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Regorafenib antagonizes BCRP-mediated multidrug resistance in colon cancer

Overexpression of breast cancer resistance protein (BCRP) has been shown to produce multidrug resistance (MDR) in colon cancer, leading to major obstacles for chemotherapy. In this study, we evaluated the effect of regorafenib, an oral multi-kinase inhibitor, in inhibiting BCRP-mediated MDR in silic... Full description

Journal Title: Cancer letters 2019-02-01, Vol.442, p.104-112
Main Author: Zhang, Yun-Kai
Other Authors: Wang, Yi-Jun , Lei, Zi-Ning , Zhang, Guan-Nan , Zhang, Xiao-Yu , Wang, De-shen , Al-Rihani, Sweilem B , Shukla, Suneet , Ambudkar, Suresh V , Kaddoumi, Amal , Shi, Zhi , Chen, Zhe-Sheng
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: Ireland: Elsevier B.V
ID: ISSN: 0304-3835
Link: https://www.ncbi.nlm.nih.gov/pubmed/30392788
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8148022
title: Regorafenib antagonizes BCRP-mediated multidrug resistance in colon cancer
format: Article
creator:
  • Zhang, Yun-Kai
  • Wang, Yi-Jun
  • Lei, Zi-Ning
  • Zhang, Guan-Nan
  • Zhang, Xiao-Yu
  • Wang, De-shen
  • Al-Rihani, Sweilem B
  • Shukla, Suneet
  • Ambudkar, Suresh V
  • Kaddoumi, Amal
  • Shi, Zhi
  • Chen, Zhe-Sheng
subjects:
  • ABC transporters
  • Adenosine triphosphatase
  • Animals
  • Antineoplastic Agents - chemistry
  • Antineoplastic Agents - pharmacology
  • Antineoplastic Combined Chemotherapy Protocols - pharmacology
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 - agonists
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 - chemistry
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism
  • Binding Sites
  • Brain tumors
  • Breast cancer
  • Cancer
  • Cancer therapies
  • Cell cycle
  • Cell Line, Tumor
  • Chemotherapy
  • Colon
  • Colon cancer
  • Colonic Neoplasms - drug therapy
  • Colonic Neoplasms - genetics
  • Colonic Neoplasms - metabolism
  • Colonic Neoplasms - pathology
  • Colorectal cancer
  • Combination chemotherapy with regorafenib
  • Docking
  • Dose-Response Relationship, Drug
  • Drug Resistance, Multiple - drug effects
  • Drug Resistance, Neoplasm - drug effects
  • Drug Synergism
  • Drugs
  • FDA approval
  • Federal regulation
  • Growth factors
  • Humans
  • Kinases
  • Liver cancer
  • Male
  • Medical research
  • Metastasis
  • Mice, Nude
  • Mitoxantrone
  • Mitoxantrone - pharmacology
  • Molecular docking
  • Molecular Docking Simulation
  • Molecular dynamics
  • Molecular Dynamics Simulation
  • Multidrug resistance
  • Neoplasm Proteins - agonists
  • Neoplasm Proteins - chemistry
  • Neoplasm Proteins - genetics
  • Neoplasm Proteins - metabolism
  • Penicillin
  • Phenylurea Compounds - chemistry
  • Phenylurea Compounds - pharmacology
  • Protein Binding
  • Protein Conformation
  • Pyridines - chemistry
  • Pyridines - pharmacology
  • Reversal of multidrug resistance
  • Substrates
  • Synergistic effect
  • Synergy
  • Topotecan
  • Topotecan - pharmacology
  • Tumor Burden - drug effects
  • Tumors
  • Xenograft Model Antitumor Assays
  • Xenografts
ispartof: Cancer letters, 2019-02-01, Vol.442, p.104-112
