Backstabbing P-gp: Side-Chain Cleaved Ecdysteroid 2,3-Dioxolanes Hyper-Sensitize MDR Cancer Cells to Doxorubicin without Efflux Inhibition
P-glycoprotein (P-gp, ABCB1) over-expression, causing a multi-drug resistant (MDR) phenotype, is a major problem in cancer chemotherapy that urgently requires novel approaches. Our previous studies showed certain ecdysteroid derivatives as promising chemo-sensitizers against MDR and non-MDR cancer c...
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| Format: | Article |
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MDPI AG
2017-01-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/22/2/199 |
| _version_ | 1818893626679230464 |
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| author | Attila Hunyadi József Csábi Ana Martins Joseph Molnár Attila Balázs Gábor Tóth |
| author_facet | Attila Hunyadi József Csábi Ana Martins Joseph Molnár Attila Balázs Gábor Tóth |
| author_sort | Attila Hunyadi |
| collection | DOAJ |
| description | P-glycoprotein (P-gp, ABCB1) over-expression, causing a multi-drug resistant (MDR) phenotype, is a major problem in cancer chemotherapy that urgently requires novel approaches. Our previous studies showed certain ecdysteroid derivatives as promising chemo-sensitizers against MDR and non-MDR cancer cell lines while also exerting mild to moderate inhibition of P-gp function. Here we report the preparation of a set of substituted 2,3-dioxolane derivatives of poststerone, a known in vivo metabolite of 20-hydroxyecdysone (20E). In contrast with previously studied ecdysteroid dioxolanes, the majority of the new compounds did not inhibit the efflux function of P-gp. Nevertheless, a strong, dose dependent sensitization to doxorubicin was observed on a P-gp transfected cancer cell line and on its susceptible counterpart. We also observed that the MDR cell line was more sensitive to the compounds’ effect than the non-MDR. Our results showed for the first time that the chemo-sensitizing activity of ecdysteroids can be fully independent of functional efflux pump inhibition, and suggest these compounds as favorable leads against MDR cancer. |
| first_indexed | 2024-12-19T18:15:36Z |
| format | Article |
| id | doaj.art-934ac7a80b634a07bcbbf590f41f9896 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-19T18:15:36Z |
| publishDate | 2017-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-934ac7a80b634a07bcbbf590f41f98962022-12-21T20:11:07ZengMDPI AGMolecules1420-30492017-01-0122219910.3390/molecules22020199molecules22020199Backstabbing P-gp: Side-Chain Cleaved Ecdysteroid 2,3-Dioxolanes Hyper-Sensitize MDR Cancer Cells to Doxorubicin without Efflux InhibitionAttila Hunyadi0József Csábi1Ana Martins2Joseph Molnár3Attila Balázs4Gábor Tóth5Institute of Pharmacognosy, University of Szeged, 6720 Szeged, HungaryInstitute of Pharmacognosy, University of Szeged, 6720 Szeged, HungaryDepartment of Medical Microbiology and Immunobiology, University of Szeged, Dóm sq. 9, 6720 Szeged, HungaryDepartment of Medical Microbiology and Immunobiology, University of Szeged, Dóm sq. 9, 6720 Szeged, HungaryNMR Group, Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Szt. Gellért Sq. 4, H-1111 Budapest, HungaryNMR Group, Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Szt. Gellért Sq. 4, H-1111 Budapest, HungaryP-glycoprotein (P-gp, ABCB1) over-expression, causing a multi-drug resistant (MDR) phenotype, is a major problem in cancer chemotherapy that urgently requires novel approaches. Our previous studies showed certain ecdysteroid derivatives as promising chemo-sensitizers against MDR and non-MDR cancer cell lines while also exerting mild to moderate inhibition of P-gp function. Here we report the preparation of a set of substituted 2,3-dioxolane derivatives of poststerone, a known in vivo metabolite of 20-hydroxyecdysone (20E). In contrast with previously studied ecdysteroid dioxolanes, the majority of the new compounds did not inhibit the efflux function of P-gp. Nevertheless, a strong, dose dependent sensitization to doxorubicin was observed on a P-gp transfected cancer cell line and on its susceptible counterpart. We also observed that the MDR cell line was more sensitive to the compounds’ effect than the non-MDR. Our results showed for the first time that the chemo-sensitizing activity of ecdysteroids can be fully independent of functional efflux pump inhibition, and suggest these compounds as favorable leads against MDR cancer.http://www.mdpi.com/1420-3049/22/2/199ecdysteroid metabolitepoststerone acetonideABCB1 efflux transportercancermulti-drug resistancechemo-sensitizationcombination therapy |
| spellingShingle | Attila Hunyadi József Csábi Ana Martins Joseph Molnár Attila Balázs Gábor Tóth Backstabbing P-gp: Side-Chain Cleaved Ecdysteroid 2,3-Dioxolanes Hyper-Sensitize MDR Cancer Cells to Doxorubicin without Efflux Inhibition Molecules ecdysteroid metabolite poststerone acetonide ABCB1 efflux transporter cancer multi-drug resistance chemo-sensitization combination therapy |
| title | Backstabbing P-gp: Side-Chain Cleaved Ecdysteroid 2,3-Dioxolanes Hyper-Sensitize MDR Cancer Cells to Doxorubicin without Efflux Inhibition |
| title_full | Backstabbing P-gp: Side-Chain Cleaved Ecdysteroid 2,3-Dioxolanes Hyper-Sensitize MDR Cancer Cells to Doxorubicin without Efflux Inhibition |
| title_fullStr | Backstabbing P-gp: Side-Chain Cleaved Ecdysteroid 2,3-Dioxolanes Hyper-Sensitize MDR Cancer Cells to Doxorubicin without Efflux Inhibition |
| title_full_unstemmed | Backstabbing P-gp: Side-Chain Cleaved Ecdysteroid 2,3-Dioxolanes Hyper-Sensitize MDR Cancer Cells to Doxorubicin without Efflux Inhibition |
| title_short | Backstabbing P-gp: Side-Chain Cleaved Ecdysteroid 2,3-Dioxolanes Hyper-Sensitize MDR Cancer Cells to Doxorubicin without Efflux Inhibition |
| title_sort | backstabbing p gp side chain cleaved ecdysteroid 2 3 dioxolanes hyper sensitize mdr cancer cells to doxorubicin without efflux inhibition |
| topic | ecdysteroid metabolite poststerone acetonide ABCB1 efflux transporter cancer multi-drug resistance chemo-sensitization combination therapy |
| url | http://www.mdpi.com/1420-3049/22/2/199 |
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