Clinical Significance of Multi-Drug Resistance Associated Protein and P-Glycoprotein in Patients with Bladder Cancer

Nakagawa, Masayuki; Emoto, Akio; Nasu, Nobuyoshi; Hanada, Toshikatsu; Kuwano, Michihiko; Cole, Susan P.C.; Nomura, Yoshio

doi:10.1016/s0022-5347(01)64944-9

Cited by 60 publications

(28 citation statements)

References 22 publications

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“…The association between ABC transporters with bladder cancers was previously established. Recent studies have reported the overexpression of ABC transporters in chemotherapeutic patients with bladder cancer (32,49). CEBPD is also responsive to stimuli involving the activation of either p38 MAPK or STAT3.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

Wang

Chu

et al. 2017

Clinical Cancer Research

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Purpose: Cisplatin (CDDP) is frequently used in combination chemotherapy with paclitaxel for treating urothelial carcinoma of the urinary bladder (UCUB). CDDP cross-resistance has been suggested to develop with paclitaxel, thus hindering successful UCUB treatment. Therefore, elucidating the mechanisms underlying CDDP-induced anticancer drug resistance is imperative and may provide an insight in developing novel therapeutic strategy.Experimental Design: Loss-of-function assays were performed to elucidate the role of the EGFR and STAT3 in CDDP-induced CCAAT/enhancer-binding protein delta (CEBPD) expression in UCUB cells. Reporter and in vivo DNA-binding assays were employed to determine whether CEBPD directly regulates ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily C member 2 (ABCC2) activation. Finally, a xenograft animal assay was used to examine the abilities of gefitinib and S3I-201 (a STAT3 inhibitor) to reverse CDDP and paclitaxel sensitivity.Results: CEBPD expression was maintained in postoperative chemotherapy patients, and this expression was induced by CDDP even in CDDP-resistant UCUB cells. Upon CDDP treatment, CEBPD activated ABCB1 and ABCC2. Furthermore, the EGFR/STAT3 pathway contributed to CDDP-induced CEBPD expression in UCUB cells. Gefitinib and S3I-201 treatment significantly reduced the expression of CEBPD and enhanced the sensitivity of CDDP-resistant UCUB cells to CDDP and paclitaxel.Conclusions: Our results revealed the risk of CEBPD activation in CDDP-resistant UCUB cells and suggested a therapeutic strategy for patients with UCUB or UCUB resisted to CDDP and paclitaxel by combination with either gefitinib or S3I-201.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

Wang

Chu

et al. 2017

Clinical Cancer Research

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“…We are not aware of any report describing mevalonate pathway overactivation in bladder cancer. In view of the limited therapeutic efficacy of current chemotherapeutic regimens [6] and the inability to explain the intrinsic and acquired urothelial carcinoma doxorubicin resistance by increased drug efflux alone [16][17][18][19], our finding calls for a more intense investigation of the function of this pathway in bladder cancer. In particular, if mevalonate pathway activation should be a critical factor in bladder cancer development and therapy resistance, it would offer a novel pharmacological target.…”

Section: Discussionmentioning

confidence: 99%

“…Their molecular analysis yielded an enhanced drug efflux as a major chemoresistance mechanism, either alone [10][11][12] or in association with a partial or complete loss of the therapeutic target, DNA topoisomerase II [13,14], or with a concomitant activation of antiapoptotic signalling pathways [15]. The analysis of clinical tumours, while corroborating the clinical significance of increased expression of drug efflux pumps like ABCB1 (MDR-1) or ABCC1 (MRP), suggested nevertheless that this is unlikely to represent the only resistance mechanism [16][17][18][19]. Here, we describe the establishment of a new cell culture model of doxorubicin resistance in bladder cancer and its molecular analysis.…”

Section: Introductionmentioning

confidence: 92%

Establishment and characterization of a bladder cancer cell line with enhanced doxorubicin resistance by mevalonate pathway activation

et al. 2015

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Resistance to chemotherapy is a major problem in the treatment of urothelial bladder cancer. Several mechanisms have been identified in resistance to doxorubicin by analysis of resistant urothelial carcinoma (UC) cell lines, prominently activation of drug efflux pumps and diminished apoptosis. We have derived a new doxorubicin-resistant cell line from BFTC-905 UC cells, designated BFTC-905-DOXO-II. A doxorubicin-responsive green fluorescent protein (GFP) reporter assay indicated that resistance in BFTC-905-DOXO-II was not due to increased drug efflux pump activity, whereas caspase-3/7 activation was indeed diminished. Gene expression microarray analysis revealed changes in proapoptotic and antiapoptotic genes, but additionally induction of the mevalonate (cholesterol) biosynthetic pathway. Treatment with simvastatin restored sensitivity of BFTC-905-DOXO-II to doxorubicin to that of the parental cell line. Induction of the mevalonate pathway has been reported as a mechanism of chemoresistance in other cancers; this is the first observation in bladder cancer. Combinations of statins with doxorubicin-containing chemotherapy regimens may provide a therapeutic advantage in such cases.