description: Overexpression of breast cancer resistance protein (BCRP) has been shown to produce multidrug resistance (MDR) in colon cancer, leading to major obstacles for chemotherapy. In this study, we evaluated the effect of regorafenib, an oral multi-kinase inhibitor, in inhibiting BCRP-mediated MDR in silico, in vitro and in vivo. We found that regorafenib significantly sensitized MDR colon cancer cells to BCRP substrates by increasing their intracellular accumulation. There are no significant changes in the expression level or the subcellular distribution of BCRP in the cells exposed to regorafenib. Investigation of the mechanism revealed that regorafenib stimulated BCRP ATPase activity. Our induced-fit docking and molecular dynamics simulations suggested the existence of a strong and stable interaction between regorafenib and the transmembrane domain of human crystalized BCRP. In vivo tumor xenograft study revealed that the combination of regorafenib and topotecan exhibited synergistic effects on mitoxantrone-resistant S1-M1-80 xenograft tumors. In conclusion, our studies indicate that regorafenib would be beneficial in combating MDR in colon cancer. •Regorafenib reversed BCRP-mediated MDR in colorectal cancer cell lines by increasing intracellular BCRP substrates concentrations.•We found a synergistic effect of regorafenib and BCRP substrate chemotherapy drugs in BCRP-overexpressing xenograft tumors.•The sensitizing effects of regorafenib in MDR colorectal cancers could be beneficial in developing combination chemotherapy for patients.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0304-3835
fulltext: fulltext
issn:
  • 0304-3835
  • 1872-7980
url: Link


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titleRegorafenib antagonizes BCRP-mediated multidrug resistance in colon cancer
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creatorZhang, Yun-Kai ; Wang, Yi-Jun ; Lei, Zi-Ning ; Zhang, Guan-Nan ; Zhang, Xiao-Yu ; Wang, De-shen ; Al-Rihani, Sweilem B ; Shukla, Suneet ; Ambudkar, Suresh V ; Kaddoumi, Amal ; Shi, Zhi ; Chen, Zhe-Sheng
creatorcontribZhang, Yun-Kai ; Wang, Yi-Jun ; Lei, Zi-Ning ; Zhang, Guan-Nan ; Zhang, Xiao-Yu ; Wang, De-shen ; Al-Rihani, Sweilem B ; Shukla, Suneet ; Ambudkar, Suresh V ; Kaddoumi, Amal ; Shi, Zhi ; Chen, Zhe-Sheng
descriptionOverexpression of breast cancer resistance protein (BCRP) has been shown to produce multidrug resistance (MDR) in colon cancer, leading to major obstacles for chemotherapy. In this study, we evaluated the effect of regorafenib, an oral multi-kinase inhibitor, in inhibiting BCRP-mediated MDR in silico, in vitro and in vivo. We found that regorafenib significantly sensitized MDR colon cancer cells to BCRP substrates by increasing their intracellular accumulation. There are no significant changes in the expression level or the subcellular distribution of BCRP in the cells exposed to regorafenib. Investigation of the mechanism revealed that regorafenib stimulated BCRP ATPase activity. Our induced-fit docking and molecular dynamics simulations suggested the existence of a strong and stable interaction between regorafenib and the transmembrane domain of human crystalized BCRP. In vivo tumor xenograft study revealed that the combination of regorafenib and topotecan exhibited synergistic effects on mitoxantrone-resistant S1-M1-80 xenograft tumors. In conclusion, our studies indicate that regorafenib would be beneficial in combating MDR in colon cancer. •Regorafenib reversed BCRP-mediated MDR in colorectal cancer cell lines by increasing intracellular BCRP substrates concentrations.•We found a synergistic effect of regorafenib and BCRP substrate chemotherapy drugs in BCRP-overexpressing xenograft tumors.•The sensitizing effects of regorafenib in MDR colorectal cancers could be beneficial in developing combination chemotherapy for patients.
