotherapy is one of the most important methods in the treatment of cancer. However, development of drug resistance during chemotherapy is the leading cause of treatment failure and decreased survival in cancer patients. Multidrug resistance (MDR) is one of the extensively studied forms of drug resistance for more than 30 years. The members of ATP-binding cassette protein family are responsible for multidrug resistance with P-glycoprotein as most representative transporter. To overcome multidrug resistance, pharmacological modulation of the transporters by efflux pump inhibitors seem to be the first choice, but preclinical studies did not lead to clinical applications. Therefore, a systematical research for pharmacophor structures is a promising strategy to increase the efficacy of those drugs still influencing multidrug resistance. In this study a range of phenothiazine derivatives was synthesizied with systematical variation of three molecule domains. The biochemical determination of multidrug resistance reversal activity was achieved with the crystalviolet assay on LLC-PK1/MDR1 cells. The results will be discussed considering of hypotheses in the literature directed to new structure-acitivity relationships to overcome drug resistance in the future.

Quinoline derivative KB3-1 potentiates paclitaxel induced cytotoxicity and cycle arrest via multidrug resistance reversal in MES-SA/DX5 cancer cells

Aims The resistance to chemotherapeutic drugs is a major problem for successful cancer treatment. Multidrug resistance (MDR) phenotype is characterized by over-expression of P-glycoprotein (P-gp) on the cancer cell plasma membrane that extrudes drugs out of the cells. Therefore, novel MDR reversal agents are desirable for combination therapy to reduce MDR and enhance anti-tumor activity. Thus, the present study was aimed to evaluate the potent efficacy of novel quinoline derivative KB3-1 as a potent MDR-reversing agent for combined therapy with TAX. Main methods MDR reversing effect and TAX combined therapy were examined by Rhodamine accumulation and efflux assay and Confocal immunofluorescence microscopy, Western blotting, TUNEL assay, and cell cycle analysis. Key findings The discovery of quinoline-3-carboxylic acid [4-(2-{benzyl-3[-(3,4-dimethoxy-phenyl)-propionyl]-amino}-ethyl)-phenyl]-amide (KB3-1) as a novel MDR-reversal agent. KB3-1 significantly enhanced the accumulation and retention of a P-gp substrate, rhodamine-123 in the P-gp-expressing MES-SA/DX5 uterine sarcoma cells but not in the P-gp-negative MES-SA cells at non-toxic concentrations of 1 μM and 3 μM. Similarly, fluorescence microscopy observation revealed that KB3-1 reduced the effluxed rhodamine-123 expression on the membrane of MES-SA/DX5 cells. Consistent with decreased P-gp pumping activity, confocal microscopic observation revealed that KB3-1 effectively diminished the expression of P-gp in paclitaxel (TAX)-treated MES-SA/DX-5 cells. Furthermore, Western blotting confirmed that KB3-1 reduced P-gp expression and enhanced cytochrome C release and Bax expression in TAX treated MES-SA/DX-5 cells. In addition, KB3-1 enhanced TAX-induced apoptotic bodies in MES-SA/DX5 cells by TdT-mediated-dUTP nick-end labeling (TUNEL) staining assay aswell as potentiated TAX- induced cytotoxicity, G2/M phase arrest and sub-G1 apoptosis in MES-SA/DX5 cells but not in MES-SA cells. Interestingly, KB3-1 at 3 μM had comparable MDR-reversal activity to 10 μM verapamil, a well-known MDR- reversal agent. Significance KB3-1 can be a MDR-reversal drug candidate for combination chemotherapy with TAX.