This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research
Wenxing Chen
Nanjing University of Chinese Medicine
Corresponding Author
ORCiD: https://orcid.org/0000-0003-4571-7622
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Not only a long-term anti-estrogen therapy, but also estrogen receptor-negative breast cancer are generally prone to induce resistance, causing poor prognosis in clinic. Breast cancer resistance protein (BCRP) plays an important role in multidrug resistance. Here it is to elucidate the mechanism that a natural compound cryptotanshinone inhibits BCRP.
Methods
HPLC was for analyzing the special compound concentration and molecular docking assay for the affinity of compound with protein. Non-reducing gradient gel electrophoresis and fluorescence resonance energy transfer (FRET) microscopy imaging were used to detect polymer and stain the membrane protein. Immunofluorescence staining, plasmids transfection, real-time PCR and western blot were also used.
Results
Cryptotanshinone, an anti-estrogen compound was firstly found to inhibit breast cancer resistance protein (BCRP) membrane dimerization to attenuate its transport function. And this process is dependent on estrogen receptor α (ERα) in breast cancer. Furthermore, the resistant breast cancer cells with high BCRP expression are also sensitive to cryptotanshinone because it can bind to BCRP and significantly inhibit membrane dimer of BCRP although they are ERα-negative, suggesting that BCRP expression is essential to cryptotanshinone reversing the resistance; Meanwhile, the combination of cryptotanshinone and chemotherapy drugs could obviously enhance the chemotherapeutic effect.
Conclusion
Cryptotanshinone is a novel natural BCRP inhibitor via blocking the formation of BCRP membrane dimer by an ERα-dependent and -independent way. Cryptotanshinone reverses resistance dependent on BCRP in breast cancer.
Keywords
Cryptotanshinone, Breast cancer resistance protein, Estrogen Receptor α, Multidrug resistance
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research
Wenxing Chen
Nanjing University of Chinese Medicine
Corresponding Author
ORCiD: https://orcid.org/0000-0003-4571-7622
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 24 Sep, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Clinical Pharmacology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Not only a long-term anti-estrogen therapy, but also estrogen receptor-negative breast cancer are generally prone to induce resistance, causing poor prognosis in clinic. Breast cancer resistance protein (BCRP) plays an important role in multidrug resistance. Here it is to elucidate the mechanism that a natural compound cryptotanshinone inhibits BCRP.
Methods
HPLC was for analyzing the special compound concentration and molecular docking assay for the affinity of compound with protein. Non-reducing gradient gel electrophoresis and fluorescence resonance energy transfer (FRET) microscopy imaging were used to detect polymer and stain the membrane protein. Immunofluorescence staining, plasmids transfection, real-time PCR and western blot were also used.
Results
Cryptotanshinone, an anti-estrogen compound was firstly found to inhibit breast cancer resistance protein (BCRP) membrane dimerization to attenuate its transport function. And this process is dependent on estrogen receptor α (ERα) in breast cancer. Furthermore, the resistant breast cancer cells with high BCRP expression are also sensitive to cryptotanshinone because it can bind to BCRP and significantly inhibit membrane dimer of BCRP although they are ERα-negative, suggesting that BCRP expression is essential to cryptotanshinone reversing the resistance; Meanwhile, the combination of cryptotanshinone and chemotherapy drugs could obviously enhance the chemotherapeutic effect.
Conclusion
Cryptotanshinone is a novel natural BCRP inhibitor via blocking the formation of BCRP membrane dimer by an ERα-dependent and -independent way. Cryptotanshinone reverses resistance dependent on BCRP in breast cancer.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
This is a list of supplementary files associated with this preprint. Click to download.
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