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“…For example, transcription of P-gp mRNA in tumor tissue of patients with metastatic osteosarcoma was rapidly enhanced in response to doxorubicin injection (59). Furthermore, multi-drug resistance and overexpression of P-gp in urinary cancer tissues were observed in urinary cancer patients after chronic anticancer chemotherapy by using anthracyclines, including doxorubicin and daunorubicin (38,60,61). On the other hand, cytotoxic agents, including doxorubicin (62), paclitaxel (63), and ETP (64), in conjunction with specific and/or potent inhibitors of P-gp such as cyclosporine or its analogues (PSC833 or GF120918) increased the residual levels of cytotoxic agents within tumor tissues in several clinical trials for patients with low sensitivity to anticancer chemotherapy, suggesting that resistance to these anticancer drugs was defeated.…”

Section: Alteration In the Expression And Function Of P-gp Induced Bymentioning

confidence: 99%

Mechanisms of P-Glycoprotein Alteration During Anticancer Treatment: Role in the Pharmacokinetic and Pharmacological Effects of Various Substrate Drugs

et al. 2014

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Abstract. In clinical pharmacotherapy, therapeutic benefits and adverse effects of medicines differ substantially between individuals and are often determined by their blood levels. Critical regulators influencing the pharmacokinetics and pharmacodynamics of drugs include drug transporters and drug-metabolizing enzymes. Among these, we have focused on P-glycoprotein (P-gp), a drug efflux transporter. A growing body of evidence indicates that the expression and functional activity of P-gp are altered under several pathological conditions, by exposure to substrate drugs of P-gp, and by ingestion of certain foods. In this critical review, we discuss the mechanisms by which anticancer drugs, most of which are P-gp substrates, alter the expression and functional activity of P-gp in tumors and normal tissues after chronic treatment. Accumulating evidence shows that various transcription factors, in addition to epigenetic and post-translational factors, modulate P-gp expression, which alters the pharmacokinetics and pharmacological effects of drugs. Therefore, it is important to consider individual patients with regard to drug-taking history, as well as levels of P-gp expression and function, when providing clinical pharmacotherapy.Keywords: P-glycoprotein, anticancer drug, drug-drug interaction, opioid, cancer *Corresponding author. stoku@pharm.Kobegakuin.ac.jp Published online in J-STAGE on July 2, 2014 doi: 10.1254/jphs.14R01CRInvited article 243 Changes in P-gp by Anticancer Treatment targeted anticancer drugs acting on specific genes or their products has grown rapidly. In fact, combination treatment with molecularly targeted drugs and cytotoxic chemotherapy against cancers such as acute leukemia or lymphatic malignancy improved therapeutic outcome in comparison to conventional anticancer chemotherapy (8, 9). However, solid tumors often have greater inherent resistance and are less sensitive to anticancer drugs (10). Furthermore, chronic exposure to anticancer drugs frequently leads to multi-drug resistance where the therapeutic effects of these drugs on tumors is largely reduced (11). The development of resistance to anticancer chemotherapy remains one of the major obstacles in effective pharmacological therapy for cancer using current treatment strategies (12).Research revealing the role of drug transporters in cancer began with the discovery of P-glycoprotein (P-gp). In 1976, during research to elucidate the mechanism by which cancer cell lines acquire multi-drug resistance, Juliano et al. discovered that P-gp is over-expressed on the surface membranes of multi-drug resistant cancer cells (13). Subsequent studies have demonstrated that P-gp is present in cancer tissue (11,14), as well as in normal tissues such as small intestine, where it regulates drug absorption, and liver and kidney, where it modulates drug clearance (15). These results suggest that P-gp determines blood levels of its substrate drugs. Furthermore, P-gp is now considered to be an extremely important factor in the pharmacokinetics of drugs bec...

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Clinical Significance of Multi-Drug Resistance Associated Protein and P-Glycoprotein in Patients with Bladder Cancer

Abstract: Multi-drug resistance associated protein as well as P-glycoprotein mediated multi-drug resistance may be induced after chemotherapy for bladder tumors. However, the presence of P-glycoprotein before chemotherapy does not predict clinical outcome in patients with bladder cancer.

Cited by 60 publications

References 22 publications

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

Establishment and characterization of a bladder cancer cell line with enhanced doxorubicin resistance by mevalonate pathway activation

Mechanisms of P-Glycoprotein Alteration During Anticancer Treatment: Role in the Pharmacokinetic and Pharmacological Effects of Various Substrate Drugs

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