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languageeng
publisherIreland: Elsevier B.V
subjectABC transporters ; Adenosine triphosphatase ; Animals ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; ATP Binding Cassette Transporter, Subfamily G, Member 2 - agonists ; ATP Binding Cassette Transporter, Subfamily G, Member 2 - chemistry ; ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics ; ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism ; Binding Sites ; Brain tumors ; Breast cancer ; Cancer ; Cancer therapies ; Cell cycle ; Cell Line, Tumor ; Chemotherapy ; Colon ; Colon cancer ; Colonic Neoplasms - drug therapy ; Colonic Neoplasms - genetics ; Colonic Neoplasms - metabolism ; Colonic Neoplasms - pathology ; Colorectal cancer ; Combination chemotherapy with regorafenib ; Docking ; Dose-Response Relationship, Drug ; Drug Resistance, Multiple - drug effects ; Drug Resistance, Neoplasm - drug effects ; Drug Synergism ; Drugs ; FDA approval ; Federal regulation ; Growth factors ; Humans ; Kinases ; Liver cancer ; Male ; Medical research ; Metastasis ; Mice, Nude ; Mitoxantrone ; Mitoxantrone - pharmacology ; Molecular docking ; Molecular Docking Simulation ; Molecular dynamics ; Molecular Dynamics Simulation ; Multidrug resistance ; Neoplasm Proteins - agonists ; Neoplasm Proteins - chemistry ; Neoplasm Proteins - genetics ; Neoplasm Proteins - metabolism ; Penicillin ; Phenylurea Compounds - chemistry ; Phenylurea Compounds - pharmacology ; Protein Binding ; Protein Conformation ; Pyridines - chemistry ; Pyridines - pharmacology ; Reversal of multidrug resistance ; Substrates ; Synergistic effect ; Synergy ; Topotecan ; Topotecan - pharmacology ; Tumor Burden - drug effects ; Tumors ; Xenograft Model Antitumor Assays ; Xenografts
ispartofCancer letters, 2019-02-01, Vol.442, p.104-112
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1Wang, Yi-Jun
2Lei, Zi-Ning
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4Zhang, Xiao-Yu
5Wang, De-shen
6Al-Rihani, Sweilem B
7Shukla, Suneet
8Ambudkar, Suresh V
9Kaddoumi, Amal
10Shi, Zhi
11Chen, Zhe-Sheng
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0Regorafenib antagonizes BCRP-mediated multidrug resistance in colon cancer
1Cancer letters
addtitleCancer Lett
descriptionOverexpression of breast cancer resistance protein (BCRP) has been shown to produce multidrug resistance (MDR) in colon cancer, leading to major obstacles for chemotherapy. In this study, we evaluated the effect of regorafenib, an oral multi-kinase inhibitor, in inhibiting BCRP-mediated MDR in silico, in vitro and in vivo. We found that regorafenib significantly sensitized MDR colon cancer cells to BCRP substrates by increasing their intracellular accumulation. There are no significant changes in the expression level or the subcellular distribution of BCRP in the cells exposed to regorafenib. Investigation of the mechanism revealed that regorafenib stimulated BCRP ATPase activity. Our induced-fit docking and molecular dynamics simulations suggested the existence of a strong and stable interaction between regorafenib and the transmembrane domain of human crystalized BCRP. In vivo tumor xenograft study revealed that the combination of regorafenib and topotecan exhibited synergistic effects on mitoxantrone-resistant S1-M1-80 xenograft tumors. In conclusion, our studies indicate that regorafenib would be beneficial in combating MDR in colon cancer. •Regorafenib reversed BCRP-mediated MDR in colorectal cancer cell lines by increasing intracellular BCRP substrates concentrations.•We found a synergistic effect of regorafenib and BCRP substrate chemotherapy drugs in BCRP-overexpressing xenograft tumors.•The sensitizing effects of regorafenib in MDR colorectal cancers could be beneficial in developing combination chemotherapy for patients.
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0ABC transporters
1Adenosine triphosphatase
2Animals
3Antineoplastic Agents - chemistry
4Antineoplastic Agents - pharmacology
5Antineoplastic Combined Chemotherapy Protocols - pharmacology
6ATP Binding Cassette Transporter, Subfamily G, Member 2 - agonists
7ATP Binding Cassette Transporter, Subfamily G, Member 2 - chemistry
8ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics
9ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism
10Binding Sites
11Brain tumors
12Breast cancer
13Cancer
14Cancer therapies
15Cell cycle
16Cell Line, Tumor
17Chemotherapy
18Colon
19Colon cancer
20Colonic Neoplasms - drug therapy
21Colonic Neoplasms - genetics
22Colonic Neoplasms - metabolism
23Colonic Neoplasms - pathology
24Colorectal cancer
25Combination chemotherapy with regorafenib
26Docking
27Dose-Response Relationship, Drug
