BBA, a Derivative of 23-Hydroxybetulinic Acid, Potently Reverses ABCB1-Mediated Drug Resistance <i>in Vitro</i> and <i>in Vivo</i>

Zhang, Dongmei; Shu, Chang; Chen, Jun-Jiang; Sodani, Kamlesh; Wang, Jiao; Bhatnagar, Jaya; Lan, Ping; Ruan, Zhixiong; Xiao, Zhijie; Ambudkar, Suresh V.; Chen, Weimin; Chen, Zhe‐Sheng; Ye, Wen‐Cai

doi:10.1021/mp300249s

Cited by 46 publications

(45 citation statements)

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“…Since our patients almost always received taxane in combination with platinum, we could not separately determine the association between ABCB1 and survival in patients who received only platinum or only taxane. Cisplatin and carboplatin are not substrates for the ABCB1 transporter [27,28], which argues against a contribution from these agents to the survival effects we observed. However, a recent study identified a novel ABCB1 transporter function, caspase-3 blockade, a mechanism whereby variation in ABCB1 might explain cisplatin resistance [29].…”

Section: Discussionmentioning

confidence: 99%

Inherited Variation in the ATP-Binding Cassette Transporter ABCB1 and Survival after Chemotherapy for Stage III–IV Lung Cancer

Weissfeld

Diergaarde

Nukui

et al. 2014

Journal of Thoracic Oncology

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Background The ATP-binding cassette transporter gene ABCB1 and the glutathione S-transferase gene GSTP1 code for a multidrug resistance (MDR) protein and for a detoxifying phase II metabolic enzyme, respectively, with substrate specificities that include chemotherapy drugs commonly used to treat lung cancer. Methods We genotyped 11 ABCB1 and 8 GSTP1 single nucleotide polymorphisms (SNPs) in 698 white lung cancer patients (all current or former cigarette smokers) and used log-rank test statistics and proportional hazards regression to evaluate associations between SNP genotype and survival. Results Using data from all 698 cases, one SNP in ABCB1 (rs2235013) was statistically significantly associated with overall survival (p=0.038, log-rank test). Chemotherapy and stage jointly (p=0.025) significantly modified the association between rs2235013 and survival, with statistically significant (p=0.013, log-rank test) association observed in the subgroup of stage III-IV lung cancer patients who received chemotherapy as part of their first course of treatment (N=160; 93.1% non-small cell). Patients who inherited the minor T allele at ABCB1 rs2235013 experienced better overall and recurrence-free survival [hazard ratio, per minor T allele, (95% confidence interval): 0.66 (0.49-0.90) and 0.55 (0.31-0.95), respectively; adjusted for year of diagnosis, sex, age at diagnosis, cigarette pack years, and stage]. In addition, in the advanced-stage chemotherapy-treated subgroup, four ABCB1 SNPs (rs6949448, rs2235046, rs1128503, and rs10276036) in mutual high linkage disequilibrium with rs2235013 and an independent ABCB1 SNP (rs1045642) showed statistically significant association (p<0.05) with survival. Conclusions Inherited variation in ABCB1 may affect survival specifically in advanced-stage lung cancer patients who receive chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Inherited Variation in the ATP-Binding Cassette Transporter ABCB1 and Survival after Chemotherapy for Stage III–IV Lung Cancer

Weissfeld

Diergaarde

Nukui

et al. 2014

Journal of Thoracic Oncology

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“…Recently, we reported for the first time that BBA could potently reverse P-gp-mediated MDR by directly inhibiting the transport function of P-gp and increase the intracellular accumulation of chemotherapeutic agents in P-gp-overexpressing cells in vitro . In addition, BBA could also reverse P-gp-mediated resistance to paclitaxel in nude mouse xenograft model [22]. In the present study, we examined whether BBA could reverse MRP7-mediated drug resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Search on active ingredients of natural products used for cancer treatment in clinic is one of the promising pathways to investigate novel inhibitors for reversal of ABC transporters-mediated MDR. Recently, our group reported 23- O -(1,4'-bipiperidine-1-carbonyl) betulinic acid (BBA), a synthetic derivative of 23-hydroxybutulinic acid (23-HBA), the major active constituent isolated from the root of Pulsatilla chinensis , could significantly reverse P-gp-mediated MDR [22,23]. The present study was designed to determine whether BBA could modulate MRP7-mediated MDR.…”

