Kuguacin J isolated from Momordica charantia leaves inhibits P-glycoprotein (ABCB1)-mediated multidrug resistance

Multidrug resistance (MDR) is a major factor in the failure of chemotherapy in cancer patients. Resistance to chemotherapy has been correlated to the overexpression of ABC drug transporters including P-glycoprotein (P-gp) that actively efflux chemotherapeutic drugs from cancer cells. Our previous st...

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Main Authors: Pornsiri Pitchakarn, Shinobu Ohnuma, Komsak Pintha, Wilart Pompimon, Suresh V. Ambudkar, Pornngarm Limtrakul
Format: Journal
Published: 2018
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http://cmuir.cmu.ac.th/jspui/handle/6653943832/51431
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spelling th-cmuir.6653943832-514312018-09-04T06:12:58Z Kuguacin J isolated from Momordica charantia leaves inhibits P-glycoprotein (ABCB1)-mediated multidrug resistance Pornsiri Pitchakarn Shinobu Ohnuma Komsak Pintha Wilart Pompimon Suresh V. Ambudkar Pornngarm Limtrakul Biochemistry, Genetics and Molecular Biology Medicine Nursing Multidrug resistance (MDR) is a major factor in the failure of chemotherapy in cancer patients. Resistance to chemotherapy has been correlated to the overexpression of ABC drug transporters including P-glycoprotein (P-gp) that actively efflux chemotherapeutic drugs from cancer cells. Our previous study showed that bitter melon (Momordica charantia) leaf extract (BMLE) was able to reverse the MDR phenotype by increasing the intracellular accumulation of chemotherapeutic drugs. In the present study, bioguided fractionation was used to identify the active component(s) of BMLE that is able to modulate the function of P-gp and the MDR phenotype in a human cervical carcinoma cell line (KB-V1). We found that kuguacin J, one of the active components in BMLE, increased sensitivity to vinblastine and paclitaxel in KB-V1 cells. A flow cytometry assay indicated that kuguacin J inhibits the transport function of P-gp and thereby significantly increases the accumulation of rhodamine 123 and calcein AM in the cells. These results were confirmed by [3H]-vinblastine transport assay. Kuguacin J significantly increases intracellular [3H]-vinblastine accumulation and decreased the [3H]-vinblastine efflux in the cells. Kuguacin J also inhibited the incorporation of [125I]-iodoarylazidoprazosin into P-gp in a concentration-dependent manner, indicating that kuguacin J directly interacts with the drug-substrate-binding site on P-gp. These results indicate that kuguacin J modulates the function of P-gp by directly interacting at the drug-substrate-binding site, and it appears to be an effective inhibitor of P-gp activity in vitro and thus could be developed as an effective chemosensitizer to treat multidrug-resistant cancers. © 2012 Elsevier Inc. 2018-09-04T06:01:48Z 2018-09-04T06:01:48Z 2012-01-01 Journal 18734847 09552863 2-s2.0-83355172162 10.1016/j.jnutbio.2010.11.005 https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=83355172162&origin=inward http://cmuir.cmu.ac.th/jspui/handle/6653943832/51431
institution Chiang Mai University
building Chiang Mai University Library
country Thailand
collection CMU Intellectual Repository
topic Biochemistry, Genetics and Molecular Biology
Medicine
Nursing
spellingShingle Biochemistry, Genetics and Molecular Biology
Medicine
Nursing
Pornsiri Pitchakarn
Shinobu Ohnuma
Komsak Pintha
Wilart Pompimon
Suresh V. Ambudkar
Pornngarm Limtrakul
Kuguacin J isolated from Momordica charantia leaves inhibits P-glycoprotein (ABCB1)-mediated multidrug resistance
description Multidrug resistance (MDR) is a major factor in the failure of chemotherapy in cancer patients. Resistance to chemotherapy has been correlated to the overexpression of ABC drug transporters including P-glycoprotein (P-gp) that actively efflux chemotherapeutic drugs from cancer cells. Our previous study showed that bitter melon (Momordica charantia) leaf extract (BMLE) was able to reverse the MDR phenotype by increasing the intracellular accumulation of chemotherapeutic drugs. In the present study, bioguided fractionation was used to identify the active component(s) of BMLE that is able to modulate the function of P-gp and the MDR phenotype in a human cervical carcinoma cell line (KB-V1). We found that kuguacin J, one of the active components in BMLE, increased sensitivity to vinblastine and paclitaxel in KB-V1 cells. A flow cytometry assay indicated that kuguacin J inhibits the transport function of P-gp and thereby significantly increases the accumulation of rhodamine 123 and calcein AM in the cells. These results were confirmed by [3H]-vinblastine transport assay. Kuguacin J significantly increases intracellular [3H]-vinblastine accumulation and decreased the [3H]-vinblastine efflux in the cells. Kuguacin J also inhibited the incorporation of [125I]-iodoarylazidoprazosin into P-gp in a concentration-dependent manner, indicating that kuguacin J directly interacts with the drug-substrate-binding site on P-gp. These results indicate that kuguacin J modulates the function of P-gp by directly interacting at the drug-substrate-binding site, and it appears to be an effective inhibitor of P-gp activity in vitro and thus could be developed as an effective chemosensitizer to treat multidrug-resistant cancers. © 2012 Elsevier Inc.
format Journal
author Pornsiri Pitchakarn
Shinobu Ohnuma
Komsak Pintha
Wilart Pompimon
Suresh V. Ambudkar
Pornngarm Limtrakul
author_facet Pornsiri Pitchakarn
Shinobu Ohnuma
Komsak Pintha
Wilart Pompimon
Suresh V. Ambudkar
Pornngarm Limtrakul
author_sort Pornsiri Pitchakarn
title Kuguacin J isolated from Momordica charantia leaves inhibits P-glycoprotein (ABCB1)-mediated multidrug resistance
title_short Kuguacin J isolated from Momordica charantia leaves inhibits P-glycoprotein (ABCB1)-mediated multidrug resistance
title_full Kuguacin J isolated from Momordica charantia leaves inhibits P-glycoprotein (ABCB1)-mediated multidrug resistance
title_fullStr Kuguacin J isolated from Momordica charantia leaves inhibits P-glycoprotein (ABCB1)-mediated multidrug resistance
title_full_unstemmed Kuguacin J isolated from Momordica charantia leaves inhibits P-glycoprotein (ABCB1)-mediated multidrug resistance
title_sort kuguacin j isolated from momordica charantia leaves inhibits p-glycoprotein (abcb1)-mediated multidrug resistance
publishDate 2018
url https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=83355172162&origin=inward
http://cmuir.cmu.ac.th/jspui/handle/6653943832/51431
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