28Drug Resistance, Multiple - drug effects
29Drug Resistance, Neoplasm - drug effects
30Drug Synergism
31Drugs
32FDA approval
33Federal regulation
34Growth factors
35Humans
36Kinases
37Liver cancer
38Male
39Medical research
40Metastasis
41Mice, Nude
42Mitoxantrone
43Mitoxantrone - pharmacology
44Molecular docking
45Molecular Docking Simulation
46Molecular dynamics
47Molecular Dynamics Simulation
48Multidrug resistance
49Neoplasm Proteins - agonists
50Neoplasm Proteins - chemistry
51Neoplasm Proteins - genetics
52Neoplasm Proteins - metabolism
53Penicillin
54Phenylurea Compounds - chemistry
55Phenylurea Compounds - pharmacology
56Protein Binding
57Protein Conformation
58Pyridines - chemistry
59Pyridines - pharmacology
60Reversal of multidrug resistance
61Substrates
62Synergistic effect
63Synergy
64Topotecan
65Topotecan - pharmacology
66Tumor Burden - drug effects
67Tumors
68Xenograft Model Antitumor Assays
69Xenografts
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titleRegorafenib antagonizes BCRP-mediated multidrug resistance in colon cancer
authorZhang, Yun-Kai ; Wang, Yi-Jun ; Lei, Zi-Ning ; Zhang, Guan-Nan ; Zhang, Xiao-Yu ; Wang, De-shen ; Al-Rihani, Sweilem B ; Shukla, Suneet ; Ambudkar, Suresh V ; Kaddoumi, Amal ; Shi, Zhi ; Chen, Zhe-Sheng
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0ABC transporters
1Adenosine triphosphatase
2Animals
3Antineoplastic Agents - chemistry
4Antineoplastic Agents - pharmacology
5Antineoplastic Combined Chemotherapy Protocols - pharmacology
6ATP Binding Cassette Transporter, Subfamily G, Member 2 - agonists
7ATP Binding Cassette Transporter, Subfamily G, Member 2 - chemistry
8ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics
9ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism
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14Cancer therapies
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21Colonic Neoplasms - genetics
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25Combination chemotherapy with regorafenib
26Docking
27Dose-Response Relationship, Drug
28Drug Resistance, Multiple - drug effects
29Drug Resistance, Neoplasm - drug effects
30Drug Synergism
31Drugs
32FDA approval
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34Growth factors
35Humans
36Kinases
37Liver cancer
38Male
39Medical research
40Metastasis
41Mice, Nude
42Mitoxantrone
43Mitoxantrone - pharmacology
44Molecular docking
45Molecular Docking Simulation
46Molecular dynamics
47Molecular Dynamics Simulation
48Multidrug resistance
49Neoplasm Proteins - agonists
50Neoplasm Proteins - chemistry
51Neoplasm Proteins - genetics
52Neoplasm Proteins - metabolism
53Penicillin
54Phenylurea Compounds - chemistry
55Phenylurea Compounds - pharmacology
56Protein Binding
57Protein Conformation
58Pyridines - chemistry
59Pyridines - pharmacology
60Reversal of multidrug resistance
61Substrates
62Synergistic effect
63Synergy
64Topotecan
65Topotecan - pharmacology
66Tumor Burden - drug effects
67Tumors
68Xenograft Model Antitumor Assays
69Xenografts
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abstractOverexpression of breast cancer resistance protein (BCRP) has been shown to produce multidrug resistance (MDR) in colon cancer, leading to major obstacles for chemotherapy. In this study, we evaluated the effect of regorafenib, an oral multi-kinase inhibitor, in inhibiting BCRP-mediated MDR in silico, in vitro and in vivo. We found that regorafenib significantly sensitized MDR colon cancer cells to BCRP substrates by increasing their intracellular accumulation. There are no significant changes in the expression level or the subcellular distribution of BCRP in the cells exposed to regorafenib. Investigation of the mechanism revealed that regorafenib stimulated BCRP ATPase activity. Our induced-fit docking and molecular dynamics simulations suggested the existence of a strong and stable interaction between regorafenib and the transmembrane domain of human crystalized BCRP. In vivo tumor xenograft study revealed that the combination of regorafenib and topotecan exhibited synergistic effects on mitoxantrone-resistant S1-M1-80 xenograft tumors. In conclusion, our studies indicate that regorafenib would be beneficial in combating MDR in colon cancer. •Regorafenib reversed BCRP-mediated MDR in colorectal cancer cell lines by increasing intracellular BCRP substrates concentrations.•We found a synergistic effect of regorafenib and BCRP substrate chemotherapy drugs in BCRP-overexpressing xenograft tumors.•The sensitizing effects of regorafenib in MDR colorectal cancers could be beneficial in developing combination chemotherapy for patients.
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