Section: Introductionmentioning

confidence: 99%

BBA, a Synthetic Derivative of 23-hydroxybutulinic Acid, Reverses Multidrug Resistance by Inhibiting the Efflux Activity of MRP7 (ABCC10)

et al. 2013

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Natural products are frequently used for adjuvant chemotherapy in cancer treatment. 23-O-(1,4'-bipiperidine-1-carbonyl) betulinic acid (BBA) is a synthetic derivative of 23-hydroxybutulinic acid (23-HBA), which is a natural pentacyclic triterpene and the major active constituent of the root of Pulsatilla chinensis . We previously reported that BBA could reverse P-glycoprotein (P-gp/ABCB1)-mediated multidrug resistance (MDR). In the present study, we investigated whether BBA has the potential to reverse multidrug resistance protein 7 (MRP7/ABCC10)-mediated MDR. We found that BBA concentration-dependently enhanced the sensitivity of MRP7-transfected HEK293 cells to paclitaxel, docetaxel and vinblastine. Accumulation and efflux experiments demonstrated that BBA increased the intracellular accumulation of [3H]-paclitaxel by inhibiting the efflux of [3H]-paclitaxel from HEK293/MRP7 cells. In addition, immunoblotting and immunofluorescence analyses indicated no significant alteration of MRP7 protein expression and localization in plasma membranes after treatment with BBA. These results demonstrate that BBA reverses MRP7-mediated MDR through blocking the drug efflux function of MRP7 without affecting the intracellular ATP levels. Our findings suggest that BBA has the potential to be used in combination with conventional chemotherapeutic agents to augment the response to chemotherapy.

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“…After that, cells were collected by centrifugation at 1,000 rpm and washed for three times with cold PBS. Finally, the cells were re-suspended in PBS buffer and analyzed by flow cytometry (Beckman Coulter, U.S.A.) equipped at an excitation wavelength of 488 nm and an emission wavelength 590 nm, respectively [18].…”

Section: Methodsmentioning

confidence: 99%

The Reversal Effects of 3-Bromopyruvate on Multidrug Resistance In Vitro and In Vivo Derived from Human Breast MCF-7/ADR Cells

Yuan

et al. 2014

PLoS ONE

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PurposeP-glycoprotein mediated efflux is one of the main mechanisms for multidrug resistance in cancers, and 3-Bromopyruvate acts as a promising multidrug resistance reversal compound in our study. To test the ability of 3-Bromopyruvate to overcome P-glycoprotein-mediated multidrug resistance and to explore its mechanisms of multidrug resistance reversal in MCF-7/ADR cells, we evaluate the in vitro and in vivo modulatory activity of this compound.MethodsThe in vitro and in vivo activity was determined using the MTT assay and human breast cancer xenograft models. The gene and protein expression of P-glycoprotein were determined using real-time polymerase chain reaction and the Western blotting technique, respectively. ABCB-1 bioactivity was tested by fluorescence microscopy, multi-mode microplate reader, and flow cytometry. The intracellular levels of ATP, HK-II, and ATPase activity were based on an assay kit according to the manufacturer’s instructions.Results3-Bromopyruvate treatment led to marked decreases in the IC50 values of selected chemotherapeutic drugs [e.g., doxorubicin (283 folds), paclitaxel (85 folds), daunorubicin (201 folds), and epirubicin (171 folds)] in MCF-7/ADR cells. 3-Bromopyruvate was found also to potentiate significantly the antitumor activity of epirubicin against MCF-7/ADR xenografts. The intracellular level of ATP decreased 44%, 46% in the presence of 12.5.25 µM 3-Bromopyruvate, whereas the accumulation of rhodamine 123 and epirubicin (two typical P-glycoprotein substrates) in cells was significantly increased. Furthermore, we found that the mRNA and the total protein level of P-glycoprotein were slightly altered by 3-Bromopyruvate. Moreover, the ATPase activity was significantly inhibited when 3-Bromopyruvate was applied.ConclusionWe demonstrated that 3-Bromopyruvate can reverse P-glycoprotein-mediated efflux in MCF-7/ADR cells. Multidrug resistance reversal by 3-Bromopyruvate occurred through at least three approaches, namely, a decrease in the intracellular level of ATP and HK-II bioactivity, the inhibition of ATPase activity, and the slight decrease in P-glycoprotein expression in MCF-7/ADR cells.

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BBA, a Derivative of 23-Hydroxybetulinic Acid, Potently Reverses ABCB1-Mediated Drug Resistance in Vitro and in Vivo

Cited by 46 publications

References 45 publications

Inherited Variation in the ATP-Binding Cassette Transporter ABCB1 and Survival after Chemotherapy for Stage III–IV Lung Cancer

Inherited Variation in the ATP-Binding Cassette Transporter ABCB1 and Survival after Chemotherapy for Stage III–IV Lung Cancer

BBA, a Synthetic Derivative of 23-hydroxybutulinic Acid, Reverses Multidrug Resistance by Inhibiting the Efflux Activity of MRP7 (ABCC10)

The Reversal Effects of 3-Bromopyruvate on Multidrug Resistance In Vitro and In Vivo Derived from Human Breast MCF-7/ADR Cells

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